Clinical trial NCT03783442
Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
Sponsor: BeiGene
Start date: 2018-12-11; Completion date: 2024-08-22
Enrollment: 649 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of tislelizumab as first line treatment in combination with chemotherapy in participants with advanced unresectable/metastatic esophageal squamous cell carcinoma (ESCC).

Detailed description:

Arms: arm 1: Participants received tislelizumab 200 milligrams (mg) administered intravenously (IV) on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

Chemotherapy options were a platinum agent (cisplatin 60-80 mg/m² intravenously on Day 1 or oxaliplatin 130 mg/m² intravenously on Day 1) combined with a fluoropyrimidine (fluorouracil \[750-800 mg/m² intravenously on Days 1-5\] or capecitabine \[1000 mg/m² orally twice daily on Days 1-14\]) or paclitaxel (175 mg/m² intravenously on Day 1). arm 2: Participants received placebo administered IV on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

Chemotherapy options were a platinum agent (cisplatin 60-80 mg/m² intravenously on Day 1 or oxaliplatin 130 mg/m² intravenously on Day 1) combined with a fluoropyrimidine (fluorouracil \[750-800 mg/m² intravenously on Days 1-5\] or capecitabine \[1000 mg/m² orally twice daily on Days 1-14\]) or paclitaxel (175 mg/m² intravenously on Day 1).
Interventions: intervention 1: Cisplatin intervention 2: Oxaliplatin intervention 3: Fluorouracil (5-FU) intervention 4: Capecitabine intervention 5: Paclitaxel intervention 6: Tislelizumab intervention 7: Placebo
Intervention descriptions: intervention 1: Cisplatin 60-80 mg/m² administered by intravenous infusion every 3 weeks. Cisplatin was used as the platinum agent in China, Taiwan, and Japan. intervention 2: Oxaliplatin 130 mg/m² administered by intravenous infusion every 3 weeks. intervention 3: Fluorouracil 750-800 mg/m² administered by intravenous infusion on Days 1-5 of each treatment cycle. intervention 4: Capecitabine 1000 mg/m² administered orally twice daily on Days 1-14 of each treatment cycle intervention 5: Paclitaxel 175 mg/m² administered by intravenous infusion every 3 weeks. intervention 6: Tislelizumab 200 mg administered by intravenous infusion every 3 weeks. intervention 7: Placebo to match tislelizumab administered by intravenous infusion every 3 weeks.

Protocol documents:
Prot_002.pdf: 
BGB-A317-306 
BeiGene 
Protocol Amendment 5.0 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL TITLE PAGE 
A Randomized, Placebo-Controlled, Double-Blind Phase 3 Study to Evaluate 
the Efficacy and Safety of Tislelizumab (BGB-A317) in Combination With 
Chemotherapy as First-Line Treatment in Patients with Unresectable, Locally 
Advanced Recurrent or Metastatic Esophageal Squamous Cell Carcinoma 
Brief Title: 
A study of tislelizumab (BGB-A317) in combination with chemotherapy as first-line treatment in 
participants with advanced esophageal squamous cell carcinoma  
Protocol Number: 
BGB-A317-306 
Amendment Number: 
5.0 
Investigational Medicinal 
Product: 
Tislelizumab (BGB-A317) 
Regulatory Agency 
Identification Number(s): 
EudraCT Number 2018-000587-28 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive, 3rd Floor 
San Mateo, California 94404 
USA 
Approval Date: 
See electronic signature 
Contact Information: 
BeiGene Medical Officer 
Phone: 1.877.828.5568 
Email: clinicaltrials@beigene.com 
Approved Date
3/13/2024
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of BeiGene, Ltd., and its 
affiliates. Any unauthorized use or disclosure of such information without the prior written 
authorization of BeiGene, Ltd. or any of its affiliates, or outside the cases and forms provided for by 
applicable legal provisions, is expressly prohibited. 
NCT Number
NCT03783442


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INVESTIGATOR SIGNATURE PAGE  
I have read the protocol, appendices, and accessory materials related to study BGB-A317-306 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials. 
• To protect the rights, safety, and welfare of the patients under my care. 
• To provide oversight to all personnel to whom study activities have been delegated.  
This includes personnel at my site as well as personnel working in any facility where 
study activities are my responsibility. 
• To control all investigational products provided by the sponsor and maintain records 
of the disposition of those products. 
• To conduct the study in accordance with all applicable laws and regulations, the 
requirements of the ethics committee of record for my clinical site, and current GCP 
as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to patients 
before initiating the study at my site. 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all patients enrolled at my study site before initiating any 
study-specific procedures or administering investigational products to those patients. 
• To maintain records of each patient’s participation and all data required by the 
protocol in an accurate and timely manner. 
Acceptance of this protocol constitutes my agreement that no confidential information contained 
herein will be published or disclosed without prior written approval from BeiGene, Ltd. or one of 
its affiliates, unless and only to the extent required by applicable laws and regulations. 
Name:   
Title:   
Institution:   
  
  
  
Signature:   
Date:   
  
  
Approved Date
3/13/2024


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DOCUMENT HISTORY  
Amendment Version Number 
Approval Date 
Type of Protocol Amendment  
BGB-A317-306 Amendment 4.0 
30 April 2021 
Substantial 
BGB-A317-306 Amendment 3.0 
25 May 2020 
Substantial 
BGB-A317-306 Amendment 2.0 
15 August 2019 
Substantial 
BGB-A317-306 Amendment 1.0 
19 September 2018 
Substantial 
Original protocol 
13 February 2018 
Not applicable 
Approved Date
3/13/2024


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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
This Protocol Amendment 5.0 replaces the previous Protocol Amendment 4.0. The amendment 
is considered substantial based on the criteria set forth in Regulation (EU) No 536/2014 of the 
European Parliament and the Council of the EU. The primary purpose of this amendment is to: 
• Add description of unblinding and placebo discontinuation of the study after its interim 
analysis. 
A few clarifications or non-substantial updates have also been made and summarized in this 
summary.  
Additionally, some editorial and formatting changes or corrections have also been made but are 
not included in this summary.  
Approved Date
3/13/2024


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Protocol Amendment Summary of Changes Table 
Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 3.1 Summary of Study Design, 
Section 5.5.3 Blinding 
 
Added IDMC recommendation of unblinding based on 
interim analysis results. Added the conduct of official 
unblinding on 20 April 2022 and subsequent activities. 
Added description of unblinding after analysis. 
The study was unblinded according to 
IDMC recommendation after interim 
analysis in 2022, and placebo was 
discontinued after the unblinding. 
Amendment here is intended to reflect 
those changes at that time.  
Section 3.7 End of Study 
Added description of a rollover study. Updated the 
language regarding patients who may benefit from 
tislelizumab could be offered the option to continue 
treatment after study closeout. 
Clarify there would be options for 
patients to continue treatment after 
study closeout.  
Section 1.4.2 Toxicology 
Updated the language to comply with GLP. 
Text was revised for consistency with 
sponsor’s protocol template. 
Section 3.4 End of Treatment/Safety 
Follow-up, 
Appendix 1 Schedule of Assessments 
Added the requirement of patients completing an 
End-of-Treatment/Safety Follow-up Visit before 
continuing in a long-term extension/posttrial supply 
study. 
Clarify the request for the 
End-of-Treatment/Safety Follow-up 
Visit 
Section 9.2.2 Secondary Efficacy Analysis 
Updated the patient-reported outcome endpoint 
language 
Text was revised for consistency with 
sponsor’s protocol template. 
Appendix 1 Schedule of Assessments 
Added language that allows for PK and ADA sample 
collection and patient-reported outcome collection to 
stop after patients finish the 3-year follow up.  
Remove unnecessary examinations 
after the 3-year follow-up 
Throughout document 
Changed “immune-related adverse events” to 
“immune-mediated adverse events.” 
Text was revised for consistency with 
sponsor’s protocol template. 
Section 5.1.3 Cisplatin, 
Section 5.1.4 Oxaliplatin, 
Section 5.1.5 5-Fluorouracil, 
Section 5.1.6 Capecitabine, 
Section 5.1.7 Paclitaxel 
Added that the labels described are for drugs supplied 
by the sponsor or its designee. 
Clarified the labels are for drugs 
supplied by the sponsor or the 
designee. 
Approved Date
3/13/2024


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Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 5.1.7 Paclitaxel 
 
Added that the appearance and composition of the 
product may depend on the respective marketed 
product sourced for the participating country. 
Updated the text for clarity. 
Section 5.2 Dosage, Administration, and 
Compliance 
Added language that the sponsor or designee will 
either supply or reimburse sites where the sponsor is 
required to provide chemotherapy doublet products.   
Updated the text for clarity. 
Section 13 Ethics/Protection of Human 
Patients 
Updated language to comply with ICH GCP and local 
regulations. 
Text was revised for consistency with 
the protocol template. 
Clinical Study Title Page, Investigator 
Signature Page, Protocol Synopsis  
Updated the current study information per the current 
regulations and guidance. 
To update for administrative purposes 
Document History 
Added Document History page 
Text was revised for consistency with 
the protocol template. 
.
Approved Date
3/13/2024


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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE ......................................................................................2 
DOCUMENT HISTORY ..............................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
SYNOPSIS ....................................................................................................................................14 
LIST OF ABBREVIATIONS AND TERMS ................................................................................25 
1. 
INTRODUCTION ......................................................................................................28 
1.1. 
Background Information on Esophageal Carcinoma ..................................................28 
1.2. 
Current Treatment of Esophageal Carcinoma and Unmet Clinical Needs .................28 
1.3. 
Anti-PD-1 Therapy for Esophageal Squamous Cell Carcinoma ................................30 
1.4. 
Background Information on Tislelizumab ..................................................................33 
1.4.1. 
Pharmacology .............................................................................................................33 
1.4.2. 
Toxicology ..................................................................................................................33 
1.4.3. 
Clinical Pharmacology ................................................................................................34 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................34 
1.5. 
Study Rationales .........................................................................................................38 
1.5.1. 
Rationale for Tislelizumab in the Treatment of Esophageal Carcinoma ....................38 
1.5.2. 
Rationale for Selection of Tislelizumab Dose ............................................................38 
1.5.3. 
Rationale for Matched Placebo in Combination with Chemotherapy as the 
Comparator .................................................................................................................39 
1.6. 
Benefit-Risk Assessment ............................................................................................39 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Study Objectives .........................................................................................................40 
2.1.1. 
Primary Objective .......................................................................................................40 
2.1.2. 
Secondary Objectives .................................................................................................40 
2.1.3. 
Exploratory Objectives ...............................................................................................40 
2.2. 
Study Endpoints ..........................................................................................................41 
2.2.1. 
Primary Endpoint ........................................................................................................41 
2.2.2. 
Secondary Endpoints ..................................................................................................41 
2.2.3. 
Exploratory Endpoints ................................................................................................41 
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3. 
STUDY DESIGN .......................................................................................................42 
3.1. 
Summary of Study Design ..........................................................................................42 
3.2. 
Screening Period .........................................................................................................43 
3.3. 
Treatment Period ........................................................................................................43 
3.4. 
End of Treatment/Safety Follow-up ...........................................................................44 
3.5. 
Survival Follow-up .....................................................................................................45 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................45 
3.6.1. 
Patient Discontinuation from Study Treatment ..........................................................45 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........46 
3.7. 
End of Study ...............................................................................................................46 
3.8. 
Enrollment of Japanese Patients .................................................................................47 
4. 
STUDY POPULATION .............................................................................................48 
4.1. 
Inclusion Criteria ........................................................................................................48 
4.2. 
Exclusion Criteria .......................................................................................................49 
5. 
STUDY TREATMENT ..............................................................................................52 
5.1. 
Formulation, Packaging, and Handling ......................................................................52 
5.1.1. 
Tislelizumab ...............................................................................................................52 
5.1.2. 
Matched Placebo .........................................................................................................52 
5.1.3. 
Cisplatin ......................................................................................................................52 
5.1.4. 
Oxaliplatin ..................................................................................................................53 
5.1.5. 
5-Fluorouracil .............................................................................................................53 
5.1.6. 
Capecitabine ...............................................................................................................53 
5.1.7. 
Paclitaxel .....................................................................................................................54 
5.2. 
Dosage, Administration, and Compliance ..................................................................54 
5.2.1. 
Tislelizumab ...............................................................................................................55 
5.2.2. 
Matched Placebo .........................................................................................................55 
5.2.3. 
Chemotherapy Doublet A: Platinum (Cisplatin or Oxaliplatin) in Combination 
with 5-Fluorouracil .....................................................................................................56 
5.2.4. 
Chemotherapy Doublet B: Platinum (Cisplatin or Oxaliplatin) in Combination 
with Capecitabine .......................................................................................................56 
5.2.5. 
Chemotherapy Doublet C: Platinum (Cisplatin or Oxaliplatin) in Combination 
with Paclitaxel ............................................................................................................57 
5.3. 
Overdose .....................................................................................................................58 
Approved Date
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5.4. 
Investigational Medicinal Product Accountability .....................................................59 
5.5. 
Dose Delay or Modification .......................................................................................59 
5.5.1. 
Dose Delay or Modification for Tislelizumab/Placebo ..............................................60 
5.5.2. 
Dose Delay, Interruption, or Modifications for Chemotherapy .................................60 
5.5.3. 
Blinding ......................................................................................................................65 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................67 
6.1. 
Concomitant Therapy .................................................................................................67 
6.1.1. 
Permitted Concomitant Medications ..........................................................................67 
6.1.2. 
Prohibited Concomitant Medications/Procedures ......................................................68 
6.1.3. 
Restricted Concomitant Medications/Procedures .......................................................68 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant Medications .......68 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................71 
7.1. 
Screening ....................................................................................................................71 
7.1.1. 
Demographic Data and Medical History ....................................................................71 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................72 
7.1.3. 
Informed Consent and Screening Log ........................................................................72 
7.1.4. 
Pulmonary Function Tests ..........................................................................................72 
7.2. 
Enrollment ..................................................................................................................72 
7.2.1. 
Confirmation of Eligibility .........................................................................................72 
7.2.2. 
Patient Numbering ......................................................................................................72 
7.2.3. 
Enrollment/Randomization .........................................................................................72 
7.3. 
Tislelizumab and Comparator Drug Dispensation .....................................................73 
7.4. 
Safety Assessments .....................................................................................................73 
7.4.1. 
Vital Signs ..................................................................................................................73 
7.4.2. 
Physical Examinations ................................................................................................73 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................73 
7.4.4. 
Laboratory Safety Tests ..............................................................................................74 
7.4.5. 
Cardiac Enzyme Monitoring .......................................................................................74 
7.4.6. 
Electrocardiograms .....................................................................................................74 
7.4.7. 
Adverse Events ...........................................................................................................74 
7.4.8. 
Hepatitis B and C Testing ...........................................................................................74 
7.5. 
Tumor and Response Evaluations ..............................................................................75 
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7.6. 
Pharmacokinetic and Anti-Drug Antibody Testing ....................................................76 
7.7. 
On-Study Biopsies ......................................................................................................77 
7.8. 
Biomarkers ..................................................................................................................77 
7.9. 
Patient-Reported Outcomes ........................................................................................78 
7.10. 
Visit Windows ............................................................................................................78 
7.11. 
Unscheduled Visits .....................................................................................................78 
8. 
SAFETY MONITORING AND REPORTING .........................................................79 
8.1. 
Risks Associated with Study Drugs ............................................................................79 
8.1.1. 
Risks Associated with Tislelizumab ...........................................................................79 
8.1.2. 
Risks Associated with Comparator Drugs ..................................................................79 
8.2. 
General Plan to Manage Safety Concerns ..................................................................83 
8.2.1. 
Eligibility Criteria .......................................................................................................83 
8.2.2. 
Safety Monitoring Plan ...............................................................................................84 
8.3. 
Adverse Events ...........................................................................................................85 
8.3.1. 
Definitions and Reporting ...........................................................................................85 
8.3.2. 
Assessment of Severity ...............................................................................................85 
8.3.3. 
Assessment of Causality .............................................................................................86 
8.3.4. 
Following Adverse Events ..........................................................................................86 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................87 
8.4. 
Definition of a Serious Adverse Event .......................................................................87 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................88 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................88 
8.6.1. 
Adverse Event Reporting Period ................................................................................88 
8.6.2. 
Reporting Serious Adverse Events .............................................................................89 
8.6.3. 
Eliciting Adverse Events ............................................................................................90 
8.6.4. 
Disease Progression ....................................................................................................90 
8.6.5. 
Deaths .........................................................................................................................91 
8.6.6. 
Pregnancies .................................................................................................................91 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees .............................................................91 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................91 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................92 
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8.7. 
Management of AE of Special Interest .......................................................................92 
8.7.1. 
Managing Infusion-Related Reactions .......................................................................92 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................94 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................94 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................96 
9.1. 
Statistical Analysis ......................................................................................................96 
9.1.1. 
Randomization Methods .............................................................................................96 
9.1.2. 
Analysis Sets ...............................................................................................................96 
9.1.3. 
Patient Disposition ......................................................................................................96 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................96 
9.1.5. 
Prior and Concomitant Medications ...........................................................................97 
9.2. 
Efficacy Analyses .......................................................................................................97 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................97 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................98 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................99 
9.3. 
Safety Analyses ........................................................................................................100 
9.3.1. 
Extent of Exposure ...................................................................................................100 
9.3.2. 
Adverse Events .........................................................................................................100 
9.3.3. 
Laboratory Analyses .................................................................................................101 
9.3.4. 
Vital Signs ................................................................................................................101 
9.3.5. 
Ophthalmologic Examination ...................................................................................101 
9.4. 
Pharmacokinetic Analysis ........................................................................................101 
9.5. 
Immunogenicity Analyses ........................................................................................101 
9.6. 
Sample Size Consideration .......................................................................................101 
9.7. 
Interim Analyses .......................................................................................................102 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................103 
10.1. 
Blinded Independent Review Committee .................................................................103 
10.2. 
Independent Data Monitoring Committee ................................................................103 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................104 
11.1. 
Access to Information for Monitoring ......................................................................104 
11.2. 
Access to Information for Auditing or Inspections ..................................................104 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................105 
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12.1. 
Regulatory Authority Approval ................................................................................105 
12.2. 
Quality Assurance .....................................................................................................105 
12.3. 
Study Site Inspections...............................................................................................105 
12.4. 
Drug Accountability .................................................................................................105 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................107 
13.1. 
Ethical Standard ........................................................................................................107 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................107 
13.2.1. 
Protocol Amendments ..............................................................................................107 
13.3. 
Informed Consent .....................................................................................................107 
13.4. 
Patient and Data Confidentiality ...............................................................................108 
13.5. 
Financial Disclosure .................................................................................................109 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................110 
14.1. 
Data Collection and Management Responsibilities ..................................................110 
14.1.1. 
Data Collection .........................................................................................................110 
14.1.2. 
Data Management/Coding ........................................................................................110 
14.2. 
Data Integrity and In-House Blinding ......................................................................110 
14.3. 
Study Records Retention ..........................................................................................111 
14.4. 
Protocol Deviations ..................................................................................................112 
14.5. 
Publication and Data Sharing Policy ........................................................................112 
14.6. 
Study and Study Center Closure ...............................................................................112 
14.7. 
Information Disclosure and Inventions ....................................................................113 
15. 
REFERENCES .........................................................................................................115 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................118 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................123 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................124 
APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................125 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................134 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................135 
APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................136 
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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................147 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................148 
APPENDIX 10. EORTC-QLQ-C30 QUESTIONNAIRE ........................................................150 
APPENDIX 11. EORTC QLQ-OES18 QUESTIONNAIRE ....................................................152 
APPENDIX 12. EQ-5D-5L QUESTIONNAIRE......................................................................153 
APPENDIX 13. FLOW CHART ..............................................................................................155 
APPENDIX 14. AMERICAN JOINT COMMITTEE ON CANCER TNM 
CLASSIFICATION OF CARCINOMA OF THE ESOPHAGUS AND 
ESOPAGOGASTRIC JUNCTION (7TH ED, 2010) .................................................156 
APPENDIX 15. NUTRITIONAL RISK INDEX .....................................................................158 
 
LIST OF TABLES  
Table 1.  First-Line Treatment and Outcomes for Esophageal Squamous Cell Carcinoma ..........30 
Table 2.  Selection and Timing of Dose for Each Patient ..............................................................54 
Table 3: 
BGB-A317-306 Dose Reduction Level of Chemotherapy .........................................61 
Table 4: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Treatment Arms .................................................................................................89 
Table 5.  Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee .........................................................................................89 
Table 6.  Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................93 
Table 7.  Immune-Mediated Adverse Events ................................................................................95 
Table 8.  Stopping Boundaries (in p-Value and Z Score) of Primary Analysis of Overall 
Survival .......................................................................................................................98 
 
LIST OF FIGURES  
Figure 1.  Study Schema ................................................................................................................42 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Medicinal Product: Tislelizumab (BGB-A317) 
Title of Study: A randomized, placebo-controlled, double-blind Phase 3 study to evaluate the efficacy 
and safety of tislelizumab (BGB-A317) in combination with chemotherapy as first-line treatment in 
patients with unresectable, locally advanced, recurrent or metastatic esophageal squamous cell 
carcinoma 
Protocol Identifier: BGB-A317-306 
Amendment Version: 5.0 
Regulatory Agency Identifier Number(s): EudraCT Number 2018-000587-28  
Number of Patients: Approximately 622 
Study Centers: At least 120 centers internationally 
Study Objectives: 
Primary: 
• 
To evaluate and compare the overall survival (OS) following treatment with tislelizumab in 
combination with chemotherapy compared to placebo in combination with chemotherapy when 
given as first-line treatment in patients with unresectable, locally advanced recurrent or 
metastatic ESCC 
Secondary: 
• 
To evaluate and compare the efficacy of tislelizumab in combination with chemotherapy 
compared to placebo in combination with chemotherapy as a first-line treatment in 
unresectable, locally advanced recurrent or metastatic ESCC as measured by progression-free 
survival (PFS), objective response rate (ORR), and duration of response (DOR) assessed by the 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 
• 
To evaluate and compare the efficacy of tislelizumab in combination with chemotherapy with 
the efficacy of placebo in combination with chemotherapy as a first-line treatment in 
unresectable, locally advanced recurrent or metastatic ESCC as measured by OS in the 
programmed cell death protein ligand-1 (PD-L1) visually estimated combined positive score 
(vCPS) ≥ 10% subgroup 
• 
To evaluate and compare health-related quality of life (HRQoL) based on patient-reported 
outcomes (PROs) between tislelizumab in combination with chemotherapy and placebo in 
combination with chemotherapy  
• 
To compare the safety between tislelizumab in combination with chemotherapy and placebo in 
combination with chemotherapy  
Exploratory: 
• 
To characterize the disease control rate (DCR) with tislelizumab in combination with 
chemotherapy assessed by the investigator per RECIST v1.1 
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• 
To evaluate PFS, ORR, DOR, and DCR assessed by blinded independent review committee 
(BIRC) per RECIST v1.1 
• 
To assess PFS after next line of treatment (PFS2) 
• 
To evaluate the potential association of biomarkers with patient prognosis, response, or 
resistance to tislelizumab in combination with chemotherapy 
• 
To assess the pharmacokinetics of tislelizumab in combination with chemotherapy 
• 
To assess host immunogenicity to tislelizumab in combination with chemotherapy 
Study Endpoints: 
Primary: 
• 
OS - defined as the time from the date of randomization until the date of death due to any cause 
Secondary: 
• 
PFS - defined as the time from the date of randomization to the date of first documentation of 
disease progression assessed by the investigator per RECIST v1.1 or death, whichever occurs 
first 
• 
ORR - defined as the proportion of patients whose best overall response (BOR) is complete 
response (CR) or partial response (PR) assessed by the investigator per RECIST v1.1 
• 
OS in the PD-L1 vCPS ≥ 10% subgroup 
• 
HRQoL - defined as scores of the European EORTC QLQ-C30 (QLQ-C30), its esophageal 
cancer module - EORTC QLQ-OES18 (OES18), and the European Quality of Life 5-
Dimension 5-Level (EQ-5D-5L) 
• 
DOR - defined as the time from the first determination of an objective response until the first 
documentation of progression assessed by the investigator per RECIST v1.1 or death, 
whichever comes first 
• 
The incidence and severity of adverse events (AEs) according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 
Exploratory: 
• 
DCR - defined as the proportion of patients whose BOR is CR, PR, and stable disease (SD) 
assessed by the investigator per RECIST v1.1 
• 
PFS, ORR, DOR, and DCR assessed by BIRC per RECIST v1.1 
• 
PFS2 - defined as the time from randomization to the objective disease progression after next 
line of treatment or death from any cause, whichever occurs first 
• 
To explore biomarkers in tumor tissues and/or blood samples before and after study treatment 
and/or at progressive disease (PD)/reoccurrence, and the association between these biomarkers 
and clinical efficacy, disease status, and resistance. Biomarker assessment will consist of PD-
L1 expression, gene expression profiling (GEP), tumor mutation burden (TMB)/microsatellite 
instability (MSI)/mutation profile, and tumor-infiltrating immune cells. Other assessments may 
be conducted as allowed by local regulations. 
• 
Assessments of pharmacokinetics of tislelizumab when given with chemotherapy 
• 
Assessments of immunogenicity of tislelizumab to determine the incidence of anti-drug 
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antibodies (ADA) 
Study Design: 
This is a randomized, placebo-controlled, double-blind, global Phase 3 study comparing OS following 
treatment with the anti-programmed cell death protein-1 (PD-1) monoclonal antibody tislelizumab in 
combination with standard chemotherapy compared to placebo in combination with chemotherapy 
when given as the first-line treatment in patients with unresectable, locally advanced recurrent or 
metastatic ESCC who have Stage IV unresectable ESCC at first diagnosis (ie, Stage IV disease at the 
original diagnosis of ESCC) or who have unresectable, locally advanced recurrent or metastatic disease 
with at least a 6-month treatment-free interval, if definitive treatment (neo-adjuvant or adjuvant 
treatment chemotherapy, chemo-radiation therapy and/or surgery) was given. Staging criteria for this 
study are defined by the American Joint Committee on Cancer (AJCC), 7th Edition (Edge et al 2010). 
After providing written informed consent, completing all screening assessments, and being confirmed 
as eligible for study participation, approximately 622 patients will be randomized 1:1 to receive either 
tislelizumab in combination with a chemotherapy doublet (Arm A) or placebo with a chemotherapy 
doublet (Arm B). The choice of chemotherapy must be determined prior to randomization.  
Patient randomization will be stratified by the following 3 factors: 
• 
Geographic region (Asia [excluding Japan] vs Japan vs Rest of World) 
• 
Prior definitive therapy (yes vs no) 
• 
Investigator choice of chemotherapy (platinum with fluoropyrimidine vs platinum with 
paclitaxel) 
After randomization, patients will begin double-blind treatment with one of the following regimens.  
• 
Arm A:   
o Tislelizumab + chemotherapy doublet 
o The chemotherapy doublet will consist of: 
▪ 
Platinum (cisplatin or oxaliplatin) and a fluoropyrimidine (capecitabine or 
5-fluorouracil [5-FU]) 
OR 
▪ 
Platinum (cisplatin or oxaliplatin) and paclitaxel 
• 
Arm B:   
o Placebo + chemotherapy doublet 
o The chemotherapy doublet will consist of: 
▪ 
Platinum (cisplatin or oxaliplatin) and a fluoropyrimidine (capecitabine or 
5-FU) 
OR 
▪ 
Platinum (cisplatin or oxaliplatin) and paclitaxel 
The platinum agent may be cisplatin or oxaliplatin (except in China, Taiwan, Japan, and countries 
where oxaliplatin substitution is not permitted) according to site or investigator preference or standard 
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practice as determined prior to randomization. 
Cross-over between treatment arms or between fluoropyrimidine and paclitaxel during the study 
treatment period will not be allowed. 
Study treatment will be administered until disease progression, intolerable toxicity, or another reason 
for treatment discontinuation criterion is met. Platinum therapy may be stopped after 6 cycles, per site 
or investigator preference or standard practice. If platinum treatment is stopped, the non-platinum agent 
(fluoropyrimidine or paclitaxel) may continue at the regular schedule. 
The study design schema is as follows: 
 
Abbreviations: BIRC, blinded independent review committee; chemo, chemotherapy; DCR, disease control rate; 
DOR, duration of response; ESCC, esophageal squamous cell carcinoma; HRQoL, health-related quality of life; 
ICC, investigator choice of chemotherapy; ORR, objective response rate; OS, overall survival; PD-L1, 
programmed cell death protein ligand-1; PFS, progression-free survival; PFS2, PFS after next line of treatment; 
vCPS, visually estimated combined positive score.  
Study Assessments: 
Response to treatment will be assessed by the investigator and BIRC. Tumor imaging (computed 
tomography [CT] with or without contrast or magnetic resonance imaging [MRI]) must be performed 
within 28 days prior to randomization. On-treatment tumor assessments will occur every 6 weeks 
(± 7 days) for the first 48 weeks, then every 9 weeks (± 7 days) based on RECIST v1.1, regardless of 
treatment delays, until disease progression. Patients who discontinue study treatment early for reasons 
other than documented radiographic disease progression (eg, toxicity) will continue to undergo tumor 
assessments following the original plan until the patient experiences disease progression, withdraws 
consent, is lost to follow-up, or dies, or until the study completes, whichever occurs first. Investigators 
Study Population: 
unresectable, locally 
advanced recurrent or 
metastatic ESCC 
Arm A 
Tislelizumab in 
combination with 
chemotherapy 
Screening 
• Treatment until disease 
progression, intolerable 
toxicity, or withdrawal for 
other reasons  
• Safety Follow-up & Survival 
Follow-up 
---------------------------------- 
Primary endpoint:  
• OS 
Secondary endpoints: 
• PFS, ORR, and DOR 
assessed by investigator 
• OS in the PD-L1 vCPS ≥ 
10% subgroup 
• HRQoL 
• Adverse events  
Exploratory endpoints: 
• DCR 
• PFS, ORR, DOR, and DCR 
assessed by BIRC 
• PFS2 
• Correlation of biomarker 
results to response and/or 
resistance to treatment   
• Pharmacokinetics 
• Assessment of 
immunogenicity 
Arm B 
Placebo in combination 
with chemotherapy 
Randomization & 
Stratification: 
n=622 eligible patients 
• 1:1 randomization to 
tislelizumab+chemo 
or placebo+chemo  
Stratification  
• Geographic region 
(Asia [excluding 
Japan] vs Japan vs 
Rest of World) 
• Prior definitive 
therapy (yes vs no) 
• ICC (platinum/ 
fluoropyrimidine vs 
platinum/paclitaxel) 
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must obtain written informed consent for treatment beyond radiologic disease progression and inform 
patients that this practice is not considered standard in the treatment of cancer. 
HRQoL will be measured via 3 validated patient-reported outcomes (PROs) instruments: the QLQ-
C30, OES18, and the EQ-5D-5L at baseline, after randomization, prior to dosing or any clinical 
activities at every treatment cycle for the first 6 cycles, then every other cycle afterwards, and at the 
End-of-Treatment (EOT) Visit. 
All AEs will be reported during the study (AEs from the time of the first dose and serious adverse 
events (SAEs) from the time of signing of informed consent) and for up to 30 days after the last dose of 
study drug(s) (including chemotherapy) or until initiation of another anticancer therapy, whichever 
occurs first. Immune-mediated AEs (serious or non-serious) should be reported up to 90 days after the 
last dose of tislelizumab, regardless of whether the patient starts a new anticancer therapy. The 
investigator should report any SAEs that are assessed as related to tislelizumab treatment, at any time 
after treatment discontinuation. AEs will be graded according to NCI CTCAE v4.03. 
Safety and efficacy monitoring will be performed by an Independent Data Monitoring Committee 
(IDMC). The IDMC may recommend modifications to the study, including termination due to safety 
and/or efficacy concerns. The functions and membership of the IDMC will be described in an IDMC 
Charter. 
The IDMC convened on 20 April 2022 to review the efficacy and safety data of the preplanned interim 
analysis (data cutoff date of 28 February 2022, with 422 death events which corresponds to 86.5% of 
the number of total planned death events for the final analysis [488 OS events]). After reviewing the 
data, the IDMC confirmed that the study met the specified 1-sided p-value boundary for superiority of 
the primary endpoint and recommended to unblind/unmask the study due to compelling efficacy. Based 
on the IDMC recommendation, a decision was made to unblind all patients, and inform all investigators 
and IRB/IEC as required. Patients randomized to Arm B were to discontinue placebo after unblinding. 
Duration of Patient Participation: 
Duration of study participation will vary by patient, depending on the duration of treatment and 
treatment outcomes. Each patient treatment course will include: 
• 
Screening up to 28 days 
• 
Treatment until disease progression (or other reason for discontinuation before progression) 
o In select cases, patients may continue treatment beyond disease progression. See 
Section 3.6.1 for requirements related to treatment beyond disease progression. 
o Platinum therapy may be stopped after 6 cycles, per site or investigator preference or 
standard practice. If platinum treatment is stopped, the non-platinum agent 
(fluoropyrimidine or paclitaxel) may continue at the regular schedule, if appropriate. 
• 
End of Treatment (EOT)/Safety Follow-up Visit up to 30 days after the last dose 
• 
Survival Follow-up Visits every 3 months until death (or other reason before death) 
Study Population: Patients with unresectable, locally advanced recurrent or metastatic ESCC who 
have Stage IV unresectable ESCC at first diagnosis (ie, Stage IV disease at the original diagnosis of 
ESCC) or who have unresectable, locally advanced recurrent or metastatic disease with at least a 
6-month treatment-free interval, if prior definitive therapy (chemotherapy, chemo-radiation therapy or 
surgery) was given. Appendix 13 contains a flow chart to help determine which patients are appropriate 
for this study. 
Prior to opening full enrollment in Japan, close monitoring measures will be taken to observe the safety 
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and tolerability of the combination of tislelizumab with cisplatin and 5-FU in ESCC in Japanese 
patients as described in Section 3.8. 
Key Eligibility Criteria: 
The following are key disease-specific criteria. For the complete list of eligibility criteria for this study, 
please refer to Section 4. 
• 
Key inclusion criteria 
o Pathologically (histologically) confirmed diagnosis of ESCC 
o Stage IV unresectable ESCC at first diagnosis OR unresectable, locally advanced 
recurrent or metastatic disease (per AJCC 7th Edition, Appendix 14), if there is prior 
neoadjuvant/adjuvant therapy with platinum-based chemotherapy, a treatment-free 
interval of at least 6 months is required 
• 
Key exclusion criteria 
o Palliative radiation treatment for ESCC within 4 weeks of study treatment initiation 
o Prior systemic therapy for unresectable, locally advanced recurrent or metastatic ESCC  
o Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage or medical intervention (clinically significant recurrence requiring an 
additional intervention within 2 weeks of intervention) 
o Evidence of complete esophageal obstruction not amenable to treatment 
o Received prior therapies targeting PD-1, PD-L1 or PD-L2 
o Unintentional weight loss ≥ 5% within 1 month prior to randomization or Nutritional 
Risk Index (NRI) < 83.5 (Appendix 15) per investigator’s choice 
Investigational Product, Dose, and Mode of Administration:   
Tislelizumab will be administered at a dose of 200 mg intravenously (IV) on Day 1 of every 21-day 
cycle. Tislelizumab will be given in combination with 1 of the 3 chemotherapy doublets listed below. 
The platinum agent may be cisplatin or oxaliplatin (except in China, Taiwan, Japan, and countries 
where oxaliplatin substitution is not permitted) according to site and investigator preference or standard 
practice as determined prior to randomization.  
o Platinum (cisplatin or oxaliplatin) + 5-FU:  
o Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 Q3W 
o 5-FU 750 to 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1 to 5 Q3W 
o Platinum (cisplatin or oxaliplatin) + capecitabine: 
o Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 Q3W 
o Capecitabine 1000 mg/m2 orally (PO) twice daily (BID) on Days 1 to 14 Q3W 
o Platinum (cisplatin or oxaliplatin) + paclitaxel:  
o 
Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 or 2 Q3W 
▪ 
Depending on local guidelines, cisplatin may be given in 3 divided doses on 
Days 1, 2, and 3. The total dose given must be between 60 to 80 mg/m2 per cycle. 
o 
Paclitaxel 175 mg/m2 IV on Day 1 Q3W 
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Reference Therapy, Dose, and Mode of Administration:   
Matched placebo will be administered on Day 1 of every 21-day cycle. Matched placebo will be given 
in combination with 1 of the 3 chemotherapy doublets listed below. The platinum agent may be 
cisplatin or oxaliplatin (except in China, Taiwan, Japan, and countries where oxaliplatin substitution is 
not permitted), according to site or investigator preference or standard practice as determined prior to 
randomization. 
o Platinum (cisplatin or oxaliplatin) + 5-FU:  
o Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 Q3W 
o 5-FU 750 to 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1 to 5 Q3W 
o Platinum (cisplatin or oxaliplatin) + capecitabine: 
o Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 Q3W 
o Capecitabine 1000 mg/m2 orally BID on Days 1 to 14 Q3W 
o Platinum (cisplatin or oxaliplatin) + paclitaxel:  
o Cisplatin 60 to 80 mg/m2 OR oxaliplatin 130 mg/m2 IV on Day 1 or 2 Q3W 
▪ 
Depending on local guidelines, cisplatin may be given in 3 divided doses on 
Days 1, 2, and 3. The total dose given must be between 60 to 80 mg/m2 per cycle. 
o Paclitaxel 175 mg/m2 IV on Day 1 Q3W 
Statistical Methods 
The primary endpoint of OS in the Intention-to-Treat (ITT) analysis set will be tested at a one-sided 
alpha of 0.025. By using the graphic approach of Bretz et al (2009), if the null hypothesis for OS in the 
ITT analysis set is rejected, the corresponding alpha will be shifted to the hypothesis tests of the 
secondary endpoints PFS by the investigator in the ITT analysis set, ORR by the investigator in the ITT 
analysis set, OS in the PD-L1 vCPS ≥ 10% subgroup, and HRQoL in the ITT analysis set, which will 
be tested sequentially. The inferential test will be stopped at the first non-significant endpoint. 
Analysis Sets: 
• 
The ITT analysis set includes all randomized patients. It will be the primary analysis 
population for the efficacy analysis  
• 
The Safety analysis set includes all patients who received at least 1 dose of study treatment. It 
will be the primary analysis population for safety analysis 
• 
The Pharmacokinetics (PK) analysis set includes all patients who are receive at least 1 dose of 
tislelizumab per the protocol, for whom any post dose PK data are available 
• 
The ADA analysis set includes all patients who have a baseline and at least 1 post-baseline 
ADA result 
Primary Efficacy Endpoint Analysis: 
OS in the ITT analysis set: 
The null hypothesis to be tested is: 
H0:  OS in Arm A ≤ OS in Arm B 
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against the alternative: 
H1:  OS in Arm A > OS in Arm B 
The primary analysis of OS will be carried out when approximately 488 OS events are reached. In 
absence of confirmation of death, patients will be censored either at the date that the patient was last 
known to be alive or the date of data cut-off, whichever comes earlier. 
OS will be compared between Arm A and Arm B in a one-sided, stratified log-rank test using 
stratification factors of pooled geographic region (Asia [including Japan] vs Rest of World), prior 
definitive therapy (yes vs no), and the investigator’s choice of chemotherapy (ICC) option (platinum 
with fluoropyrimidine vs platinum with paclitaxel). A one-sided significance level of 0.025 will be 
used for the OS testing. 
The median OS and the cumulative probability of OS at every 3 months including 9-month OS and 
18-month OS, if estimable, will be calculated for each treatment arm and presented with 2-sided 
95% confidence intervals (CIs). Kaplan-Meier survival probabilities for each arm will be plotted over 
time. OS rate at 9 and 18 months based on Kaplan-Meier estimate will be compared between 2 
treatment arms for landmark analysis. 
The treatment effect will be estimated by fitting a Cox regression model to the OS times including 
treatment arm as a covariate and region of enrollment and prior definitive therapy as strata. From this 
model, the HR of OS will be estimated and presented with a 2-sided 95% CI. 
Primary Analyses of OS 
There will be 1 interim analysis of OS utilizing the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. The interim analysis will 
be performed at the time when approximately 423 death events (87% of the target number of OS 
events) among the 2 treatment arms are observed. It is estimated that it will take approximately 33 
months to observe 423 death events. An IDMC will oversee the interim analysis of OS. The final 
analysis of OS will take place after approximately 488 OS events have been observed. Stopping 
boundaries in p-value and Z score for primary analyses of OS are shown in the table below. The 
boundaries will be updated according to the actual numbers of events in the interim and final analyses, 
and the revised alpha level due to alpha shifting as described above, using the above pre-specified 
alpha spending function. 
Stopping Boundaries (in p-value and Z score) of Primary Analysis of  
Overall Survival 
Endpoint 
Analysis 
Analysis 
Time 
(month) 
# Events 
p-value1 (Z score) for 
Efficacy 
Approximate HR 
Threshold 
OS 
Interim 
analysis 
33 
423 
< 0.0145 (> 2.18) 
0.809 
Final 
analysis 
40 
488 
< 0.0216 (> 2.02) 
0.833 
Abbreviations: HR = hazard ratio; OS = overall survival 
1one-sided 
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Secondary Efficacy Endpoint Analyses: 
Progression Free Survival (PFS) 
There will be one analysis of PFS in the ITT analysis set, which will be carried out after superiority of 
OS in the ITT analysis set has been demonstrated. Similar statistical analysis methods used for OS 
testing will be applied to PFS analysis. 
The p-value from one-sided, stratified log-rank test will be presented using the stratification factors of 
pooled geographic regions (Asia [including Japan] vs Rest of World), prior definitive therapy (yes vs 
no), and ICC option.  
PFS assessed by the investigator will be estimated using the Kaplan-Meier method in the ITT analysis 
set. The PFS censoring rule will follow United States (US) Food and Drug Administration (FDA) 
Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and Biologics (FDA 
2018). Data for patients without disease progression or death at the time of analysis will be censored at 
the time of the last tumor assessment. Data for patients who are lost to follow-up prior to documented 
disease progression will be censored at the last tumor assessment date when the patient is known to be 
free of disease progression. Data for patients who start to receive new anti-cancer therapy will be 
censored at the last tumor assessment date prior to the introduction of a new therapy.  
The median PFS and the cumulative probability of PFS at every 3 months, including 6-month PFS, if 
estimable, will be calculated for each treatment arm and presented with 2-sided 95% CIs. Kaplan-Meier 
estimates of PFS for each arm will be plotted over time. The PFS rate at 6 months based on the Kaplan-
Meier estimate will be compared between the 2 treatment arms for landmark analysis. 
HR estimated from a Cox regression model will be presented with its 95% CI. 
OS in the vCPS ≥ 10% subgroup: 
This analysis for the PD-L1 vCPS ≥ 10% subgroup is similar as the OS analysis in the ITT analysis set.  
Other secondary efficacy endpoints 
ORR per RECIST v1.1 by the investigator in the ITT analysis set will be tested in a Cochran-Mantel-
Haenszel (CMH) test, adjusting for stratification factors of pooled geographic region, prior definitive 
therapy, and ICC options. Patients with no post-baseline response assessment (for any reason) will be 
considered non-responders. The 2-sided 95% CIs for the odds ratio in ORR will be calculated along 
with Clopper-Pearson 95% CIs of ORR for each treatment arm. 
DOR assessed by the investigator will be calculated similarly to PFS by the investigator in the 
responders. Median DOR per arm, if estimable, will be presented. 
HRQoL will be analyzed and compared between the treatment arms via the post-baseline scores of 
QLQ-C30’s Global Health Status/QoL (GHS), functional scales and symptom scores and symptoms 
single item scores, QLQ-OES18’s index score and symptoms scales and single item scores, and EQ-
5D-5L descriptive scale scores as well as the visual analogue scale (VAS) scores. Observed values and 
changes from baseline will be summarized using descriptive statistics. A mixed-effect model analysis 
for measuring clinically meaningful changes post-baseline will be performed using the patient-reported 
outcome endpoints of GHS, physical function, and fatigue domains of QLQ-C30 and dysphagia, reflux, 
pain and eating of QLQ-OES18.  
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Time to clinically meaningful deterioration in the aforementioned scales will be estimated using the 
Kaplan-Meier method and Cox regression model. Deterioration thresholds will be defined based on the 
published 10-point EORTC threshold, and a secondary deterioration threshold based on data may be 
explored. 
Exploratory Efficacy Analyses: 
BOR is defined as the best response per RECIST v1.1 by the investigator recorded from randomization 
till data cut, progressive disease (PD) or start of new anti-cancer treatment. The proportion and its 
corresponding Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will 
be presented by treatment arm. 
DCR will be analyzed similarly as ORR in the ITT analysis set. 
To calculate PFS2, data from patients without disease progression after next line of treatment or death 
at the time of analysis will be censored at the last time known to be alive. Kaplan-Meier method as 
described in the PFS and OS analyses will be used in the analysis of PFS2. 
In addition, PFS, ORR, DOR, and DCR assessed by the BIRC per RECIST v1.1 are summarized 
similarly the data assessed by the investigator for exploratory analysis. 
Exploratory biomarkers may also be assessed. 
Safety Analyses: 
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (eg, hematology, clinical chemistry, coagulation, and urinalysis), dosing, vital signs, 
ECGs, and physician examinations will also be evaluated in defining the safety profile of each 
treatment arm. Descriptive statistics will be used to analyze all safety data in the Safety analysis set. 
Extent of exposure to each study drug will be summarized descriptively as the number of doses 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA®) terms and graded per NCI CTCAE v4.03. 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 (pre-treatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation or initiation of new anti-cancer therapy, whichever occurs first. TEAEs also include 
immune-mediated AEs recorded up to 90 days after the last dose of tislelizumab or placebo, regardless 
of whether the patient starts a new anticancer therapy. SAEs, deaths, TEAEs that are Grade 3 or above, 
infusion-related reactions, treatment-related TEAEs, TEAEs that led to treatment discontinuation, dose 
reduction, dose interruption or dose delay, and immune-mediated AEs will be summarized. 
Clinical laboratory data with values outside of the normal ranges will be identified. Select laboratory 
data will be summarized by grade. Changes in vital signs will also be summarized by visit. 
Sample Size Considerations: 
The initial sample size calculation was based on the primary efficacy analysis of PFS and OS in the 
comparison between tislelizumab in combination with chemotherapy arm and placebo plus 
chemotherapy arm in the ITT analysis set. Hazard ratios in PFS and OS were assumed as 0.65 and 
0.73, respectively, with median PFS of 5 months and OS of 9 months in the comparator arm. A total of 
480 patients would be enrolled in a 1:1 randomization over a 17-month period at enrollment rates of 10 
patients/month in the first month, 20 patients/month in the second month and 30 patients/month in the 
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next 15 months. Approximately 319 PFS events were planned in the PFS hypothesis testing to have a 
power of 90% with an alpha of 0.005. A group sequential testing of OS would be performed. The 
interim analysis was planned after approximately 67% of the total planned death events had occurred 
(241). The final analysis of OS would be performed when approximately 360 death events have been 
observed. The sample size calculation of OS was based on overall power of 82% and an alpha level of 
0.02. 
The previous version of protocol amendment 3.0 was amended on 25 May 2020. The study sample size 
was increased from 480 to 622 to allow increased targeted numbers of events in the PFS and OS 
analyses, which was to account for the delayed treatment effect and increased usage of subsequent 
immunotherapies that were observed in the newly published immuno-oncology trials in the second-line 
ESCC (Kojima et al 2019; Kato et al 2019; Huang et al 2019).  
By 24 November 2020, enrollment was completed with 649 randomized patients. In the current 
protocol amendment, BIRC-assessed PFS has been removed from the primary efficacy analysis based 
on the results from KEYNOTE-590 (Kato et al 2020) in the first-line treatment of ESCC. OS is the sole 
primary efficacy endpoint. The HR for OS is assumed to be 0.74 at the time of final analysis after an 
initial 1-month delayed treatment effect (eg, assuming HR = 1 in the first month), the number of deaths 
required in the final analysis will be approximately 488 with 90% power by simulation. The planned 
interim analysis with a power of 81% will occur after 423 events have been observed. A 5% annual 
dropout rate is assumed and one-sided alpha of 0.025 is used in the sample size calculation. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADA 
antidrug antibody 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-A317 
humanized monoclonal antibody directed at PD-1; tislelizumab  
BID 
twice daily 
BIRC 
blinded independent review committee 
BSA 
body surface area 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
Clearance 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 
EORTC QLQ-OES18  
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Oesophagus Cancer Module  
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level 
ESCC 
esophageal squamous cell carcinoma 
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
GC 
gastric carcinoma 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBcAb 
hepatitis B core antibody 
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Abbreviation 
Definition 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
OCT 
optical coherence tomography 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PD-L2 
programmed cell death protein ligand-2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS2 
PFS after next line of treatment 
PK 
pharmacokinetic(s) 
PR 
partial response 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
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Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TFT 
thyroid function tests 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
vCPS 
visually estimated combined positive score 
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1. 
INTRODUCTION  
1.1. 
Background Information on Esophageal Carcinoma  
Esophageal cancer is the eighth most common cancer worldwide and the sixth most common 
cause of death from cancer (Ferlay et al 2012). The incidence, prevalence, and histologic type of 
esophageal cancer varies between geographic regions, particularly between Western countries 
(United States [US] and Europe) and an area commonly referred to as the “esophageal cancer 
belt,” which is a geographic area stretching across Central-Eastern Asia from the Caspian region 
to northern China (Arnold et al 2015). To illustrate, an estimated 16,940 people in the US will be 
diagnosed with esophageal cancer and 15,690 people will eventually die of their disease in 2017 
(Siegel et al 2017). The predominant histologic type of these new diagnoses in the US will be 
adenocarcinoma. The 5-year survival rates are 18.4% in the United States (Siegel et al 2017) and 
12% in Europe (De Angelis et al 2014). In contrast, in China, an estimated 477,900 people will be 
diagnosed with esophageal cancer, 90% of which will be of the squamous cell carcinoma 
histology, and 375,000 people will die of this disease (Chen et al 2016; Arnold et al 2015). The 
age-standardized 5-year relative survival rate for patients in China diagnosed in 2003 to 2005 is 
20.9% (Li et al 2017).  
Recognized risk factors for developing both adenocarcinoma and squamous cell esophageal 
carcinoma include poor nutritional status, low intake of fruits and vegetables, drinking alcohol, 
smoking tobacco, chewing betel quid, and drinking liquids, such as mate, 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% (Lin et al 2016; Drahos et al 2013). 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 Esophageal Carcinoma and Unmet Clinical 
Needs  
Esophageal cancer treatment is based on the extent of disease at presentation and tumor histology. 
International treatment guidelines are consistent in the approach to the treatment of this disease. 
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 (Lordick 
et al 2016; NCCN Guidelines Version 1, 2017; Japanese Gastric Cancer Association 2017; Stahl 
et al 2009). Chemoradiation therapy may be given to those with larger tumors in the neo-adjuvant, 
peri adjuvant or in the adjuvant setting. Post-operative chemotherapy or chemoradiation is 
commonly given to patients who have positive lymph nodes after R0 resection, or those with 
microscopic or macroscopic residual cancer (R1 and R2 resection, respectively) after surgery. 
Systemic regimens given in the pre-operative or peri-operative setting commonly include 
chemotherapy doublets which include taxanes, platinum agents, fluorouracil, or irinotecan. Triplet 
combinations may also be considered, such as epirubicin, oxaliplatin and 
fluorouracil/capecitabine, but are more toxic and restricted to those patients with good 
performance status. In the pre-operative or peri-operative setting, the choice of chemotherapy 
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regimen is made independent of the tumor histology (Lordick et al 2016; NCCN Guidelines 
Version 1, 2017; Japanese Gastric Cancer Association 2017; Stahl et al 2009).  
The choice of systemic chemotherapy agents for patients who are not surgical candidates or those 
who have recurrent or metastatic disease that cannot be adequately treated with local therapy are 
like those described above, and are similar to treatments given to patients with advanced gastric 
cancer (Lordick et al 2016). The choice of agents or regimen may be based on the patient’s 
performance status, and underlying comorbidities. Fluoropyrimidines (either 5-Fluorouracil [5-
FU] or capecitabine) as monotherapy or in combination with either cisplatin or oxaliplatin, 
taxanes (either paclitaxel or docetaxel) given as monotherapy or with platinum agents, or 
irinotecan in combination with 5-FU are suitable front-line treatments.  
The overall response rate to first-line chemotherapy for advanced or metastatic disease ranges 
from 20% to 48% and 5-year survival rates of lower than 30% with significant toxicity rates 
(Grunberger et al 2007). There is no global consensus on the optimal first-line treatment; but 
combination chemotherapy combination therapy is typically given. Treatment regimens 
commonly include a platinum agent (cisplatin or oxaliplatin) in combination with paclitaxel or 5-
FU (NCCN Guidelines Version 1, 2017). There are regional preferences for the chemotherapy of 
choice and may be based on the toxicity profile of each agent. The following table (Table 1) 
summarizes the efficacy outcomes between the chemotherapy regimens allowed in this protocol. 
It should be noted that one publication summarizes data from retrospective analysis (Liu et al 
2016). Given these caveats, the ORRs and median survival durations appear comparable amongst 
the various regimens. 
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Table 1.  First-Line Treatment and Outcomes for Esophageal Squamous Cell Carcinoma 
Reference 
Sample Size 
by Histology 
(n) 
Treatment 
setting 
Regimen 
ORR 
(%) 
PFS 
(median 
months 
OS 
(median 
months) 
Cisplatin + 5-fluorouracil 
Bleiberg, 
1997 
ESCC (44) 
1st line 
Cisplatin 100 mg/m2 IV Day 1 Q3W 
5-FU 1000 mg/m2 IV infusion over 24h 
Days 1-5 Q3W 
35 
6.8 
8.3 
Hayashi, 
2001 
ESCC (36) 
85% 1st line 
Cisplatin 20 mg/m2 IV Day 1-5 Q4W 
5-FU 800 mg/m2 IV infusion over 24h 
Days 1-5 Q4W 
33.3 
N/A 
7.2 
Lorenzen, 
2009 
ESCC (30) 
1st line 
Cisplatin 75-100 mg/m2 IV Day 1 Q4W 
5-FU 250-1000 mg/m2 IV infusion over 
24h Days 1-4 Q4W 
13 
3.6 
5.5 
Liu, 
2016 
ESCC (203) 
1st line 
Cisplatin 75 mg/m2 IV Day 1 Q3W 
5-FU 750 mg/m2 IV over 24h Days 1-5 
Q3W 
38.4 
6.5 
12.7 
Wang, 
2017 
ESCC (48) 
85% 1st line 
Cisplatin 15 mg/m2 IV Day 1-5 Q3W 
5-FU 750 mg/m2 IV infusion over 24h 
Days 1-5 Q3W 
46.8 
4.9 
8.9 
Cisplatin + capecitabine 
Lee, 
2008 
ESCC (45) 
1st line 
Cisplatin 60 mg/m2 IV Day 1 Q3W 
Capecitabine 1250 mg/m2 BID PO Day   
1-14 Q3W 
57.8 
4.7 
11.2 
Lee, 
2015 
ESCC (46) 
1st line 
Cisplatin 75 mg/m2 IV Day 1 Q3W 
Capecitabine 1000 mg/m2 BID PO Day   
1-14 Q3W 
57 
5.1 
10.5 
Cisplatin + paclitaxel 
Petrasch, 
1998 
ESCC (18)     
EAC (6) 
1st line 
Cisplatin 50 mg/m2 IV Day 1 Q2W 
Paclitaxel 90 mg/m2 IV Day 1 Q2W 
40 
N/A 
7.0 
Cho, 
2005 
ESCC (32) 
31% 1st line 
Cisplatin 50 mg/m2 IV Day 1 Q2W 
Paclitaxel 90 mg/m2 IV Day 1 Q2W 
41 
5.0 
7.0 
Huang, 
2013 
ESCC (46) 
1st line 
Cisplatin 50 mg/m2 IV Day 2 Q2W 
Paclitaxel 150 mg/m2 IV Day 1 Q2W 
56.5 
5.6 
17.0 
Liu, 
2016 
ESCC (195) 
1st line 
Cisplatin 75 mg/m2 IV Day 1 Q3W 
Paclitaxel 175 mg/m2 IV Day 1 Q3W 
42.5 
7.9 
13.5 
Abbreviations: 5-FU, 5-fluorouracil; BID, twice daily; EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell 
carcinoma; IV, intravenous; N/A, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; 
PO, orally; Q2W, once every 2 weeks; Q3W, once every 3 weeks; Q4W, once every 4 weeks  
1.3. 
Anti-PD-1 Therapy for Esophageal Squamous Cell Carcinoma  
Clinical outcome data are available from early phase studies evaluating tislelizumab, nivolumab, 
and pembrolizumab in patients with advanced esophageal carcinoma.  
Tislelizumab  
As of 28 August 2017, 49 patients with advanced esophageal carcinoma have been enrolled to an 
ongoing Phase 1 clinical study. The median age of these enrolled patients is 62 years (range: 30 to 
80 years), 36 patients are men and 28 patients are of the white race. Prior to study enrollment, 
these patients had received a median of 2 (range: 0 to 7) prior treatment regimens for their 
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esophageal cancer, with 12 patients receiving at least 3 prior treatments. The duration of follow-
up in this study was 3.4 months (range: 0.2 to 10.6 months).  
Tislelizumab was administered for a median of 2 months (range: 0.2 to 10.6 months) in this 
patient cohort. All but 1 patient received tislelizumab at a dose of 5 mg/kg; 1 patient was treated at 
the 2 mg/kg dose.  
The majority (n = 46) of patients experienced at least 1 treatment-emergent adverse event 
(TEAE). Twenty-three patients experienced a treatment-related adverse event (AE). The most 
common AEs reported in at least 3 patients in the esophageal cohort of any grade or causality 
included nausea, constipation, dysphagia, abdominal pain (including upper abdominal pain), 
diarrhea, vomiting, pneumonia, upper respiratory tract infection, cough, dyspnea, pleural effusion, 
decreased appetite, hypercalcemia, fatigue, pyrexia, peripheral edema, back pain, arthralgia, 
myalgia, weight decrease, alkaline phosphatase increase, pruritus, headache, hypothyroidism, 
insomnia, proteinuria, infusion related reaction, and anemia. Of these events, nausea, fatigue, 
hypothyroidism, infusion related reaction, decreased appetite, and myalgia were reported as 
related to tislelizumab in more than 2 patients. Twenty-two patients experienced an AE that was 
reported as National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Grade 3 or higher; none of these events occurred in more than 3 patients.  
Serious adverse events (SAEs) were reported in 25 patients. The only SAE that occurred in more 
than 2 patients was pneumonia in 4 patients.  
Six patients who received tislelizumab at the 5 mg/kg dose died of causes reported as AEs: 
mediastinitis, sepsis, esophageal hemorrhage, pleural effusion, tumor hemorrhage, and 
hemoptysis. These events are recognized complications of esophageal carcinoma; none were 
considered related to study treatment. 
Radiographic anti-tumor activity results were available for 42 of the 49 enrolled patients. Of these 
patients, 6 experienced a partial response (PR). Three of these patients had squamous cell 
carcinoma and 3 had adenocarcinoma. Three of these responses were confirmed, and the 
remaining PRs were not confirmed per Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 criteria. Twelve additional patients had confirmed a best response of stable disease (SD). 
There were no complete responses (CR) reported.  
At the time of the data cutoff, 12 patients were still receiving tislelizumab treatment. 
Nivolumab  
Efficacy results in esophageal squamous cell carcinoma (ESCC) patients treated with nivolumab, 
an anti-programmed cell death protein-1 (PD-1) monoclonal antibody, were reported from an 
open-label, single-arm, multi-center Phase 2 study (Kudo et al 2017). This study enrolled 65 
patients with squamous cell esophageal carcinoma even though the study was designed to recruit 
patients with squamous, adenocarcinoma, or adeno-squamous cell histologies. These patients were 
considered refractory or intolerant to fluoropyrimidine, platinum, and taxane-based 
chemotherapies. Patients were treated with nivolumab 3 mg/kg given IV once every 2 weeks 
(Q2W). Tumor response was assessed every 6 weeks. Median follow-up was 10.8 months 
(interquartile range: 4.9 to 14.3 months) and patients received a median of 3 nivolumab cycles 
(range: 1 to 10 cycles). The ORR by central radiology assessment was 17% (95% confidence 
interval [CI]: 10 to 28%) and 22% (95% CI: 14 to 33%) by investigator assessment. The disease 
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control rate (DCR), defined as the number of patients with a CR or PR, and those with SD of any 
duration was 42% (95% CI: 31 to 54%) by central assessment and 53% (95% CI: 41 to 65%) 
patients by investigator assessment. The median duration of OS was 10.8 months (95% CI:7.4 to 
13.9 months). The 2-year OS was 17.2%. The median durations of progression-free survival (PFS) 
were 1.5 months (95% CI: 1.4 to 2.8 months) and 2.3 months (95% CI: 1.5 to 3.0 months), by 
central and investigator assessment, respectively.  
Pembrolizumab  
KEYNOTE-028 (NCT02054806), a multicohort, Phase 1b trial recruited advanced ESCC and 
adenocarcinoma patients with disease progression (PD) following standard therapy. Patients 
received pembrolizumab 10 mg/kg Q2W. Response was assessed every 8 weeks for the first 
6 months and every 12 weeks thereafter. Primary endpoint was ORR per RECIST v1.1 by 
investigator review. In this cohort of 23 patients, 87% received ≥ 2 prior therapies for metastatic 
disease and 78% of 17 patients had ESCC. After a median follow-up of 7 months (range: 1 to 
33 months), ORR was 30% (95% CI: 13 to 53%). Median PFS was 1.8 months and median OS 
was 7 months. The median duration of response (DOR) was 15 months (range: 6 to 26 months) 
(Doi et al 2017). 
KEYNOTE-590 (NCT03189719) is a multicenter, randomized, double-blind, placebo-controlled 
Phase 3 study that enrolled 749 patients with metastatic or locally advanced esophageal or 
esophagogastric junction (GEJ) carcinoma who were not candidates for surgical resection or 
definitive chemoradiation. Patients were randomized (1:1) to receive either pembrolizumab 
(200 mg on Day 1 every three weeks [Q3W]) or placebo (on Day 1 Q3W) in combination with 
cisplatin (80 mg/m2 on Day 1 Q3W for ≤ 6 cycles) plus 5-FU (800 mg/m2 per day on Days 1 to 5 
Q3W, or per local standard for 5-FU administration, for ≤ 35 cycles). Treatment with 
pembrolizumab or chemotherapy continued until unacceptable toxicity, disease progression, 
withdrawal, or 2 years. The major efficacy outcome measures were OS and PFS (assessed by the 
investigator). The pre-specified analyses of OS and PFS were performed in the following 
subgroups: patients with ESCC, patients with ESCC with PD-L1-positive tumors with combined 
positive score (CPS) ≥ 10, and all patients. Additional efficacy outcome measures were ORR and 
DOR assessed by the investigator. Both patients with squamous (ESCC, 73%) and 
adenocarcinoma (27%) histologies were accrued. After a median follow-up of 10.8 months, the 
interim analysis of KEYNOTE-590 demonstrated that pembrolizumab combined with 
chemotherapy showed statistically significant and clinical meaningful improvement in OS 
compared with chemotherapy alone in the all-patient population (HR 0.73, median OS 12.4 
months [pembro+chemo] versus 9.8 months [chemo], p < 0.0001), ESCC subgroup (HR 0.72, 
median OS 12.6 months [pembro+chemo] versus 9.8 months [chemo], p = 0.0006), and ESCC 
PD-L1 CPS ≥ 10 subgroup (HR 0.57, median OS 13.9 months [pembro+chemo] versus 8.8 
months [chemo], p < 0.0001). A superior PFS in both the all-patient population (HR 0.65, median 
PFS 6.3 months [pembro+chemo] versus 5.8 months [chemo], p < 0.0001) and the ESCC 
subgroup (HR 0.65, median PFS 6.3 months [pembro+chemo] versus 5.8 months [chemo], 
p < 0.0001) was also observed in the pembrolizumab combined with chemotherapy group. ORR 
was 45% (95% CI: 39.9% to 50.2%) versus 29.3% (95% CI: 24.7% to 34.1%) and DOR was 8.3 
months (range: 1.2+ to 31.0+ months) versus 6.0 months (range: 1.5+ to 25.0+ months) for 
pembrolizumab combined with chemotherapy and chemotherapy alone groups, respectively (Kato 
et al 2020). 
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1.4. 
Background Information on Tislelizumab  
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 programmed cell death protein ligand-1 (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 peripheral blood mononuclear 
cells. In addition, tislelizumab has demonstrated antitumor activity in several allogeneic xenograft 
models, in which peripheral blood mononuclear cell were co-injected with human cancer cells 
(A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
The IgG4 variant antibody has very low binding affinity to gamma fragment crystallizable region 
(Fc) receptor IIIA (Fcγ-RIIIA) and complement 1q, a subunit of complement 1, by in vitro assays, 
suggesting either low or no antibody-dependent cellular cytotoxicity (ADCC) or complement-
dependent cytotoxicity (CDC) effects in humans (Labrijn et al 2009). 
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 intravenous (IV) 
toxicology studies in mice and monkeys, and in two separate repeated-dose IV toxicology studies 
in cynomolgus monkeys dosed once every two weeks for 13 weeks. The tissue cross-reactivity 
was evaluated in the normal frozen tissues from both humans and monkeys. In addition, the 
potential off-target binding of tislelizumab was screened using the Retrogenix microarray and 
subsequently verified by Biacore assays. The cytokine release assays were also evaluated using 
fresh human whole blood cells. Cynomolgus monkey was the only relevant species based on the 
target sequence homology and binding activity.  
Overall, no apparent toxicity was noted in mice or monkeys at single doses up to 100 mg/kg. No 
apparent tislelizumab-related toxicity was noted in the 13-week repeated-dose monkey toxicology 
studies at doses up to 30 mg/kg. Apparent but likely immunogenicity-related toxicity was noted in 
individual monkeys given 60 mg/kg repeatedly. However, immunogenicity-related changes due to 
formation of antidrug antibodies (ADAs) and immune complex formation in nonhuman primates 
is generally considered not translatable to humans (Vahle 2018). The 
No-Observed-Adverse-Effect Level of tislelizumab in the 13-week monkey toxicology studies 
was considered to be 30 mg/kg, approximately 10-fold higher than the clinical dose (200 mg, once 
every 3 weeks). The toxicokinetic profile was well characterized in cynomolgus monkeys with 
dose-proportional increases in systemic exposure, without apparent accumulation or sex 
difference.  
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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. In addition, the Retrogenix microarray 
screen of > 6000 human proteins and follow-up verification by Biacore assays revealed no 
biologically significant off-target binding of tislelizumab.  
The safety profile of tislelizumab is considered adequate to support the current Study BGB-A317-
306.   
Refer to the tislelizumab Investigator’s Brochure for more information regarding IV toxicology 
studies. 
1.4.3. 
Clinical Pharmacology  
In the Phase 1 BGB-A317_Study_001 study and Study BGB-A317-102, interim pharmacokinetics 
(PK) analysis (with a cut-off date of 28 August 2017) was conducted using non-compartmental 
methods, using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, 10 mg/kg 
Q2W and 2.0 mg/kg, 5.0 mg/kg, 200 mg once every 3 weeks (Q3W) (Phase 1a Part 1, 2, 3, and 
Phase 1b in Study BGB-A317_Study_001) and patients who received doses of 200 mg Q3W in 
Phase 1 of Study BGB-A317-102 (n = 19). The maximum observed plasma concentration (Cmax) 
and the area under the plasma or serum concentration-time curve (AUC) increased in a nearly 
dose-proportional manner from 0.5 mg/kg to 10 mg /kg, after single-dose administration at steady 
state. Preliminary PK data from 27 patients who were administered 1 dose of 200 mg Q3W (Phase 
1a, Part 3 and Study BGB-A317-102) showed tislelizumab concentrations between the range of 
concentrations observed for patients who were administered 2 mg/kg and 5 mg/kg doses. The PK 
profile of tislelizumab was consistent between Chinese patients and Caucasian patients. 
Preliminary population PK analysis using a 2-compartment model with first order elimination 
shows a systemic plasma clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution 
(Vd) in the central and peripheral compartments of 2.89 L and 1.76 L, respectively, and half-life of 
approximately 19 days. Race, gender, and body weight are not significant covariates on the CL of 
tislelizumab, which supports fixed-dosing across different ethnic groups.  
For more detailed information, please refer to the tislelizumab Investigator’s Brochure.    
1.4.4. 
Prior Clinical Experience of Tislelizumab  
As of 28 February 2018, there are 13 ongoing studies with tislelizumab, including monotherapy 
and combination studies in solid tumors and hematological malignancies. Of the ongoing 
monotherapy studies in solid tumors, available data from BGB-A317_Study_001 and BGB-A317-
102 are summarized below (with a data cutoff date of 28 August 2017). Of the ongoing 
combination studies, available data from BGB-A317-206 (data cutoff date of 21 February 2018) 
and BGB-A317-205 (data cutoff date of 13 June 2018) are summarized below. Please refer to the 
tislelizumab Investigator’s Brochure for the most current data set. 
1.4.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017)  
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts to establish the maximum tolerated dose (MTD), if any, a 
recommended Phase 2 dose (RP2D) for the Phase 1b, and a flat dose (fixed dose) followed by a 
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Phase 1b component to investigate efficacy in select tumor types in indication expansion arms and 
to further evaluate safety and tolerability of tislelizumab. 
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens 
including 0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg Q2W; 2 mg/kg or 5 mg/kg Q3W; and 200 
mg Q3W. In Phase 1b, 323 patients had received tislelizumab across 9 indication-expansion 
cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the population 
was male, and 65.6% of patients were white. The median number of prior anticancer therapy 
regimens was 2 (range: 0 to 12). The median treatment exposure duration was 2.50 months (range: 
0 to 23.0), and the median study follow-up duration was 5.56 months (range: 0.0 to 26.9). The 
recommended Phase 2 dose (RP2) was established as fixed dose of 200 mg IV Q3W. As of 
28 August 2017, there were 210 patients (47.8%) remaining on study. 
Preliminary Safety 
Of the 439 total patients in the Safety analysis set for Study BGB-A317_Study_001, 240 (54.7%) 
experienced at least 1 treatment-emergent adverse event (TEAE) assessed as related to 
tislelizumab by the investigator and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE. 
The most commonly occurring related TEAEs for patients treated with the tislelizumab 
monotherapy in Study BGB-A317_Study_001 were fatigue (12.8%), rash (7.7%), nausea (6.8%), 
diarrhea (6.6%), and hypothyroidism (4.8%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 
patients were pneumonitis (6 patients, 1.4%); colitis and alanine aminotransferase (ALT) 
increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate aminotransferase 
(AST) increased (3 patients each, 0.7%); and diarrhea, gamma-glutamyltransferase (GGT) 
increased, and diabetic ketoacidosis (2 patients each, 0.5%). All other events occurred in single 
patients. Lastly, 18 patients (4.1%) experienced an infusion-related reaction; all were 
mild/moderate in severity.  
Preliminary Efficacy 
For patients in Phase 1a (n = 116, evaluable), there were 20 patients with a confirmed response 
and 42 patients with a best overall response (BOR) of stable disease. 
For patients in Phase 1b (n = 286 evaluable), a total of 26 patients had a confirmed response.  
Additionally, there were 101 patients with a BOR of stable disease. 
1.4.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017)  
This Phase 1/2 study was a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.   
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of 
the population was male, and 100% of patients were Asian (Chinese). The median number of prior 
anti-cancer therapy regimens was 2 (range: 0 to 9). The median treatment exposure duration was 
1.78 months (range: 0 to 8.0), and the median study follow-up duration was also 1.78 months 
(range: 0.0 to 8.0). As of 28 August 2017, there were 113 patients (91.9%) remaining on study in 
Study BGB-A317-102. Please refer to the tislelizumab Investigator’s Brochure for the most 
current data set. 
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Preliminary Safety 
Of the 123 total patients in the Safety analysis set for Study BGB-A317-102, 69 (56.1%) 
experienced at least 1 TEAE assessed as related to tislelizumab by the investigator and 10 (8.1%) 
were ≥ Grade 3 in severity. The most commonly occurring related TEAEs were AST increased 
(20 patients, 16.3%), ALT increased (17 patients, 13.8%), and blood bilirubin increased and 
anaemia (13 patients each, 10.6%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 patients were 
AST increased (3 patients, 2.4%) and ALT increased (2 patients, 1.6%). All other events occurred 
in single patients, including a case of retinal detachment (Grade 4). 
Preliminary efficacy data are not yet available. 
1.4.4.3. 
Study BGB-A317-206 (Data Cutoff 21 February 2018)  
This multi-arm Phase 2 study, consisting of safety run-in and dose-extension phases, assessed 
tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a 
potential first-line treatment for Chinese patients with lung cancer. 
As of 21 Feb 2018, 48 patients (median age: 62 years [range: 36 to 75]; 71% male; 
71% current/former smokers) received tislelizumab treatment (median: 3 cycles [range: 1 to 7]); 
44 patients remain on the study. 
Preliminary Safety 
The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly 
reported ≥ 3 Grade  treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the 
most common Grade 3 immune-mediated AEs (imAEs) were pyrexia (6.3%) and rash (6.3%). 
One sq-NSCLC patient experienced a fatal myocarditis/myositis following 1 cycle of 
paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug 
interruption (n=15) or discontinuation (n=4) and appropriate treatment. 
Preliminary Efficacy 
Across the 4 cohorts, confirmed and unconfirmed partial responses were observed in 13 and 
9 patients, respectively. 
1.4.4.4. 
Study BGB-A317-205 (Data Cutoff 13 June 2018)  
This is a Phase 2, multi-cohort study to investigate the safety, pharmacokinetics and preliminary 
antitumor activity of the anti-PD-1 monoclonal antibody tislelizumab in combination with 
chemotherapy as first-line treatment in adults with inoperable, locally advanced or metastatic 
esophageal, gastric, or gastroesophageal junction (GEJ) carcinoma. 
As of 13 June 2018, in the ESCC cohort, 15 patients (median age: 61 years) were enrolled 
(93% male; median treatment duration: 108 [21, 201] days; 3 patients received prior 
chemotherapy). In the GC (gastric carcinoma)/GEJ cohort, 15 GC/GEJ patients (median age: 57.9 
years) were enrolled (73% male; median treatment duration: 171 [21, 251] days). There were 5 
patients (33.3%) remaining on study treatment. 
Preliminary Safety 
In the ESCC cohort, a total of 22 patients experienced ≥1 tislelizumab- (n=8) or chemotherapy- 
(n=14) related AE. Two patients experienced a tislelizumab-related SAE (abnormal hepatic 
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function, pneumonitis); 4 patients experienced ≥1 chemotherapy-related SAE (thrombocytopenia, 
atrial fibrillation, fatigue, abnormal hepatic function, lung infection, decreased appetite). Rash 
(n=2) was the only imAE reported in ≥2 patients. One patient experienced ≥ 3 Grade increased 
AST and a fatal abnormal hepatic function. 
In the GC/GEJ cohort, 14 patients (93.3 %) experienced treatment-related AEs of any grade, most 
commonly asthenia (n=8, 53.3%), nausea (n=7, 46.7%), AST increased (n=7, 46.7%), vomiting 
(n=6, 40.0%), ALT increased (n=6, 40.0%), Blood bilirubin increased (n=5, 33.3%), platelet 
count decreased (n=5, 33.3%), thrombocytopenia (n=5, 33.3%), decreased appetite (n=5, 33.3%). 
Nine patients (60.0 %) experienced ≥ 3 Grade treatment-related AEs including AST increased, 
ALT increased, blood bilirubin increased, neutrophil count decreased, amylase increased, lipase 
increased, vomiting, diarrhea, thrombocytopenia, granulocytopenia, decreased appetite, 
paronychia, all of which occurred in 1 patient. Tislelizumab (BGB-A317) treatment-related AEs 
occurred in 10 patients (66.7%), commonly asthenia (n=4, 26.7%) ALT increased (n=3, 20.0%), 
AST increased (n=3, 20.0%). Tislelizumab (BGB-A317) treatment-related ≥ 3 Grade AEs were 
observed in 5 patients including AST increased, ALT increased, neutrophil count decreased, 
amylase increased, lipase increased, decreased appetite, all of which occurred in 1 patient. One 
tislelizumab (BGB-A317) treatment-related SAE was reported (AST increased, ALT increased). 
Preliminary Efficacy 
Preliminary efficacy data are not yet available. 
1.4.4.5. 
Immune-Mediated Reactions  
In patients treated with tislelizumab monotherapy, the following imAEs were observed: 
Acute hepatitis and abnormal liver function have been reported, including 1 patient with fatal 
hepatitis. Additionally, 3.2% of patients experienced treatment-related abnormal liver function 
tests, and 1.4% of patients experienced immune-mediated hepatitis or hyperbilirubinaemia. 
Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal pneumonitis.   
Colitis has been reported in approximately 2% of patients treated. Diarrhoea has been reported in 
6.6% of patients.  
Endocrinopathies have been reported including diabetes mellitus (hyperglycemia and 
ketoacidosis). In addition, thyroiditis, including thyrotoxicosis and hypothyroidism has been 
reported. Furthermore, hypophysitis has been reported in < 1% of patients treated.  
Other immune-mediated events (< 1% of patients with tislelizumab monotherapy except where 
noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); haemolytic 
anaemia, nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, pancreatitis, stomatitis, 
uveitis, and dry eye (1.4%).   
Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in combination 
with paclitaxel and cisplatin. The patient’s initial symptoms were dyspnea and tea-colored urine 2 
weeks after starting treatment. Elevated urine and serum cardiac and skeletal muscle enzymes 
were reported. The patient died of multi-organ failure 6 days later. 
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1.5. 
Study Rationales  
1.5.1. 
Rationale for Tislelizumab in the Treatment of Esophageal Carcinoma  
High levels of FcγR-expressing myeloid derived cells (eg, M2 macrophage, myeloid-derived 
suppressor cell [MDSC]) in tumor tissues predict a poor survival of tumor-bearing animals after 
anti-PD-1 monoclonal antibody treatment; this is possibly due to Fc-FcγR-mediated 
antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular 
phagocytosis (ADCP) depletion of effector T-cells (Gül and van Egmund 2015; Prieto et al 2015; 
Makarova-Rusher et al 2015; Beers et al 2016; Dahan et al 2015). As a no- to low-FcγR-binding 
agent (thus causing minimal ADCC/ADCP effect), tislelizumab may theoretically show superior 
efficacy and lower toxicity in esophageal carcinoma. Available data from a clinical trial with other 
anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have shown the drugs to have 
both manageable safety profiles and promising antitumor activity in patients with esophageal 
carcinoma (Section 1.6). 
Finally, according to the latest data collected from the Phase 1 BGB-A317_Study_001, 
tislelizumab monotherapy has established a manageable safety profile, with the most common 
side effects consistent with known class effects of other anti-PD-1 antibodies, as well as evidence 
for anti-tumor activity (Section 1.6). 
1.5.2. 
Rationale for Selection of Tislelizumab Dose  
The PK, safety and efficacy data obtained from the first-in-human study BGB-A317_Study_001, 
as well as other clinical study data, were analyzed in aggregate to determine the recommended 
dose for pivotal studies of tislelizumab. The flat dose of 200 mg IV Q3W was selected for 
subsequent trials. 
Rates of treatment-related adverse events (AEs) and serious adverse events (SAEs) observed in 
patients receiving 2 mg/kg and 5 mg/kg Q2W and Q3W were comparable suggesting no clear 
dose dependence across these regimens. Similarly, confirmed objective response rates (ORRs) in 
patients treated with tislelizumab 2 mg/kg and 5 mg/kg Q2W ranged between 10% and 15%, 
compared to a range of 15% and 38% for patients treated at 2 mg/kg and 5 mg/kg Q3W.   
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender and the observed serum exposure of a 
200-mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose range 
with comparable safety and efficacy rates).   
Additionally, no unexpected treatment-related AEs occurred in 200 mg fixed-dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n = 13), 3 patients (23%) had a best overall response (BOR) of partial 
response (PR), 4 patients (31%) had a BOR of stable disease (SD) and 6 patients (46%) had a 
BOR of progressive disease (PD). Therefore, clinical activity with a manageable and tolerable 
safety profile is expected to be maintained in patients receiving tislelizumab 200 mg Q3W. 
In conclusion, tislelizumab 200 mg Q3W is the recommended dose for pivotal studies. 
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1.5.3. 
Rationale for Matched Placebo in Combination with Chemotherapy as the 
Comparator  
In this blinded, Phase 3 study, the comparator arm will consist of a chemotherapy doublet in 
combination with a matched placebo. In this study, a “matched” placebo will be used, which will 
contain the same composition as the solution for the active drug (tislelizumab), except that no 
active drug will be present in the formulation. A placebo is being used to preserve the scientific 
integrity of the study and reduce any potential observational or assessment bias. Patients in the 
placebo arm will still receive the recommended chemotherapy doublet for this patient population, 
minimizing the risk generally associated with placebo-alone arms in controlled studies.  
1.6. 
Benefit-Risk Assessment  
Patients with unresectable recurrent or metastatic ESCC represent a population with a great unmet 
medical need.  
Data from a Phase 1/2 clinical trial of nivolumab, a similar anti-PD-1 antibody, indicated an 
objective response of 22% (95% CI: 14% to 33%) that is durable, which suggests the potential 
efficacy of anti-PD-1 antibody for the treatment of patients with advanced ESCC (for additional 
discussion, see Section 1.1) (Kudo et al 2017). In a cohort of patients (n=49, 42 evaluable) with 
esophageal carcinoma treated with tislelizumab at 5 mg/kg in Phase 1b of Study 
BGB-A317_Study_001, PR was observed in 6 patients as of the 28 August 2017 data cut-off date.  
These patients had received a median of 2 prior lines of therapy. Responses were assessed after 
every 9 weeks on therapy. Confirmation of response required occurred at least 4 weeks after 
initial response assessment. Three of these patients had squamous cell carcinoma and 3 had 
adenocarcinoma. Twelve additional patients had confirmed a best response of SD. There were no 
CRs reported.  
More than 800 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) and in combination. The safety profile is consistent with known class effects of 
anti-PD-1 antibodies and included mostly mild/moderate AEs. Very few Grade 3/4 imAEs have 
been observed, and they have been generally reversible and manageable with study drug 
interruption and/or steroid treatment. For further discussion on safety profile of tislelizumab, 
please refer to the Investigator’s Brochure. 
Given the unmet medical need and limited treatment options in this indication, the benefit/risk 
assessment, based on available tislelizumab Phase 1 data and the publication from nivolumab and 
pembrolizumab, is considered favorable. To assess the potential benefit and safety of tislelizumab 
in combination with chemotherapy over chemotherapy alone, a randomized, blinded trial 
comparing tislelizumab to placebo will be conducted.   
An Independent Data Monitoring Committee (IDMC) will be established to regularly monitor the 
safety of tislelizumab when compared with placebo. An interim analysis for OS superiority test is 
planned in the study (Section 9.7). 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
• To evaluate and compare the overall survival (OS) following treatment with 
tislelizumab in combination with chemotherapy compared to placebo in combination 
with chemotherapy when given as first-line treatment in patients with unresectable, 
locally advanced recurrent or metastatic ESCC 
2.1.2. 
Secondary Objectives  
• To evaluate and compare the efficacy of tislelizumab in combination with 
chemotherapy compared to placebo in combination with chemotherapy as a first-line 
treatment in unresectable, locally advanced recurrent or metastatic ESCC as measured 
by PFS, ORR, and DOR assessed by the investigator per RECIST v1.1 
• To evaluate and compare the efficacy of tislelizumab in combination with 
chemotherapy with the efficacy of placebo in combination with chemotherapy as a 
first-line treatment in unresectable, locally advanced recurrent or metastatic ESCC as 
measured by OS in the PD-L1 visually estimated combined positive score (vCPS) ≥ 
10% subgroup. PD-L1 expression will be assessed centrally using the VENTANA 
PD‑L1 (SP263) assay. The vCPS is the total percentage of the tumor area covered by 
tumor cells with PD-L1 membrane staining and tumor‑associated immune cells with 
PD-L1 staining at any intensity 
• To evaluate and compare health-related quality of life (HRQoL) based on patient-
reported outcomes (PROs) between tislelizumab in combination with chemotherapy 
and placebo in combination with chemotherapy  
• To compare the safety between tislelizumab in combination with chemotherapy and 
placebo in combination with chemotherapy 
2.1.3. 
Exploratory Objectives  
• To characterize the DCR with tislelizumab in combination with chemotherapy 
assessed by the investigator per RECIST v1.1 
• To evaluate PFS, ORR, DOR, and DCR assessed by blinded independent review 
committee (BIRC) per RECIST v1.1 
• To assess PFS after next line of treatment (PFS2) 
• To evaluate the potential association of biomarkers with patient prognosis, response, or 
resistance to tislelizumab in combination with chemotherapy 
• To assess the pharmacokinetics of tislelizumab in combination with chemotherapy 
• To assess host immunogenicity to tislelizumab in combination with chemotherapy 
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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• OS - defined as the time from the date of randomization until the date of death due to 
any cause 
2.2.2. 
Secondary Endpoints  
• PFS - defined as the time from the date of randomization to the date of first 
documentation of disease progression assessed by the investigator per RECIST v1.1 or 
death, whichever occurs first 
• ORR - defined as the proportion of patients whose BOR is CR or PR assessed by the 
investigator per RECIST v1.1 
• OS in the PD-L1 vCPS ≥ 10% subgroup 
• HRQoL - defined as scores of the European EORTC QLQ-C30 (QLQ-C30), its 
esophageal cancer module - EORTC QLQ-OES18 (OES18), and the European Quality 
of Life 5-Dimension 5-Level (EQ-5D-5L) 
• DOR - defined as the time from the first determination of an objective response until 
the first documentation of progression assessed by the investigator per RECIST v1.1 or 
death, whichever comes first 
• The incidence and severity of adverse events according to NCI-CTCAE v4.03 
2.2.3. 
Exploratory Endpoints  
• DCR - defined as the proportion of patients whose BOR is CR, PR, and SD assessed by 
the investigator per RECIST v1.1 
• PFS, ORR, DOR, and DCR assessed by BIRC per RECIST v1.1 
• PFS2 - defined as the time from randomization to the objective disease progression after 
next line of treatment or death from any cause, whichever occurs first 
• To explore biomarkers in tumor tissues and/or blood samples before and after study 
treatment and/or at PD/reoccurrence, and the association between these biomarkers and 
clinical efficacy, disease status, and resistance. Biomarker assessment will consist of PD-
L1 expression, gene expression profiling (GEP), tumor mutation burden 
(TMB)/microsatellite instability (MSI)/mutation profile, and tumor-infiltrating immune 
cells. Other assessments may be conducted as allowed by local regulations. 
• Assessments of pharmacokinetics of tislelizumab when given with chemotherapy 
• Assessments of immunogenicity of tislelizumab by determining the incidence of antidrug 
antibodies (ADA) 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
The study design schematic is presented in Figure 1.  
Figure 1.  Study Schema 
Abbreviations: BIRC, blinded independent review committee; chemo, chemotherapy; DCR, disease control rate; DOR, duration of 
response; ESCC, esophageal squamous cell carcinoma; HRQoL, health-related quality of life; ICC, investigator choice of 
chemotherapy; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death protein ligand-1; PFS, 
progression-free survival; PFS2, PFS after next line of treatment; vCPS, visually estimated combined positive score.  
The IDMC convened on 20 April 2022 to review the efficacy and safety data of the preplanned 
interim analysis (data cutoff date of 28 February 2022, with 422 death events which corresponds 
to 86.5% of the number of total planned death events for the final analysis [488 planned death 
events]). After reviewing the data, the IDMC confirmed that the study met the specified 1-sided 
p-value boundary for superiority of the primary endpoint and recommended to unblind/unmask 
the study due to compelling efficacy. Based on the IDMC recommendation, a decision was made 
to unblind all patients, and inform all investigators and IRB/IEC as required. Patients randomized 
to Arm B were to discontinue placebo after unblinding.  
For all study procedures see Section 7 and Appendix 1. 
Study Population: 
unresectable, locally 
advanced recurrent or 
metastatic ESCC 
Arm A 
Tislelizumab in 
combination with 
chemotherapy 
Screening 
• Treatment until disease 
progression, intolerable 
toxicity, or withdrawal for 
other reasons  
• Safety Follow-up & Survival 
Follow-up 
---------------------------------- 
Primary endpoint:  
• OS 
Secondary endpoints: 
• PFS, ORR, and DOR assessed 
by investigator 
• OS in the PD-L1 vCPS ≥ 10% 
subgroup 
• HRQoL 
• Adverse events  
Exploratory endpoints: 
• DCR 
• PFS, ORR, DOR, and DCR 
assessed by BIRC 
• PFS2 
• Correlation of biomarker 
results to response and/or 
resistance to treatment  
• Pharmacokinetics 
• Assessment of immunogenicity 
Arm B 
Placebo in combination 
with chemotherapy  
Randomization & 
Stratification: 
n=622 eligible patients 
• 1:1 randomization to 
tislelizumab+chemo or 
placebo+chemo  
Stratification  
• Geographic region 
(Asia [excluding Japan] 
vs Japan vs Rest of 
World) 
• Prior definitive therapy 
(yes vs no) 
• ICC (platinum/ 
fluoropyrimidine vs 
platinum/paclitaxel) 
 
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3.2. 
Screening Period  
Screening evaluations will be performed within 28 days prior to randomization. Patients will sign 
the informed consent form (ICF) prior to undergoing any screening procedure. Patients who are 
suspected to have serious respiratory concurrent illness or exhibit significant respiratory 
symptoms unrelated to underlying cancer or with a history of thoracic radiotherapy will also take 
a pulmonary function test (refer to Section 7.1.4 and Appendix 1 for details). Screening 
evaluations may be repeated once within the screening period; the investigator is to assess 
preliminary patient eligibility according to the latest screening assessment results. 
Archival tumor tissue (formalin-fixed paraffin-embedded block or approximately 15 [at least 6] 
unstained slides) must be collected for purpose of biomarker analysis. If no archival samples are 
available, a fresh tumor biopsy at baseline is needed.  Refer to Section 7.7 for details. 
3.3. 
Treatment Period  
After completing all screening activities, eligible patients will be randomized in a 1:1 ratio to 
receive either tislelizumab in combination with a chemotherapy doublet or placebo with a 
chemotherapy doublet. Randomization will be stratified according to geographic region (Asia 
[excluding Japan] vs Japan vs Rest of World), prior definitive therapy (yes vs no), and 
investigator choice of chemotherapy (platinum with fluoropyrimidine vs platinum with paclitaxel; 
see Section 5.2).  
Patients will receive blinded treatment with one of the following: 
Tislelizumab 200 mg IV Q3W in combination with chemotherapy doublet until disease 
progression assessed by the investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of 
informed consent, whichever should occur first 
Placebo IV Q3W in combination with a chemotherapy doublet until disease progression assessed 
by the investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of informed consent, 
whichever should occur first 
Platinum therapy may be stopped after 6 cycles, per site or investigator preference or standard 
practice. If platinum treatment is stopped, the non-platinum agent (fluoropyrimidine or paclitaxel) 
may continue at the regular schedule, if appropriate. In both arms, treatment beyond the initial 
investigator-assessed, RECIST v1.1-defined disease progression is permitted provided that the 
patient a) has investigator-assessed clinical benefit and b) is tolerating study drug.  Specific 
requirements for post-progression continuation of patients treated with tislelizumab (or placebo) 
and chemotherapy are described in Section 3.6.1. 
Radiological assessment of tumor-response status will be performed every 6 weeks (± 7 days) for 
the first 48 weeks, then every 9 weeks (± 7 days) after 48 weeks, based on RECIST v1.1. Tumor 
response will be assessed by BIRC and by investigators. Details are provided in Section 7.5. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] 
v4.03), and laboratory results. Vital signs, physical examinations, Eastern Cooperative Oncology 
Group (ECOG) performance status change, electrocardiogram (ECG) results, and other 
examinations will also be used for safety assessment. Safety assessments are further detailed in 
Section 7.4 and the Schedule of Assessments (Appendix 1). 
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When a patient reaches 24 months of treatment (as measured from Cycle 1 Day 1): 
Patients may continue study therapy beyond 2 years if the investigator considers this to be in the 
best interest of the patient based on an assessment of clinical benefit and potential risks. 
Continuation of study therapy beyond 2 years has to be explicitly approved by the sponsor, and 
will be contingent on the continued availability of study treatment. The study assessment and 
procedures schedule will remain the same. 
After 2 years of study treatment, if patients have confirmed CR, PR, or SD, the treatment can be 
stopped if the patient wishes. The decision should be based on the investigator’s evaluation, with 
the patient’s clinical benefit and risk taken into consideration. A treatment-interruption informed 
consent form must be signed by patients who stop treatment. The investigator should notify the 
sponsor that treatment will be stopped prior to the event. In such a case, the study assessments and 
procedures will be performed every 12 weeks (in conjunction with repeat radiographic imaging, 
as described in Section 7.5) rather than every cycle. 
 
 
 
Blood samples of approximately 10 mL will be taken at baseline (predose on Day 1 of Cycle 1) 
for all randomized patients to explore the association of blood-based biomarkers with response 
and prognosis to tislelizumab in combination with chemotherapy or chemotherapy alone. Written 
patient consent is required for blood sample collections. 
3.4. 
End of Treatment/Safety Follow-up  
The End-of-Treatment (EOT) Visit and Safety Follow-up Visit may be a combined visit. The 
EOT/Safety Follow-up is conducted when the investigator determines that tislelizumab or placebo 
with chemotherapy will no longer be used. If routine laboratory tests (eg, hematology, serum 
chemistry) are completed within 7 days before the EOT/Safety Follow-up visit, these tests need 
not be repeated. Tumor assessment is not required at the EOT/Safety Follow-up Visit provided 
that fewer than 6 weeks have passed since the last assessment. 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
EOT/Safety Follow-up Visit (to occur within 30 days [± 7 days] after the last dose of study 
treatment (including chemotherapy), or before the initiation of a new anticancer treatment, or 
before the first dose administration in the long-term extension/posttrial supply study for patients 
who are going to rollover to those studies, whichever occurs first.  In addition, telephone contacts 
with patients should be conducted to assess imAEs and concomitant medications (if appropriate, 
ie, associated with an imAE or is a new anticancer therapy) at 60 and 90 days (± 14 days) after the 
last dose of study drug (including chemotherapy), regardless of whether the patient starts a new 
anticancer therapy. If patients report 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 study treatment prior to disease progression will have their tumors 
assessed as outlined in Section 7.5. 
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Patients receiving paclitaxel will need to be followed for safety and pregnancy for 180 days 
following the last dose. 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visit. 
3.5. 
Survival Follow-up  
Patients who discontinue study drug for reasons other than documented radiographic disease 
progression (eg, toxicity) will continue to undergo tumor assessments according to Section 7.5 
and the Schedule of Assessments (Appendix 1), until the patient experiences radiographic disease 
progression, withdraws consent, is lost to follow-up, or dies, or until the study completes, 
whichever occurs first.  
Patients will be followed for survival, and further anticancer therapy information after 
discontinuation of study treatment via telephone calls, patient medical records, and/or clinic visits 
at least every 3 months (± 14 days) or more frequently to ensure data collection feasibility after 
the 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 (Section 3.7). Confirmed loss to follow-up is 
defined as ≥ 3 consecutive failures of contacting attempts, any 2 of which are ≥ 1 month apart, via 
≥ 2 different documented methods. At the time of site closure, one additional final attempt of 
contacting patients lost to follow-up should be made and documented for confirming the loss to 
follow-up. 
3.6. 
Discontinuation From the Study Treatment or From the Study  
3.6.1. 
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 the study treatment at any time. Patients 
who discontinue study treatment for reasons other than radiographic disease progression as 
documented by BIRC should be followed for assessments of antitumor activity (Section 7.5), 
safety (Section 7.4), and survival (Section 3.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients must discontinue study treatment for 
reasons which include, but are not limited to, the following:  
• Withdrawal by patient from study treatment (survival/PFS2 data can still be collected and 
biospecimens analyzed beyond that date) 
• 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 antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal medicine 
and Chinese patent medicines] for the treatment of cancer) 
• Patient noncompliance  
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Patients will be permitted to continue study drug(s) if pseudoprogression is suspected and/or there 
is a reasonable belief that the patient could derive benefit from study drug(s) after RECIST v1.1 
criteria for progressive disease are met, and if they meet all of the following criteria:  
• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values)  
• Stable ECOG performance status ≤ 1 
• Absence of rapid progression of disease 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 beyond radiologic 
disease progression and inform patients that this practice is not considered standard in the 
treatment of cancer  
The decision to continue study drug(s) beyond initial investigator-assessed progression must be 
discussed with the sponsor’s medical monitor and documented in the study records. Tumor 
assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression. Tumor assessment in these patients should continue until study 
treatment discontinuation.  
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
Patients may discontinue study for reasons which include, but are not limited to, the following: 
• Withdrawal by patient from study (no further data can be collected but biospecimens 
collected before that date can still be analyzed) 
• Death 
• Lost to follow up 
• Patients have completed all study assessments 
3.7. 
End of Study  
The end of study is defined as the timepoint when the final data for a clinical study have been 
collected, which is after the last patient has made the final visit to the study location. 
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 
• A rollover study becomes available 
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/Safety Follow-up Visit. 
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At the end of the study, any patient who, in the opinion of the investigator, continues to benefit 
from tislelizumab, will be offered the option to continue treatment in a company-sponsored 
rollover study or post-study drug supply program until tislelizumab is commercially available in 
the country of the patient’s residence. 
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. 
The sponsor has the right to close a site at any time. The decision will be notified 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  
• Noncompliance with Good Clinical Practice (GCP), applicable laws and regulations 
• Study activity is completed (ie, all patients have completed and all obligations have 
been fulfilled) 
3.8. 
Enrollment of Japanese Patients  
The safety of study treatment will be closely monitored in all patients throughout the course of the 
clinical study. Enrollment of Japanese patients will be gated to monitor for unexpected or new 
safety concerns. The safety cohort of approximately 10 Japanese patients (minimum of 5 per arm) 
will be treated and closely monitored during a 7-day hospitalization, according to local practice. 
Following discharge from this initial hospitalization, patients will be monitored with weekly 
assessments for safety, as detailed in Appendix 1 (Schedule of Assessments). The Sponsor 
unblinded Drug Safety and Pharmacovigilance group will review unblinded SAE reports, and the 
IDMC will review all safety data after this safety cohort of Japanese patients completes 1 cycle, or 
at any time there is a safety concern. DLT is defined in the IDMC charter and the occurrence of 
DLTs in patients who receive tislelizumab in combination with cisplatin and 5-FU will be 
assessed independently by the IDMC. During the IDMC review, enrollment in Japan will be held 
until the IDMC review is complete and the safety and tolerability is deemed acceptable.   
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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. Appendix 13 contains a flow chart to help determine which patients are appropriate for this 
study. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all of 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. Pathologically (histologically) confirmed diagnosis of ESCC  
Note: Patients with adenocarcinoma differentiation < 5% of the viable tumor sample are 
eligible 
4. Stage IV unresectable ESCC at first diagnosis OR unresectable, locally advanced recurrent 
or metastatic disease (per AJCC 7th Edition, Appendix 14), if there is prior 
neoadjuvant/adjuvant therapy with platinum-based chemotherapy, a treatment-free interval 
of at least 6 months is required 
5. Measurable or evaluable disease as defined per RECIST v1.1 
Note: The target lesion(s) selected that are within the field of prior local therapy have 
subsequently progressed as defined by RECIST v1.1 
6. ECOG Performance Status ≤ 1 
7. Adequate organ function as indicated by the following laboratory values ≤ 14 days prior to 
randomization. 
a. Patients must have the following laboratory values: 
i. 
Absolute neutrophil count ≥ 1.5 x 109/L 
ii. 
Platelets ≥ 100 x 109/L 
iii. 
Hemoglobin ≥ 90 g/L 
NOTE: Patients must not have required a transfusion or growth factor support ≤ 14 days 
before sample collection for neutrophil counts, platelets, or hemoglobin that were lower 
than required for the study.  
b. Serum creatinine ≤ 1.5 mg/100 mL (equivalent 130 µmol/L).   
c. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin must be 
< 3 x ULN for patients with Gilberts syndrome).  
d. AST and ALT ≤ 3 x ULN, or AST and ALT ≤ 5 x ULN for patients with liver 
metastases 
8. Have newly obtained or archival tissue sample available for biomarker assessment.  
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9. Females of childbearing potential must be willing to use a highly effective method of birth 
control for the duration of the study (in accordance with the Contraception Guidelines in 
Appendix 9), ≥ 120 days after the last dose of tislelizumab, and ≥ 180 days after the last 
dose of chemotherapy, and have a negative serum pregnancy test ≤ 7 days of 
randomization   
10. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study, ≥ 120 days after the last dose of tislelizumab, and for ≥ 180 days 
after the last dose of chemotherapy 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria must be excluded from this study: 
1. Ineligible for treatment with any of the chemotherapy doublets of protocol-specified 
chemotherapy 
2. Prior systemic therapy for unresectable, locally advanced recurrent or metastatic ESCC 
Note: Patients with prior systemic concurrent chemotherapy in concurrent 
chemoradiotherapy are eligible  
3. Palliative radiation treatment for ESCC within 4 weeks of study treatment initiation 
4. Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta)  
5. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage 
or medical intervention (clinically significant recurrence requiring an additional 
intervention within 2 weeks of intervention) 
6. Evidence of complete esophageal obstruction not amenable to treatment 
7. Received prior therapies targeting PD-1, PD-L1, or PD-L2 
8. Active leptomeningeal disease or uncontrolled brain metastasis. 
a. Patients with a history of treated and, at the time of screening, stable central nervous 
system (CNS) metastases are eligible, provided they meet all the following: 
i. 
Brain imaging at screening shows no evidence of interim progression, clinically 
stable for at least 2 weeks and have no evidence of new brain metastases 
ii. 
Have measurable and/or evaluable disease outside the CNS 
iii. 
No ongoing requirement for corticosteroids as therapy for CNS disease; off 
steroids 3 days prior to randomization; anticonvulsants at a stable dose are 
allowed 
iv. 
No stereotactic radiation or whole-brain radiation within 14 days prior to 
randomization 
b. Deleted 
i. 
Deleted 
9. Active autoimmune diseases or history of autoimmune diseases that may relapse.   
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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 is not expected to recur in the absence of external triggering 
factors 
10. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurrent 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) 
11. Any condition that required 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) 
12. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc. 
13. With infections (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal or antiviral therapy within 14 days prior to randomization. Note: antiviral 
therapy is permitted for patients with chronic hepatitis B virus (HBV) or hepatitis C virus 
(HCV) infection. 
14. A known history of HIV infection  
15. Any major surgical procedure requiring general anesthesia ≤ 28 days before randomization 
16. Prior allogeneic stem cell transplantation or organ transplantation 
17. 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 
d. Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 6) ≤ 6 months before randomization 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization  
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f. Any history of cerebrovascular accident ≤ 6 months before randomization 
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before randomization 
h. Any episode of syncope or seizure ≤ 28 days before randomization 
18. A history of severe hypersensitivity reactions to other monoclonal antibodies 
19. Has received any Chinese herbal medicine or Chinese patent medicines used to control 
cancer within 14 days of the first study drug administration  
20. Was administered a live vaccine ≤ 4 weeks before randomization 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
21. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug or affect 
the explanation of drug toxicity or AEs or might impair compliance with study conduct. 
22. Concurrent participation in another therapeutic clinical trial 
23. Unintentional weight loss ≥ 5% within one month prior to randomization or Nutritional 
Risk Index (NRI) < 83.5 (Appendix 15) per investigator’s choice 
24. Pregnant or breastfeeding woman 
25. Patients receiving chemotherapy doublet C (platinum and paclitaxel) must not have 
peripheral neuropathy ≥ Grade 2 at baseline 
26. With 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. 
27. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, 
etc) or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of 
the first study drug administration 
28. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia 
and specific laboratory abnormalities)  
29. Locally advanced esophageal carcinoma that is resectable or potentially curable with 
radiation therapy per local investigator. 
30. Patients with untreated chronic hepatitis B or chronic HBV carriers whose HBV DNA is ≥ 
500 IU/mL or patients with active hepatitis C virus (HCV) 
Note: Patients who are inactive carriers or with treated and stable hepatitis B (detectable B 
surface antigen (HBsAg), HBV DNA < 500 IU/mL) and patients with non-active hepatitis 
C can be enrolled. Management of prophylaxis antiviral therapy should be as per local 
guidelines.  
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial (20R glass, 
United States Pharmacopeia [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 label will include at a minimum, the drug name, dose strength, contents, sponsor, protocol 
number, kit number, batch/lot number, directions for use, storage conditions, caution statements, 
retest or expiry date, and space to enter the patient number and name of the investigator. The 
contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. Tislelizumab 
must be stored at temperatures between 2ºC and 8ºC and protected from light.   
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal. Please also refer to the Investigator’s Brochure for other details regarding tislelizumab. 
5.1.2. 
Matched Placebo  
All personnel at the study sites and all patients and the Sponsor will be blinded to study treatment. 
Matched placebo will be provided in a single-use vial (20R glass, USP type I), containing 10 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 label will include at a minimum, sponsor, protocol number, kit number, batch/lot number, 
directions for use, storage conditions, caution statements, retest or expiry date, and space to enter 
the patient number and name of the investigator. The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
The vials must be kept at the temperature condition as specified on the label. Vials must be stored 
at temperatures between 2ºC and 8oC and protected from light.   
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal.   
5.1.3. 
Cisplatin  
Cisplatin will be supplied in vials for infusion; however, the actual appearance and composition of 
the product may depend on the respective marketed product sourced for the participating countries  
For cisplatin supplied by sponsor or its designee, the label will include at a minimum, the drug 
name, dose strength, contents, sponsor, protocol number, kit number, lot number, directions for 
use, storage conditions, caution statements, retest or expiry date, and space to enter the patient 
number and name of investigator. The contents of the label will be in accordance with all 
applicable local regulatory requirements. 
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The study drug must be kept at the temperature condition as specified on the label. If diluted 
solution is not to be used within 6 hours, protect solution from light. 
For further details, see the manufacturer’s prescribing information for cisplatin. 
5.1.4. 
Oxaliplatin  
Oxaliplatin will be supplied in vials for infusion; however, the actual appearance and composition 
of the product may depend on the respective marketed product sourced for the participating 
countries.  
For oxaliplatin supplied by sponsor or its designee, the label will include at a minimum, the drug 
name, dose strength, contents, sponsor, protocol number, kit number, lot number, directions for 
use, storage conditions, caution statements, retest or expiry date, and space to enter the patient 
number and name of investigator. The contents of the label will be in accordance with all 
applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
For further details, see the manufacturer’s prescribing information for oxaliplatin. 
5.1.5. 
5-Fluorouracil  
5-FU will be supplied in vials for infusion; however, the actual appearance and composition of the 
product may depend on the respective marketed product sourced for the participating countries. 
For 5-FU supplied by sponsor or its designee, the label will include at a minimum, the drug name, 
dose strength, contents, sponsor, protocol number, kit number, lot number, directions for use, 
storage conditions, caution statements, retest or expiry date, and space to enter the patient number 
and name of investigator. The contents of the label will be in accordance with all applicable local 
regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
For further details, see the manufacturer’s prescribing information for 5-FU. 
5.1.6. 
Capecitabine  
Capecitabine will be supplied as tablets; however, the actual appearance and composition of the 
product may depend on the respective marketed product sourced for the participating countries.  
For capecitabine supplied by sponsor or its designee, the label will include at a minimum, the drug 
name, dose strength, contents, sponsor, protocol number, kit number, lot number, directions for 
use, storage conditions, caution statements, retest or expiry date, and space to enter the patient 
number and name of investigator. The contents of the label will be in accordance with all 
applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
For further details, see the manufacturer’s prescribing information for capecitabine. 
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5.1.7. 
Paclitaxel  
Paclitaxel will be supplied in vials for infusion; however, the actual appearance and composition 
of the product may depend on the respective marketed product sourced for the participating 
countries.  
For paclitaxel supplied by sponsor or its designee, the label will include at a minimum, the drug 
name, dose strength, contents, sponsor, protocol number, kit number, lot number, directions for 
use, storage conditions, caution statements, retest or expiry date, and space to enter the patient 
number and name of investigator. The contents of the label will be in accordance with all 
applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
For further details, see the manufacturer’s prescribing information for paclitaxel. 
5.2. 
Dosage, Administration, and Compliance  
Dosing schedules for both arms, broken out by individual arm, are provided in Table 2. One 
treatment cycle is 21 days in length. 
Table 2.  Selection and Timing of Dose for Each Patient 
Intervention 
Drug 
Dose 
Study 
Day(s) 
Frequency of 
Administration 
Route of 
Administration 
Study Drug 
Tislelizumab 
(BGB-A317) 
200 mg 
1 
Q3W 
Intravenous 
Matched Placebo 
None 
N/A 
1 
Q3W 
Intravenous 
Chemotherapy 
Doublet A*** 
Cisplatin OR 
Oxaliplatin* 
60-80 mg/m2 (cisplatin) 
130 mg/m2 (oxaliplatin) 
1 
Q3W 
Intravenous 
5-Fluorouracil 
750-800 mg/m2 
1-5 
Q3W 
Intravenous 
Chemotherapy 
Doublet B*** 
Cisplatin OR 
Oxaliplatin* 
60-80 mg/m2 (cisplatin) 
130 mg/m2 (oxaliplatin) 
1 
Q3W 
Intravenous 
Capecitabine 
1000 mg/m2 
1-14 
Twice a day 
Oral 
Chemotherapy 
Doublet C*** 
Cisplatin OR 
Oxaliplatin* 
60-80 mg/m2 (cisplatin) 
130 mg/m2 (oxaliplatin) 
1 or 2** 
Q3W 
Intravenous 
Paclitaxel 
175 mg/m2 
1 
Q3W 
Intravenous 
Abbreviations: 5-FU, 5-fluorouracil; N/A, not applicable; Q3W, every 3 weeks.  
Note: 
Platinum therapy may be stopped after 6 cycles, per site or investigator preference or standard practice. If 
platinum treatment is stopped, the non-platinum agent (fluoropyrimidine or paclitaxel) may continue at the 
regular schedule. 
* 
The platinum agent may be cisplatin or oxaliplatin (except in China, Taiwan, Japan, and countries where 
oxaliplatin substitution is not permitted) according to site or investigator preference or standard practice as 
determined prior to randomization. 
** For Chemotherapy Doublet C, cisplatin may be administered on Days 1 or 2, or in 3 divided doses on Days 1, 2, 
and 3 depending on local guidelines. The total dose given must be between 60 to 80 mg/m2 per cycle. 
*** For sites where the sponsor is required to provide these products will either be supplied or reimbursed by the 
sponsor or designee. These products may be obtained by the investigational sites as local commercial products in 
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All regimens in Arm A will contain tislelizumab in combination with 1 of the 3 listed 
chemotherapy doublets. All of the regimens in Arm B will contain matched placebo in 
combination with 1 of the 3 listed chemotherapy doublets. The first dose of study drug is to be 
administered within 2 business days of randomization. Tislelizumab/placebo will be administered 
first, followed by at least a 30-minute observation period for safety surveillance, then the 
chemotherapy doublet will be administered. The chemotherapy doublet may be administered 
without regard to the sequence of chemotherapy or according to local standard treatment practices 
and guidelines. (note that in Chemotherapy Doublet B, capecitabine is given orally daily). All 
patients will be monitored continuously for AEs. Treatment modifications (eg, dose delay, 
reduction, interruption or discontinuation) will be based on specific laboratory and adverse event 
criteria, and the investigator’s clinical assessment as described in Section 5.5. 
Alternate dose and dosing schedules are allowed according to local and institutional guidelines. 
According to clinical practice in Japan, only the cisplatin + 5-FU chemotherapy regimen will be 
used in Japan. 
5.2.1. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle Q3W.  
Tislelizumab will be administered by IV infusion through an IV line containing a sterile, 
non-pyrogenic, 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. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 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 initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion. Tislelizumab must not be concurrently administered with any 
other drug (refer to Section 6). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 7.  
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.2. 
Matched Placebo  
All personnel at the study sites and all patients and the Sponsor will be blinded to study treatment. 
Administration of matched placebo will follow the guidance given for tislelizumab, as described 
in Section 5.2.1 above. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
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5.2.3. 
Chemotherapy Doublet A: Platinum (Cisplatin or Oxaliplatin) in Combination 
with 5-Fluorouracil  
After all procedures/assessments have been completed as detailed in Appendix 1 and Section 3.2. 
Cisplatin will be administered on Day 1, given Q3W at a dose of 60 to 80 mg/m2 by IV infusion 
over 6 to 8 hours (or in doses consistent with local or country-specific treatment guidelines, or 
according to manufacturer standards or institutional standards). Oxaliplatin 130 mg/m2 IV on Day 
1 Q3W, given over 2 hours may be substituted in place of cisplatin, according to site or 
investigator preference or standard practice as determined prior to randomization (except in 
China, Taiwan, Japan, and countries where oxaliplatin substitution is not permitted). Also, 5-FU 
will be administered on Days 1 to 5, given Q3W at a dose of 750 to 800 mg/m2 by continuous IV 
infusion over 24 hours. The actual infusion time of 5-FU should be recorded, and a total infusion 
time of 120+/- 3 hours is acceptable. The initial treatment of platinum (cisplatin or oxaliplatin) in 
combination with 5-FU will be administered within 2 business days of randomization. Alternate 
dose and dosing schedules are allowed according to local and institutional guidelines.  
The first doses of platinum and 5-FU are dependent upon the patient’s baseline body weight. 
Subsequent doses must be recalculated if the change of body weight from baseline ≥ 10%. 
Subsequent doses should not be recalculated if the change (increase or decrease) of body weight 
from baseline < 10% unless there is persistent toxicity that requires dose adjustment. If the dose is 
recalculated because of a ≥ 10% change in body weight from baseline, this body weight will then 
be used as the new baseline to calculate the platinum and 5-FU dose in subsequent cycles. 
Premedication is recommended prior to infusion of cisplatin according to the manufacturer’s 
instructions. The premedication regimen should be determined by the investigator and 
administered as close to treatment as possible. Premedication may consist of hydration with 1 to 2 
liters of fluid infused 8 to 12 hours prior to dosing. The use of diuretics for fluid maintenance is 
allowable. 
There is a 3-day window for all treatments in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), the 
subsequent dosing visit should be scheduled as clinically appropriate.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of therapy. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.4. 
Chemotherapy Doublet B: Platinum (Cisplatin or Oxaliplatin) in Combination 
with Capecitabine  
After all procedures/assessments have been completed as detailed in Appendix 1 and Section 3.2, 
cisplatin will be administered on Day 1, given every 21 days at a dose of 60 to 80 mg/m2 by IV 
infusion over 6 to 8 hours (or in doses consistent with local or country-specific treatment 
guidelines, or according to manufacturer standards or institutional standards). Oxaliplatin 130 
mg/m2 IV on Day 1 Q3W, given over 2 hours may be substituted in place of cisplatin, according 
to site or investigator preference or standard practice as determined prior to randomization (except 
in China, Taiwan, Japan, and countries where oxaliplatin substitution is not permitted). 
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Capecitabine will be self-administered orally twice daily, from the morning of Day 1 to the 
evening of Day 14 or from the evening of Day 1 to the morning of Day 15 of each 21-day cycle at 
the recommended dose of 1000 mg/m2 twice daily (BID). The initial treatment of cisplatin in 
combination with capecitabine will be administered within 2 business days of randomization. 
Alternate dose and dosing schedules are allowed according to local and institutional guidelines. 
The first doses of platinum and capecitabine are dependent upon the patient’s baseline body 
weight. Subsequent doses must be recalculated if the change of body weight (increase or decrease) 
from baseline ≥ 10%. Subsequent doses should not be recalculated if the change (increase or 
decrease) of body weight from baseline < 10% unless the emergence of toxicity requires dose 
adjustment. If the dose is recalculated because of a ≥ 10% change in body weight from baseline, 
this body weight will then be used as the new baseline to calculate the platinum and capecitabine 
dose in subsequent cycles.  
Premedication is recommended prior to infusion of cisplatin according to the manufacturer’s 
instructions. The premedication regimen should be determined by the investigator and 
administered as close to treatment as possible. Premedication may consist of hydration with 1 to 2 
liters of fluid infused 8 to 12 hours prior to dosing. Urinary output must be maintained according 
to local or institutional standards of care when administering cisplatin treatment. 
An adequate amount of supply of capecitabine will be dispensed to patients on Day 1 of each new 
cycle (Q3W). Each time study drug is dispensed, compliance will be evaluated and encouraged. 
Treatment compliance will also be monitored by drug accountability and recorded in the patient’s 
medical record and eCRF. If the number of capsules returned does not agree with the expected 
number, the patient should be counseled, and proper dosing reinforced. Capecitabine should be 
taken with water, within 30 minutes after a meal. Urinary output should be maintained according 
to local or institutional standards of care. If a dose of capecitabine is missed, the patient should 
take the next dose as scheduled. A double dose of capecitabine should not be administered to 
make up for missed individual doses. Refer to the capecitabine prescribing information for 
additional details. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of therapy.   
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.5. 
Chemotherapy Doublet C: Platinum (Cisplatin or Oxaliplatin) in Combination 
with Paclitaxel  
After all procedures/assessments have been completed as detailed in Appendix 1 and Section 3.2, 
cisplatin will be administered on Day 1 or 2, given every 21 days at a dose of 60 to 80 mg/m2 by 
IV infusion over 6 to 8 hours (or in doses consistent with local or country-specific treatment 
guidelines, or according to manufacturer standards or institutional standards). Oxaliplatin 130 
mg/m2 IV on Day 1 Q3W, given over 2 hours may be substituted in place of cisplatin, according 
to site or investigator preference or standard practice as determined prior to randomization (except 
in China, Taiwan, Japan, and countries where oxaliplatin substitution is not permitted). Depending 
on local guidelines, cisplatin may be given in 3 divided doses on Days 1, 2, and 3. The total dose 
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given must be between 60 to 80 mg/m2 per cycle. Also, paclitaxel will be administered on Day 1, 
given Q3W at a dose of 175 mg/mg2 by IV infusion over 3 hours. The initial treatment of 
platinum (cisplatin or oxaliplatin) in combination with paclitaxel will be administered within 2 
business days of randomization. Alternate dose and dosing schedules are allowed according to 
local and institutional guidelines. 
The first doses of platinum and paclitaxel are dependent upon the patient’s baseline body weight 
(increase or decrease) from baseline ≥ 10%. Subsequent doses should not be recalculated if the 
change (increase or decrease) of body weight from baseline < 10%. If the dose is recalculated 
because of a ≥ 10% change in body weight from baseline, this body weight will then be used as 
the new baseline to calculate the platinum and paclitaxel dose in subsequent cycles.  
Premedication is recommended prior to infusion of cisplatin according to the manufacturer’s 
instructions. The premedication regimen should be determined by the investigator and 
administered as close to treatment as possible. Premedication may consist of hydration with 1 to 2 
liters of fluid infused 8 to 12 hours prior to dosing.  
Premedication is recommended prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards. The premedication regimen should be determined by the 
investigator and administered as close to treatment as possible. Premedication may consist of an 
oral steroid (such as dexamethasone 8 to 20 mg or equivalent administered 6 to 12 hours orally or 
30 to 60 minutes IV before paclitaxel), an antihistamine (H1 antagonist) such as diphenhydramine 
hydrochloride 50 mg IV or equivalent or H2 antagonist, such as cimetidine 300 mg IV or 
equivalent), and an antiemetic (such as ondansetron 8 mg/kg IV or equivalent administered 30 to 
120 minutes before paclitaxel). Premedication may be provided per local guidance and all 
medications will be documented on the CRF.  
There is a 3-day window for all treatments in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), the 
subsequent dosing visit should be scheduled as clinically appropriate.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs.  Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of therapy.  Patients receiving paclitaxel will need to 
be followed for safety and pregnancy for 180 days following the last dose. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Overdose  
Any overdose of tislelizumab (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or 
incorrect administration of study drug should be noted in the patient’s chart and on the appropriate 
eCRF. For chemotherapy, doses >20% of targeted total dose specified in this protocol represent an 
overdose, and the Sponsor should be notified as soon as possible. AEs associated with an 
overdose or incorrect administration of study drug will be recorded on the AE eCRF. Any SAEs 
associated with an overdose or incorrect administration are required to be reported within 24 
hours of awareness via SAE reporting process as described in Section 8.6. Supportive care 
measures should be administered as appropriate. 
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5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study (tislelizumab 
[or placebo]) will be provided by the sponsor, as required by local or country-specific guidance. 
The investigational site will acknowledge receipt of IMPs. Any damaged shipments will be 
replaced.  
Accurate records of all IMP received, dispensed, returned, and disposed should be recorded on the 
site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management.  
5.5. 
Dose Delay or Modification  
A dose delay is a deviation from prescribed dosing schedule (ie, the drug is withheld beyond visit 
window). A dose interruption is an interruption of the intravenous infusion. 
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on the 
guidelines provided below. Reasons for dose modifications or delays, the supportive measures 
taken, and the outcome will be documented in the patient's chart and recorded in the eCRF. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay or modify doses in response to other reasons (eg, AEs, 
declining weight, lab findings, etc.) as appropriate. 
In case of chemotherapy-related toxicity, chemotherapy will be delayed until it resolves to 
baseline or ≤ Grade 1 (whichever is more severe) prior to administering the next dose of 
chemotherapy, with the exception of alopecia, Grade 2 fatigue, or other AEs which, in the opinion 
of the investigator, would not affect the safety evaluation of the study drugs. Tislelizumab or 
placebo should continue as scheduled. If the AE resolves within 10 days, chemotherapy will be 
administered. The administration of chemotherapy and tislelizumab or placebo will be 
resynchronized at the subsequent cycle, which will be scheduled according to the chemotherapy 
dose administration date. If the AE does not resolve within 10 days, chemotherapy will be 
omitted. If the AE resolves within 21 days, chemotherapy and tislelizumab or placebo will be 
administered on Day 1 of the next treatment cycle according to the original schedule.  
In case of tislelizumab or placebo-related toxicity, tislelizumab or placebo will be delayed until it 
resolves to baseline or ≤ Grade 1 (whichever is more severe) prior to administering the next dose 
of tislelizumab or placebo, with the exception of alopecia, Grade 2 fatigue, or other AEs which, in 
the opinion of the investigator, would not affect the safety evaluation of the study drugs. 
Chemotherapy should continue as scheduled. If the AE is resolves within 10 days, tislelizumab or 
placebo will be administered. The administration of chemotherapy and tislelizumab or placebo 
will be resynchronized at the subsequent cycle, which will be scheduled according to the 
chemotherapy dose administration date. If the AE does not resolve within 10 days, tislelizumab or 
placebo should not be given for the current cycle. If the AE resolves within 21 days, tislelizumab 
or placebo and chemotherapy will be administered on Day 1 of the next treatment cycle according 
to the original schedule. 
In case of both tislelizumab/placebo and chemotherapy toxicity, treatment in any patient may be 
temporarily held if the toxicity is considered to be related to tislelizumab or placebo and 
chemotherapy. If the administration delay is ≤ 10 days for any delayed drug, the delayed drug will 
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be administered; if the delay is >10 days, the delayed drug will be omitted in this cycle and the 
next cycle will be administered as planned as long as the AE resolves within 21 days. Other study 
drug (tislelizumab or placebo) delay principles will be the same with that in Section 5.5.1; Other 
chemotherapy delay principles will be the same with that in Section 5.5.2. 
5.5.1. 
Dose Delay or Modification for Tislelizumab/Placebo  
There will be no dose reduction for tislelizumab/placebo in this study.  
Dose delays < 12 weeks will be permitted. Investigators should make every effort to maintain 
dose intensity in patients.  
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to tislelizumab or placebo and requires a dose to be withheld. If the administration delay is 
≤ 10 days, the delayed drug will be administered; if the delay is > 10 days, the delayed drug will 
be omitted in this cycle and the next cycle will be administered as planned as long as the AE 
resolves within 21 days. If the study drug (tislelizumab or placebo) delay is > 12 weeks, it will be 
stopped permanently. 
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. 
Dose modification related to imAEs and infusion-related reactions are described in Appendix 7 
and Section 8.7.1, respectively.   
5.5.2. 
Dose Delay, Interruption, or Modifications for Chemotherapy  
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. 
Dose level adjustments are relative to that of the preceding administration. Study drug related 
toxicities must be resolved to baseline or Grade 0 to 1 prior to administering the next dose, with 
the exception of alopecia or Grade 2 fatigue or other stable AEs that are assessed by the 
investigator as neither unfavorable to patients’ safety nor influential to the safety evaluation of the 
study drug(s). A maximum of 2 dose reductions for each chemotherapeutic agent are permitted. If 
additional reductions are required, that chemotherapeutic agent must be discontinued. Once the 
dose has been decreased, it should remain reduced for all subsequent administrations or further 
reduced if necessary. There will be no dose escalations in this study. All subsequent 
chemotherapy doses must be rescheduled according to the last chemotherapy dose administration 
date. If any chemotherapy agent is held for more than 2 cycles (6 weeks) from the anticipated 
treatment date, or the dose level -2 is not tolerated, chemotherapy should be permanently 
discontinued. 
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Table 3: BGB-A317-306 Dose Reduction Level of Chemotherapy 
Drug Dose 
Level 1 (Standard level) 
(Every 3 weeks as a cycle) 
 Level-1 
Level-2 
Cisplatin 
60-80 mg/m2 
60 mg/m2 
40 mg/m2 
Oxaliplatin 
130 mg/m2 
100 mg/m2 
80 mg/m2 
5-FU 
750-800 mg/m2 
600 mg/m2 
400 mg/m2 
Capecitabine 
1000 mg/m2, twice daily (total 14 days) 
750 mg/m2 
500 mg/m2 
Paclitaxel 
175 mg/m2 
135 mg/m2 
90 mg/m2 
Dose Modifications for Cisplatin 
A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 
mL, and/or the blood urea nitrogen (BUN) is below 25 mg/100 mL. A repeat course should not be 
given until circulating blood elements are at an acceptable level (platelets ≥ 100 x 109 /L, white 
blood cell [WBC] ≥ 4 x 109 /L). Subsequent doses of cisplatin should not be given until an 
audiometric analysis indicates that auditory acuity is within normal limits. 
Adverse Event 
Recommended Cisplatin Dose 
Serum creatinine ≥ 1.5 mg/100 mL 
Hold treatment until serum creatinine 
< 1.5 mg/100 mL 
BUN ≥ 25 mg/100 mL 
Hold treatment until BUN < 25 mg/100mL 
Platelets < 100 x 109/L 
Hold treatment until platelets ≥ 100 x 109/L 
WBC < 4 x 109/L 
Hold treatment until WBC ≥ 4 x 109/L 
Auditory acuity by audiometric analysis out 
of range 
Hold treatment until auditory acuity is within 
normal limits 
Abbreviations: BUN, blood urea nitrogen; WBC, white blood cell 
Dose Modifications for Oxaliplatin 
Prolongation of infusion from 2 hours to 6 hours may mitigate acute toxicities.  
For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose 
reduction to 100 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory 
events, discontinuing therapy should be considered. The infusional 5-FU infusion regimen need 
not be altered. 
A dose reduction to 100 mg/m2 and infusional 5-FU to 300 mg/m2 bolus and 500 mg/m2 22-hour 
infusion is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite 
prophylactic treatment) or grade 4 neutropenia or Grade 3/4 thrombocytopenia. The next dose 
should be delayed until neutrophils are ≥ 1.5 x 109 /L and platelets are ≥ 75 x 109 /L. 
Adverse Event 
Recommended Oxaliplatin Dose 
Neutrophils < 1.5 x 109/L 
Hold treatment until neutrophils ≥ 1.5 x 109/L 
Platelets < 75 x 109/L 
Hold treatment until platelets ≥ 75 x 109/L 
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In patients with normal renal function or mild to moderate renal impairment, the recommended 
dose is 130 mg/m2. In patients with severe renal impairment, the initial recommended dose should 
be reduced to 100 mg/m2. 
Dose Modifications for 5-Fluorouracil 
5-FU dose modification scheme as described below is recommended for the management of 
adverse events. 
Adverse Event 
Recommended 5-Fluorouracil Dose 
Development of angina, myocardial 
infarction/ischemia, arrhythmia, or heart failure in 
patients with no history of coronary artery disease or 
myocardial dysfunction 
Hold treatment until resolution 
Hyperammonemic encephalopathy 
Hold treatment until resolution 
Acute cerebellar confusion, disorientation, ataxia, or 
visual disturbances 
Hold treatment until resolution 
Grade 3 or 4 diarrhea 
Hold treatment until resolution to 
Grade 2 or lower 
Grade 2 or 3 palmar-plantar erythrodysesthesia 
(hand-foot syndrome) 
Hold treatment until resolution to 
Grade 1 or lower 
Grade 3 or 4 mucositis 
Hold treatment until resolution to 
Grade 2 or lower 
Grade 4 myelosuppression 
Hold treatment until resolution to 
Grade 3 or lower 
Dose Modifications for Capecitabine 
Capecitabine dose modification scheme as described below is recommended for the management 
of adverse reactions.  
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Toxicity NCIC 
Grades* 
During a Course of Therapy 
Dose Adjustment for Next Treatment 
(% of starting dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
1st appearance 
Interrupt until resolved to Grade 0-1 
100% 
2nd appearance 
75% 
3rd appearance 
50% 
4th appearance 
Discontinue treatment permanently 
- 
Grade 3 
1st appearance 
Interrupt until resolved to Grade 0-1 
75% 
2nd appearance 
50% 
3rd appearance 
Discontinue treatment permanently 
- 
Grade 4 
1st appearance 
Discontinue permanently 
OR 
If physician deems it to be in the 
patient’s best interest to continue, 
interrupt until resolved to Grade 0-1 
50% 
*National Cancer Institute of Canada (NCIC) Common Toxicity Criteria were used except for the hand-and-foot 
syndrome. 
Dose Modifications for Paclitaxel 
Paclitaxel Dose Modifications for Decreased Neutrophils 
Absolute Neutrophil Count (x 109/L) 
Paclitaxel Dose 
≥ 1.500 (Grade 1) 
Dose Level 1 
1.000 – 1.499 (Grade 2) 
Hold paclitaxel until recovery to Grade 1 and restart 
paclitaxel at Dose Level -1.  
If no recovery within 3 weeks of planned next cycle, 
consider appropriateness for growth factor support or 
discontinue paclitaxel. 
0.500 – 0.999 (Grade 3) 
Hold paclitaxel until recovery to Grade 1 and restart 
paclitaxel at Dose Level -2.  
Initiate growth factor support 
If no recovery within 3 weeks of planned next cycle 
despite growth factor support, discontinue paclitaxel. 
< 0.500 (Grade 4) 
Initiate growth factor support 
If absolute neutrophil count < 0.500 for > 7 days 
despite growth factor support, discontinue paclitaxel 
If a patient experiences febrile neutropenia or ≥ Grade 2 infection at any time, granulocyte colony 
stimulating factor (G-CSF) should be added initially and in advance of any dose reduction for the 
next cycle of paclitaxel. In the event of a second episode of febrile neutropenia or ≥ Grade 2 
infection, paclitaxel should be dose reduced to the next lower level. For a third episode of febrile 
neutropenia or ≥ Grade 2 infection, paclitaxel should be discontinued. Any dose reductions for 
neutropenic fever are permanent. 
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Paclitaxel Dose Modifications for Decreased Platelet Counts 
Platelet Count (x 109/L) 
Paclitaxel Dose 
> 100 
Dose Level 1 
75 - 100 (Grade 1) 
Hold until recovery to a platelet count > 100 x 109/L 
Restart paclitaxel at Dose level 1 
50 - 74.999 (Grade 2) 
Hold until recovery to a platelet count > 100 x 109/L 
Restart paclitaxel at Dose Level -1 
< 50 (Grade 3)  
Hold until recovery to a platelet count > 100 x 109/L 
Restart paclitaxel at dose level -2 
< 25 (Grade 4) with 
clinically significant 
bleeding 
Discontinue paclitaxel 
For any grade toxicity, if the platelet count does not recover by the next planned treatment cycle, 
paclitaxel must be discontinued. 
Paclitaxel Dose Modifications for Neuropathy  
Neuropathy Grade 
Recommended Paclitaxel Dose 
Grade 1 
Dose Level 1 
Grade 2 lasting > 7 days or  
Grade 3 lasting < 7 days 
Hold until neuropathy recovery to Grade 1 
Restart paclitaxel at Dose Level -1 
Grade 3 lasting > 7 days or Grade 4  
Discontinue paclitaxel 
All dose reductions for neuropathy are permanent.  
Paclitaxel Dose Modification for Hepatic Impairment 
Degree of Hepatic Impairment 
Recommended Paclitaxel Dose 
Transaminase levels 
 
Bilirubin Levels 
< 10 x ULN 
And 
≤ 1.25 x ULN 
Continue dosing at Dose Level 1 
< 10 x ULN 
And 
1.26 - 2.0 x ULN 
Hold until recovery to Grade 1 
Restart paclitaxel at Dose Level -1 
< 10 x ULN 
And 
2.01 - 5 x ULN 
Hold until recovery to Grade 1 
Restart paclitaxel at Dose Level -2 
≥ 10 x ULN 
OR 
> 5.0 x ULN 
Discontinue Paclitaxel 
Abbreviation: ULN = upper limit of normal. 
If the liver function test abnormalities do not recover by the next planned cycle, paclitaxel must be 
discontinued. All dose reductions for liver function abnormalities are permanent. 
Allergic Reaction/Hypersensitivity 
Patients who experience severe or life-threatening symptoms of hypersensitivity despite standard 
pretreatment medications must discontinue paclitaxel permanently. 
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Paclitaxel Dose Modification for Other Toxicities 
For other non-hepatic or non-hematologic toxicities such as Grade 3 nausea, vomiting, diarrhea or 
stomatitis that occur despite supportive care, paclitaxel will be held at the first occurrence and 
subsequently dose reduced to the next level once the toxicity has recovered to Grade 0-1 in 
severity.  
5.5.3. 
Blinding  
This is a randomized, double-blind, Phase 3 study. Patients will be randomized to receive 
tislelizumab or matched placebo in a double-blind fashion such that neither the investigator, nor 
the patient, nor medical or ancillary medical staff, nor the blinded sponsor staff or its designees, 
will know which drug is being administered in addition to chemotherapy.  
Every effort should be made to avoid unblinding the patient’s treatment assignment unless 
necessary. Unblinding may be indicated and permissible only in specific situations as described 
below and if it’s necessary for the patient’s welfare. Unblinding would occur through Interactive 
Response Technology (IRT) as per the instructions in the IRT site user manual. If unblinding has 
occurred, the sponsor must be notified immediately using the Unblinding Event Form. To ensure 
the continued blinding of study personnel, this form will not include the treatment assignment. 
Patients will remain on study for safety follow-up and, if applicable, for survival follow-up. 
• 
Emergency unblinding  
In case of an emergency, such as when a patient has an AE suspected to be related to 
the investigational drug product and for which management of the AE with one or 
more drug products with substantial toxicity or invasive procedures is being 
considered, unblinding can occur. 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 inform the medical monitor of their intent before unblinding a patient’s 
treatment assignment unless this could delay emergency treatment of the patient. If a 
patient’s treatment assignment is unblinded, the sponsor must be notified immediately.  
The investigator performs the emergency unblinding for AEs through an IRT System. 
Unblinded patients may remain on study treatment at the discretion of the investigator 
in consultation with the medical monitor and only as permissible per definitions in the 
study protocol. 
• Non-Emergency Unblinding  
Non-emergency unblinding to Tislelizumab versus placebo administration may occur 
on an individual patient basis and only after consultation with and approval from the 
medical monitor at the time of 1) documented disease progression and the patient has 
discontinued all study treatments, or 2) when the patient has discontinued all study 
treatments for toxicity and a new anticancer treatment is going to be started. 
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• Inadvertent unblinding  
Every effort will be made to blind both the patient and the investigator to the identity 
of tislelizumab or placebo, but the inadvertent unblinding of a patient may occur. If an 
investigator, site personnel performing assessments, or 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. 
• Unblinding after interim analysis per IDMC recommendation 
Sponsor, investigators and site personnel, and patients will be unblinded to treatment 
arms after the preplanned interim analysis if a recommendation is made by IDMC and 
accepted by the sponsor.  Placebo administration will be discontinued after the 
unblinding.  Crossover between the treatment arms will not be allowed. 
On 20 April 2022, upon reviewing the efficacy and safety data of preplanned interim analysis, 
IDMC confirmed that the study met the specified 1-sided p-value boundary for superiority of the 
primary endpoint and recommended to unblind/unmask the study due to compelling efficacy. The 
sponsor accepted the IDMC recommendation, and the study was unblinded after the interim 
analysis. An instruction was provided to investigators to discontinue placebo in Arm B after the 
unblinding. 
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6. 
PRIOR AND CONCOMITANT THERAPY  
All prior cancer treatments and treatments for underlying active medical conditions must be 
recorded on the appropriate eCRF. 
6.1. 
Concomitant Therapy  
6.1.1. 
Permitted Concomitant Medications  
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care at the discretion of the investigator for supportive care (eg, anti-emetics, 
antidiarrheals) and in a patient’s interest are allowed. 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.  
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 7) and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration. The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted.  
Patients with active hepatitis B defined as HBV DNA ≥ 500 IU/mL at screening must initiate 
treatment 2 weeks prior to randomization and continue until 6 months after the last dose, or per 
local guidelines/clinical practice. Patients should continue effective antiviral treatment during the 
study to decrease potential viral re-activation risk. Tenofovir and entecavir are recommended in 
the American Association for the Study of Liver Disease (AASLD) guideline because they lack 
resistance with long-term use (Terrault et al 2018; AASLD/IDSA HCV Guidance Panel 2015). 
Management of antiviral therapy is at the discretion of the investigator; however, reason(s) must 
be provided in the eCRF if a patient with active hepatitis B is not treated with antiviral 
prophylaxis. 
BeiGene does not require patients with active hepatitis C to receive treatment with antiviral 
therapy. Patients with detectable HCV RNA and who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study. Investigators can consider 
treatment with sofosbuvir alone or in combination with other antivirals following the AASLD 
guideline or the local guidelines as appropriate. However, interferon-based therapy for either 
HBV or HCV is not permitted on study. Patients who are given antiviral therapy must initiate 
treatment at least 2 weeks prior to randomization. 
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 provided 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 for RECIST v1.1 
• The case is discussed with the medical monitor, and the medical monitor agrees that the 
conditions required to receive palliative radiation are met 
• Additionally, palliative radiation or other focally ablative therapy for other non-target sites 
of the disease is permitted if clinically indicated per investigator’s discretion and after 
consultation with the medical monitor. Whenever possible, these patients should have a 
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tumor assessment of the lesion(s) before receiving the radiotherapy to rule out progression 
of disease. 
6.1.2. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited during the study: 
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy [including IL-2, interferon, thymosin, etc.] or standard or investigational 
agents [including Chinese herbal and patent medicines] for the treatment of cancer) is not 
allowed. 
• Live vaccines within 28 days before randomization, during treatment with tislelizumab 
and 60 days following the last dose of study drug(s). 
• Herbal remedies with immune-stimulating properties (ie, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions (ie, hypericin). 
Patients must notify the investigator of all herbal remedies used during the study. 
6.1.3. 
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 avoid alcohol abuse or any other drug abuse during the study. 
• 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 6.1.1. 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
• Tislelizumab 
The potential for drug-drug interaction between the study drug (tislelizumab) and 
small-molecule drug products is very low, given that tislelizumab is a therapeutic 
monoclonal antibody. Because tislelizumab is expected to be degraded into amino 
acids and recycled into other proteins, it is unlikely to have an effect on drug 
metabolizing enzymes or transporters. 
• Cisplatin 
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin 
therapy. In a randomized trial in advanced ovarian cancer, response duration was 
adversely affected when pyridoxine was used in combination with altretamine 
(hexamethylmelamine) and cisplatin. Ototoxic medicinal products will potentiate toxic 
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effects of cisplatin on auditory function. The investigator should refer to the most 
current cisplatin Summary of Product Characteristics (SmPC) for all potential 
interactions with cisplatin. 
• Oxaliplatin 
No specific cytochrome P-450-based drug interaction studies have been conducted. 
Increases of 5-FU plasma concentrations by approximately 20% have been observed 
with doses of 130 mg/m2 dosed every 3 weeks. Because platinum-containing species 
are eliminated primarily through the kidney, clearance of these products may be 
decreased by coadministration of potentially nephrotoxic compounds; although this has 
not been specifically studied. The investigator should refer to the most current 
oxaliplatin SmPC for all potential interactions with oxaliplatin. 
• 5-Fluorouracil 
Elevated coagulation times have been reported in patients taking fluorouracil 
concomitantly with warfarin. While pharmacokinetic data are not available to assess 
the effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of 
coagulation times that occurs with the fluorouracil prodrug capecitabine is 
accompanied by an increase in warfarin concentrations. Thus, the interaction may be 
due to inhibition of cytochrome P450 2C9 by fluorouracil or its metabolites. The 
investigator should refer to the most current 5-fluorouracil SmPC for all potential 
interactions with 5-fluorouracil. 
• Capecitabine 
Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin 
and phenprocoumon. These events occurred within several days and up to several 
months after initiating capecitabine therapy and, in a few cases, within 1 month after 
stopping capecitabine. These events occurred in patients with and without liver 
metastases. In a drug interaction study with single-dose warfarin administration, there 
was a significant increase in the mean AUC of S-warfarin. The maximum observed 
international normalized ratio (INR) value increased by 91%. This interaction is 
probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its 
metabolites. The level of phenytoin should be carefully monitored in patients taking 
capecitabine and phenytoin dose may need to be reduced. Post-marketing reports 
indicate that some patients receiving capecitabine and phenytoin had toxicity 
associated with elevated phenytoin levels. Formal drug-drug interaction studies with 
phenytoin have not been conducted, but the mechanism of interaction is presumed to 
be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites. Other 
than warfarin, no formal drug-drug interaction studies between capecitabine and other 
CYP2C9 substrates have been conducted. Care should be exercised when capecitabine 
is co-administered with CYP2C9 substrates. The investigator should refer to the most 
current capecitabine SmPC for all potential interactions with capecitabine. 
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• Paclitaxel 
Caution should be exercised for patients receiving paclitaxel concomitantly with 
substrates, inhibitors or inducers of CYP2C8 or CYP3A4. The metabolism of 
paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 
Caution should be exercised when paclitaxel is concomitantly administered with 
known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, 
sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. Caution 
should also be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers 
(eg, rifampin) of CYP2C8. Potential interactions between paclitaxel, a substrate of 
CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), 
which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical 
trials. The investigator should refer to the most current paclitaxel SmPC for all 
potential interactions with paclitaxel. 
• COVID-19 vaccine 
Potential immune reactivity to the coronavirus disease 2019 (COVID-19) vaccine in 
patients concurrently receiving checkpoint inhibitors or other immune-oncologic 
treatments cannot be ruled out, but current data suggest that instances are rare. As 
additional data emerge, the approach will be modified accordingly. 
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7. 
STUDY ASSESSMENTS 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. 
Screening  
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate will sign the ICF prior to undergoing any screening procedure. The screening 
period begins on the first day a screening procedure is conducted. Patients who are suspected or 
known to have serious respiratory concurrent illness or exhibit significant respiratory symptoms 
unrelated to underlying cancer or with a history of thoracic radiotherapy should take a pulmonary 
function test (refer to Appendix 1 for details). 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 prior to obtaining informed consent 
and ≤ 28 days prior to randomization may be used for the purposes of screening rather than 
repeating the standard of care tests unless otherwise indicated (only applicable if the same 
radiographic procedure will be used throughout the study). 
Procedures conducted during Screening only are described in this section. For the description of 
other assessments that are conducted during screening, as well as throughout the study, refer to 
Safety Assessments (Section 7.4), Tumor and Response Evaluations (Section 7.5) and Biomarkers 
(Section 7.8) sections. The PK sampling schedule is shown in Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with BeiGene (eg, when a 
patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression). Rescreening is allowed only once. 
7.1.1. 
Demographic Data and Medical History  
Demographic data will include age or year of birth, gender, and self-reported race/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, former or current or never); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before randomization. 
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. Cancer 
symptoms that are present at baseline will be recorded and assessed for severity using the 
NCI-CTCAE v4.03 criteria. Radiographic studies performed prior to study entry may be collected 
for review by the investigator. 
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7.1.2. 
Females of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer to 
Appendix 9 for contraception guidelines and definitions of “women of childbearing potential” and 
“no childbearing potential”  
7.1.3. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  Informed consent forms 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 randomization. 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. 
7.1.4. 
Pulmonary Function Tests  
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit 
significant respiratory symptoms unrelated to the underlying cancer or with a history of thoracic 
radiotherapy will undergo pulmonary function testing which may include, but is not limited to, 
spirometry and assessment of diffusion capacity done during the screening period to assist the 
determination of suitability on the study. 
7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient. All screening procedure 
results and relevant medical history must be available before eligibility can be determined. All 
inclusion criteria must be met and none of the exclusion criteria may apply. No eligibility waivers 
will be granted.   
After a patient is screened and the investigator determines the patient is eligible for 
randomization, study site personnel will complete an Eligibility Authorization Packet and send it 
to the medical monitor or designee to confirm eligibility before the enrollment. Study site 
personnel should ensure that a medical monitor’s confirmation has been received before 
randomization. 
7.2.2. 
Patient Numbering  
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.   
7.2.3. 
Enrollment/Randomization  
Site personnel will access the IRT system to randomize to treatment assignment and to assign 
study drugs. Study treatment must commence within 2 business days after 
randomization/treatment assignment.   
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7.3. 
Tislelizumab and Comparator Drug Dispensation  
Depending on the treatment arm and preferred chemotherapy doublet, tislelizumab (or matched 
placebo), cisplatin, oxaliplatin, 5-FU, capecitabine, and paclitaxel will be dispensed and 
administered as described in Section 5.2. 
7.4. 
Safety Assessments  
7.4.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate and blood pressure 
(systolic and diastolic) while the patient is in a seated position after resting for 10 minutes.    
7.4.2. 
Physical Examinations  
During Screening, a complete physical examination will be conducted including evaluations of 1) 
head, eyes, ears, nose, 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 v4.03 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. Changes from baseline will be recorded. New or worsened 
clinically significant abnormalities are to be recorded as AEs on eCRF. Refer to Section 8.3 
regarding AE definitions and reporting and follow-up requirements. 
7.4.2.1. 
Ophthalmologic Examination  
Due to an increased risk of ophthalmologic adverse events in patients receiving PD-1 inhibitors 
(including, but not limited to uveitis and retinal disorders), eye exam, visual acuity test, and 
optical coherence tomography (or equivalent diagnostic test) will be assessed by an appropriate 
specialist at screening. Eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining 
written informed consent and within 28 days of randomization may be used for the screening 
evaluation. All patients will undergo repeat assessments by an appropriate specialist 
approximately every 15 weeks (± 7 days) during study treatment and a final assessment at the 
EOT/Safety follow-up visit, 30 days after the last dose of study treatment.   
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, or 
ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance (see 
Appendix 7). 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 3) will be assessed during the study.  
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7.4.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of serum chemistry, hematology, coagulation, and 
urinalysis will be conducted, of which certain elements will be collected as specified in 
Appendix 2.  
If laboratory tests at screening are not performed within 7 days prior to the administration of study 
drug(s) on Cycle 1 Day 1, these tests should be repeated and reviewed before study drug(s) 
administration. Hematology and serum chemistry (including liver function tests) as specified in 
Appendix 2 should be performed weekly for the first 3 cycles and at the beginning of subsequent 
cycles. After Cycle 1, results are to be reviewed within 48 hours before study drug administration. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring 
and dosing decision.   
7.4.5. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatinine kinase (CK) and CK cardiac isoenzyme (CK-MB) are monitored in all 
tislelizumab studies to protect study participants and to quantify the risk of muscle inflammation 
(see Appendix 1 for the blood collection schedule and Appendix 7 for guidelines for management 
of suspected immune-mediated myocarditis). Serum troponins may be substituted per local 
guidelines if used consistently throughout the study. 
7.4.6. 
Electrocardiograms  
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. 
Patients should rest for at least 10 minutes prior to ECG collection.  
7.4.7. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE, v4.03. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.8. 
Hepatitis B and C Testing  
Testing will be performed by a central laboratory and/or the local laboratory at screening and will 
include HBV/HCV serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core 
antibody [HBcAb], and HCV antibody). If HBsAg or HBcAb is positive, then an HBV DNA test 
will be triggered. If HCV antibody is positive, an HCV RNA test will be triggered. 
Patients who have detectable HBV DNA or HCV RNA at screening will have the viral load 
retested every 4 cycles. 
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7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed within 28 days before randomization. Results of standard of 
care tests or examinations performed prior to obtaining informed consent and ≤ 28 days prior to 
randomization may be used for the purposes of screening rather than repeating the standard of 
care tests (only applicable if the same radiographic procedure will be used throughout the study). 
During the study, tumor imaging will be performed every 6 weeks (± 7 days) for the first 
48 weeks, then every 9 weeks (± 7 days) after 48 weeks 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 on the planned schedule. 
Screening assessments and each subsequent assessment must include computed tomography (CT) 
scans (with oral/IV contrast, unless contraindicated) or magnetic resonance imaging (MRI) of the 
chest, abdomen, and neck. Other known or suspected sites of disease must be included in the 
imaging assessments (pelvis, brain, etc.). 
Tumor assessments must include CT scans (with oral/IV contrast, unless contraindicated) or MRI, 
with preference for CT, of the neck, chest, and abdomen. 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 assess disease sites at screening are 
required to be used throughout the study (eg, the same contrast protocol for CT scans). All known 
sites of disease must be documented at screening and reassessed at each subsequent tumor 
evaluation. 
• Any patient with a history of CNS metastases will be required to undergo CT/MRI at 
baseline to ensure all sites of disease are evaluated per RECIST v1.1 criteria. Patients with 
newly diagnosed brain metastases on screening CT/MRI will be required to be treated for 
brain metastasis with standard of care treatments and be off corticosteroids prior to study 
entry. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a contrast-enhanced 
MRI (if possible) of abdomen and neck should be performed.  
• If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
• 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 afterwards, TC-99m or PET bone scans should be conducted when a 
complete response (CR) is suspected in target lesion. 
• CT scans of the extremities should also be performed if clinically indicated and followed 
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 nontarget lesions per RECIST v1.1 may be used.  
Response will be assessed by BIRC and the investigator using RECIST v1.1 (see Appendix 4). 
The same evaluator should perform assessments, if possible, to ensure internal consistency across 
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visits. For immune therapies such as tislelizumab, pseudoprogression may occur due to 
immune-cell infiltration and other mechanisms leading to an apparent increase of existing tumor 
masses or appearance of new tumor lesions. Also, some patients may benefit from additional 
immune therapies despite evidence of disease progression. The following criteria must be met in 
order to treat patients with suspected pseudoprogression or confirmed evidence of disease 
progression:  
• Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values)  
• Stable ECOG performance status ≤ 1 
• Absence of rapid progression of disease 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 beyond radiologic 
disease progression and inform patients that this practice is not considered standard in the 
treatment of cancer.  
The decision to continue study drug(s) beyond initial investigator-assessed progression must be 
agreed with the sponsor medical monitor and documented in the study records. 
Tumor assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression. Tumor assessment in such patients should continue until study 
treatment discontinuation. 
Patients who discontinue study treatment early for reasons other than documented radiographic 
disease progression (eg, toxicity) will continue to undergo tumor assessments following the 
original plan until the patient experiences disease progression, withdraws consent, is lost to 
follow-up, or dies, or until the study terminates, whichever occurs first.  
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. That is, assessments should not be adjusted for delays in 
cycles. 
7.6. 
Pharmacokinetic and Anti-Drug Antibody Testing  
Tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response to tislelizumab will be closely monitored. Validated screening and confirmatory assays 
will be employed to detect ADAs at multiple time points throughout the study (see Appendix 1). 
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy (Koren et al 
2008; Worobec and Rosenberg 2004a; Worobec and Rosenberg 2004b) to characterize ADA 
responses to tislelizumab in support of the clinical development program. This tiered strategy will 
include an assessment of whether ADA responses correlate with relevant clinical endpoints. 
Implementation of ADA characterization assays will depend on the safety profile and clinical 
immunogenicity data.  
The following assessments will be performed at a central laboratory:  
• ADA assays: serum samples will be tested for the presence of ADAs to tislelizumab using 
a validated immunoassay 
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• PK assay: serum samples will be assayed for tislelizumab concentration with use of a 
validated immunoassay 
• PK and ADA samples collected from patients randomized to receive placebo will not be 
analyzed. 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK and ADA 
assays will be managed through a central laboratory. Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
7.7. 
On-Study Biopsies  
If an on-study biopsy is performed for any reason while any patient is actively participating in the 
study, key histologic findings by local assessment will be collected. This information includes, at 
a minimum: date, type of biopsy (e.g. needle, surgical, etc.), location, and findings/results. This 
information will be collected regardless of whether the patient is actively receiving study 
treatment. 
7.8. 
Biomarkers  
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling.  
Archival tumor tissues (formalin-fixed paraffin-embedded block or approximately 15 [at least 6] 
unstained slides) need to be sent to central laboratory for central immunohistochemistry assay of 
PD-L1 status. In the PD-L1 vCPS ≥ 10% population, PD-L1 expression will be assessed centrally 
using the VENTANA PD‑L1 (SP263) assay. The vCPS is the total percentage of the tumor area 
covered by tumor cells with PD-L1 membrane staining and tumor‑associated immune cells with 
PD-L1 staining at any intensity. In addition to PD-L1 expression, other exploratory biomarkers 
consisting of gene expression profiling (GEP), tumor-infiltrating lymphocytes (TIL), 
TMB/MSI/gene mutation profile that are related to response or clinical benefit of tislelizumab in 
combination with chemotherapy may also be evaluated. Other assessments may be conducted as 
allowed by local regulations.  
If no archival samples are available, a fresh tumor biopsy at baseline (within 28 days before 
randomization) is needed. For fresh biopsy specimens, acceptable samples include core needle 
biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.  
An optional biopsy will also be taken for the patients who have confirmed disease progression 
during the study from accessible tumor sites to obtain samples to explore resistance mechanisms. 
If feasible, any follow-up biopsy should be ideally taken from the same tumor lesion as the 
baseline biopsy. Written patient consent is required for fresh tumor biopsies.  
Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. 
Blood samples will be taken at baseline (predose on Day 1 of Cycle 1) for all randomized patients 
to explore the association of blood-based biomarkers with response and prognosis to tislelizumab 
in combination with chemotherapy or chemotherapy alone. Blood samples are highly 
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recommended to be collected at first tumor response (CR/PR) and/or at confirmed disease 
progression to explore response and/or resistance mechanism to tislelizumab in combination with 
chemotherapy or chemotherapy alone. Written patient consent is required for optional blood 
sample collections. Blood-based biomarkers consist of TMB/MSI/gene mutation profile. Other 
assessments may be conducted as allowed by local regulations. 
7.9. 
Patient-Reported Outcomes  
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 prior to study treatment infusion/dose 
unless otherwise noted. Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or justifiable 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule Q3W from 
Cycle 1 Day 1 or from the last rescheduled date if resynchronization happens. 
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/focused physical examination; ECOG performance status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical examination 
of liver, spleen, and lymph nodes; review of disease-related constitutional symptoms; and 
hematology and 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 disease progression, 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 Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab 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.   
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 evaluation and management guidelines for suspected imAEs are 
provided in Appendix 7. 
8.1.2. 
Risks Associated with Comparator Drugs  
Selected risks for each chemotherapy are listed below. Please refer to the package 
insert/prescribing information for each drug for more information. 
Cisplatin 
Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. 
The serum creatinine, BUN, creatinine clearance, and magnesium, sodium, potassium, and 
calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. 
At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 
weeks. Elderly patients may be more susceptible to nephrotoxicity. A urine output of 100 
mL/hour or greater will tend to minimize cisplatin nephrotoxicity. This can be accomplished by 
increased hydration, before and after treatment. 
There are reports of severe neuropathies in patients in whom regimens are employed using higher 
doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may 
be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of 
proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral 
neuropathy.  
Loss of motor function has also been reported.  
Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within 
minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by 
administration of epinephrine, corticosteroids, and antihistamines.  
Ototoxicity has been observed in patients treated with a single dose of cisplatin. Hearing loss can 
be unilateral or bilateral and tends to become more frequent and severe with repeated doses; 
however, deafness after initial dose of cisplatin has been reported rarely. It is unclear whether 
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cisplatin induced ototoxicity is reversible. Careful monitoring by audiometry should be performed 
prior to initiation of therapy and prior to subsequent doses of cisplatin.  
Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in 
bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin 
is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes 
pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 
Patients should be advised to avoid becoming pregnant.  
The development of acute leukemia coincident with the use of cisplatin has been reported. In 
these reports, cisplatin was generally given in combination with other leukemogenic agents.  
Injection site reactions may occur during the administration of cisplatin. Given the possibility of 
extravasation, it is recommended to closely monitor the infusion site for possible infiltration 
during drug administration. A specific treatment for extravasation reactions is unknown at this 
time. 
Oxaliplatin 
Grade 3/4 hypersensitivity to oxaliplatin, including anaphylactic/anaphylactoid reactions, has been 
observed in 2 to 3% of colon cancer patients (Oxaliplatin prescribing information). These allergic 
reactions which can be fatal, can occur within minutes of administration and at any cycle, and 
were similar in nature and severity to those reported with other platinum-containing compounds, 
such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. Symptoms 
associated with hypersensitivity reactions reported in previously untreated patients included 
urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of 
breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation, and syncope. These 
reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, 
and require discontinuation of therapy.  Rechallenge is contraindicated in these patients. Drug-
related deaths associated with platinum compounds from anaphylaxis have been reported. 
Oxaliplatin is associated with 2 types of neuropathy: acute, reversible, primarily peripheral 
sensory neuropathy and persistent (> 14 days) primarily peripheral sensory neuropathy.   
• Acute, reversible, primarily peripheral, sensory neuropathy has an early onset (occurring 
within hours or 1 to 2 days of dosing), resolves within 14 days, and frequently recurs with 
further dosing. Symptoms may be precipitated or exacerbated by exposure to cold 
temperature or cold objects and they usually present as transient paresthesia, dysesthesia 
and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue 
sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. 
The acute, reversible pattern of sensory neuropathy was observed in about 56% of study 
patients who received oxaliplatin with 5-FU/leucovorin. In any individual cycle acute 
neurotoxicity was observed in approximately 30% of patients. In adjuvant patients, the 
median cycle of onset for Grade 3 peripheral sensory neuropathy was 9, and in previously 
treated patients, the median number of cycles administered on the oxaliplatin with 
5FU/leucovorin combination arm was 6. An acute syndrome of pharyngolaryngeal 
dysesthesia, seen in 1 to 2% (Grade 3/4) of previously untreated and treated patients with 
advanced colorectal cancer, is characterized by subjective sensations of dysphagia or 
dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice 
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(mucositis prophylaxis) should be avoided during the infusion of oxaliplatin because cold 
temperature can exacerbate acute neurological symptoms.   
• Persistent (> 14 days), primarily peripheral, sensory neuropathy is usually characterized by 
paresthesias, dysesthesias, and hypoesthesias, but may also include deficits in 
proprioception that can interfere with daily activities (eg, writing, buttoning, swallowing, 
and difficulty walking from impaired proprioception). These forms of neuropathy occurred 
in 48% of study patients receiving oxaliplatin with 5FU/leucovorin. Persistent neuropathy 
can occur without any prior acute neuropathy event.  Most patients (80%) who developed 
Grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms 
may improve in some patients upon discontinuation of oxaliplatin. Peripheral sensory 
neuropathy was reported in adjuvant patients treated with the oxaliplatin combination with 
a frequency of 92% (all grades) and 13% (Grade 3). At the 28-day follow-up after the last 
treatment cycle, 60% of all patients had any grade (Grade 1: 40%; Grade 2: 16%; Grade 3: 
5%) peripheral sensory neuropathy decreasing to 39% at 6 months of follow-up (Grade 1: 
31%; Grade 2: 7%; Grade 3: 1%) and 21% at 18 months of follow-up (Grade 1: 17%, 
Grade 2: 3%, Grade 3: 1%). Overall, neuropathy (all grades) was reported in 82% of 
previously untreated patients with advanced colorectal cancer (19% had Grade 3/4 
neuropathy), and in 74% of previously treated patients (7% had Grade 3/4 neuropathy). 
Information regarding reversibility of neuropathy was not available from the trial for 
patients who had not been previously treated for colorectal cancer. 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as Posterior Reversible 
Encephalopathy Syndrome [PRES]) has been observed in clinical trials (< 0.1%) and 
postmarketing experience. Signs and symptoms of RPLS can include headache, altered mental 
functioning, seizures, abnormal vision from blurriness to blindness, which may be associated with 
hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging. 
Oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be 
fatal. In adjuvant colon cancer patients, the combined incidence of cough and dyspnea was 7.4% 
(any grade) and <1% (Grade 3) with no Grade 4 events in the oxaliplatin plus infusional 
5-FU/leucovorin arm compared to 4.5% (any grade) and no Grade 3 and 0.1% Grade 4 events in 
the infusional 5-FU/leucovorin alone arm. In this study, 1 patient died from eosinophilic 
pneumonia in the oxaliplatin combination arm. In patients with previously untreated colorectal 
cancer, the combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% 
(Grade 3 and 4) in the oxaliplatin plus 5-FU/leucovorin arm compared to 32% (any grade) and 5% 
(Grade 3 and 4) in the irinotecan plus 5-FU/leucovorin arm of unknown duration. In case of 
unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or 
radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary 
investigation excludes interstitial lung disease or pulmonary fibrosis. 
Hepatotoxicity was observed more commonly in the oxaliplatin combination arm than in the 
control arm, as evidenced in the adjuvant study by increase in transaminases (57% vs 34%, 
respectively) and alkaline phosphatase (42% vs 20%, respectively). The incidence of increased 
bilirubin was similar on both arms.  Changes noted on liver biopsies include peliosis, nodular 
regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive 
lesions. Hepatic vascular disorders should be considered, and if appropriate, should be 
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investigated in case of abnormal liver function test results or portal hypertension which cannot be 
explained by liver metastases. 
Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate 
and well-controlled studies of oxaliplatin in pregnant women. Women of childbearing potential 
should be advised to avoid becoming pregnant while receiving treatment with oxaliplatin. 
5-Fluorouracil 
The daily dose of fluorouracil is not to exceed 800 mg/m2. It is recommended that patients be 
hospitalized during their first course of treatment. The first 10 patients enrolled in Japan will be 
hospitalized for the first course of treatment. 
Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose 
pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement 
of bone marrow by metastatic tumors or those with impaired hepatic or renal function.  
Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) 
associated with 5-FU has been attributed to deficiency of dipyrimidine dehydrogenase activity. A 
few patients have been rechallenged with 5-FU and despite 5-FU dose lowering, toxicity recurred 
and progressed with worse morbidity. Absence of this catabolic enzyme appears to result in 
prolonged clearance of 5-FU.  
Investigator must advise patients to take measures to minimize exposure to UV light for the 
duration of the study as 5-FU has phototoxicity potential. 
Fluorouracil may cause fetal harm when administered to a pregnant woman. Fluorouracil has been 
shown to be teratogenic in laboratory animals.  
There are no adequate and well-controlled studies with fluorouracil in pregnant women. While 
there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind that 
other drugs which inhibit DNA synthesis (eg, methotrexate and aminopterin) have been reported 
to be teratogenic in humans. Women of childbearing potential should be advised to avoid 
becoming pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while 
taking the drug, the patient should be told of the potential hazard to the fetus. Fluorouracil should 
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.  
Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses 
bone marrow function will increase the toxicity of fluorouracil. 
Capecitabine 
May result in bleeding, death. Monitor anticoagulant response (eg, INR) and adjust anticoagulant 
dose accordingly.  
Diarrhea may be severe. Interrupt capecitabine treatment immediately until diarrhea resolves or 
decreases to Grade 1. Recommend standard antidiarrheal treatments. 
Cardiotoxicity is common in patients with a prior history of coronary artery disease. 
There is an increased risk of severe or fatal adverse reactions in patients with low or absent 
dihydropyrimidine dehydrogenase (DPD) activity. Withhold or permanently discontinue 
capecitabine in patients with evidence of acute early-onset or unusually severe toxicity, which 
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may indicate near complete or total absence of DPD activity. No capecitabine dose has been 
proven safe in patients with absent DPD activity.  
In case of dehydration, interrupt capecitabine treatment until dehydration is corrected. There is a 
potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration.  
Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and 
to use effective contraception.  
Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal 
Necrolysis (TEN), have been reported. Capecitabine should be permanently discontinued in 
patients who experience a severe mucocutaneous reaction during treatment. Capecitabine may 
induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of 
fingerprints which could impact patient identification. Interrupt capecitabine treatment until the 
hand-and-foot syndrome event resolves or decreases in intensity.  
Interrupt capecitabine treatment immediately until the hyperbilirubinemia resolves or decreases in 
intensity. 
Do not treat patients with neutrophil counts < 1.5 x 109/L or platelet counts < 100 x 109/L. If 
Grade 3 to 4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. 
Investigator must advise patients to take measures to minimize exposure to UV light for the 
duration of the study as capecitabine has phototoxicity potential. 
Paclitaxel 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite 
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 
antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug.  
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting 
toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered 
to patients with baseline neutrophil counts of less than 1.5 x 109/L and platelets recover to a level 
> 100 x 109/L.  
Severe conduction abnormalities have been documented in < 1% of patients during paclitaxel 
therapy and in some cases requiring pacemaker placement. If patients develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered, 
and continuous cardiac monitoring should be performed during subsequent therapy with 
paclitaxel. 
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 tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered. Specifically, patients 
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at risk for study-emergent active autoimmune diseases, or with a history of autoimmune diseases 
that may relapse, patients who have undergone allogenic stem cell or organ transplantation and 
patients who have received a live vaccine ≤ 28 days before randomization are excluded from the 
study. Patients with contraindications for platinum (cisplatin or oxaliplatin), fluoropyrimidine (5-
FU or capecitabine), and paclitaxel treatment are also excluded from the study (see Section 4.2 for 
the full list of exclusion criteria).  
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 v4.03. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to the 
start of each cycle.  
All enrolled patients will be evaluated clinically and with standard laboratory tests before and at 
regular intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs, physical examinations, laboratory measurements (hematology, 
chemistry, etc.) and other assessments. In addition, patients will be closely monitored for the 
development of any signs or symptoms of autoimmune conditions and infection.  
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomized 
to the tislelizumab arm, if treatment assignment is known. Samples will be drawn from all patients 
but will only be analyzed in patients who are treated with tislelizumab. Administration of 
tislelizumab 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 5.2.1).   
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing of informed consent) and for up to 30 days after the last dose of study drug(s) 
(including chemotherapy) or until the initiation of another anticancer therapy, whichever occurs 
first.  At the EOT/Safety Follow-up Visit, all AEs will be followed until the event has resolved to 
baseline or ≤ Grade 1, the event is assessed by the investigator as stable, the patient is lost to 
follow-up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the AE. 
Immune-mediated AEs will be recorded up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new 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. 
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 the following sections.  
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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 a study 
drug, whether considered related to study drug 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 it may 
have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 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 cases are requested 
by the sponsor. In this instance, all patient identifiers will be blinded on the copies of the medical 
records prior to 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 the NCI-CTCAE v4.03. 
Toxicities that are not specified in the 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 (ADL)  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL  
• 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. 
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8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the 
AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab 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 prior to transmission of the SAE report to the sponsor, 
since the causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality 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 drug (ie, there are facts, evidence, or arguments to suggest possible 
causation). A number of factors should be considered in making this assessment, including:  
• 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 drug  
• Biological plausibility  
• An AE should be considered ‘related’ to study drug 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). 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. 
Following 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 
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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 
post-mortem 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  
Only abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], 
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 baseline and significantly worsen during the study. The definition of clinically 
significant is left to the judgment 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 x 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 should be recorded as “hyperkalemia”. 
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, 
which hypothetically might have caused death, if it were more severe.  
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• 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 or prevent everyday life functions, but do not constitute a substantial 
disruption.  
• 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 
one of 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 is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets the 
definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the 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 informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study drugs (including chemotherapy) or initiation 
of new anticancer therapy, whichever occurs first. Immune-mediated AEs (serious or non-serious) 
should be reported until 90 days after the last dose of tislelizumab, regardless of whether the 
patient starts a new anticancer therapy. 
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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 4.  For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2.  
Table 4: Guidance for Duration of Recording New or Worsening Adverse Events in Both 
Treatment Arms 
Event type 
Record new or worsening events that 
occur during this period 
 
 
Begin 
End  
SAEs a 
Signing of informed consent 
Up to 30 days after last dose, 
initiation of 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 new anticancer therapy, 
death, withdrawal of consent, or loss 
to follow-up, whichever occurs first 
Immune-mediated AEs (serious or 
nonserious) 
  
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. 
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 5. 
Table 5.  Timeframes and Documentation Methods for Reporting Serious Adverse Events to 
the Sponsor or Designee 
 
Timeframe for 
Sending Initial 
Report 
Documentation 
Method 
Timeframe for 
Sending 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24h of first 
knowledge of the 
AE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Email or fax 
SAE report 
form 
   Abbreviations: h, hours; SAE, serious adverse event. 
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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 
will always be completed as thoroughly as possible with 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 must not 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 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 product under clinical 
investigation.  
The investigator, or 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 suspected unexpected serious adverse reactions (as defined in Section 8.5), will be submitted 
to all applicable regulatory authorities and investigators for 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  
Disease progression, 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 disease progression should not be recorded. However, if there is any 
uncertainty to whether a nonserious AE is due to disease progression, it should be recorded as an 
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AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded and 
reported (see Section 8.6.2). 
8.6.5. 
Deaths  
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an AE (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 
investigational therapy or within 120 days after the last dose of tislelizumab or within 180 days 
after the last dose of chemotherapy, a pregnancy report form is required to 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 8 weeks following 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 be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug 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 (RSI) documents: 
• Tislelizumab Investigator’s Brochure 
• Cisplatin Package Insert 
• Oxaliplatin Package Insert 
• 5-FU Package Insert 
• Capecitabine Package Insert 
• Paclitaxel Package Insert 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 therapy 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 in the eCRF AE page until Day 90, after treatment discontinuation. 
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Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 7. 
An extensive list of potential imAEs appears in Section 8.7.3, Table 7. 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 7. 
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. These 
infusion-related AEs should be recorded as “infusion-related reaction” instead of the individual 
signs and symptoms. 
8.7. 
Management of AE of Special Interest  
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 1 hour afterwards in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a minimum of a 30-minute monitoring period is 
required in an area with resuscitation equipment and emergency agents.  
The management of infusion-related reactions, severe hypersensitivity reactions and imAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Managing Infusion-Related Reactions  
Patients should be closely monitored for such reactions. Immediate access to an Intensive Care 
Unit (ICU) or equivalent environment and appropriate medical therapy (including epinephrine, 
corticosteroids, IV antihistamines, bronchodilators, and oxygen) must be available to treat 
infusion-related reactions.   
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 6.  
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Table 6.  Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
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.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24h 
Stop infusion.  Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity.  Any 
worsening is closely monitored. Proper medical 
management should be instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: h, hours; IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued, and the patient should be withdrawn from 
tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: 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 IV glucocorticoids, epinephrine, bronchodilators, and oxygen. In the 
next cycle, patients should receive oral premedication with an antihistamine (eg, diphenhydramine 
or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they should be closely 
monitored for clinical signs and symptoms of an infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: 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 IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
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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 (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and 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), the infusion must be immediately stopped and the patient 
discontinued from the study drug(s) that caused this kind of reaction. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the patient should be placed on monitor 
immediately and ICU should be alerted for possible transfer if needed. 
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 drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients 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, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which 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 in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 7. All conditions like those listed should be 
evaluated in patients receiving tislelizumab 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 for Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017, Brahmer et al 2018) and common immune-mediated toxicities are 
detailed in Appendix 7. For any AEs not included in Appendix 7, please refer to the ASCO 
Clinical Practice Guideline (Haanen et al 2017, Brahmer et al 2018) for further guidance on 
diagnostic evaluation and management of immune-mediated toxicities.    
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Table 7.  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’s 
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 
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 7. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) 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 study 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  
9.1.1. 
Randomization Methods  
As discussed in Section 7.2.3, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization.  
9.1.2. 
Analysis Sets  
The Intent-to-Treat (ITT) analysis set includes all randomized patients. Patients will be analyzed 
according to their randomized treatment arms. This will be the primary analysis population for all 
efficacy analysis.  
The Safety analysis set includes all patients who received at least 1 dose of study drug; it will be 
the primary population for the safety analyses. 
The PK analysis set includes all patients who receive at least 1 dose of tislelizumab per the 
protocol, for whom any post-dose PK data are available. 
The ADA analysis set includes all patients who have non-missing baseline ADA and at least 1 
non-missing postbaseline ADA results. 
9.1.3. 
Patient Disposition  
The number of patients randomized, treated, and discontinued from study drug and/or study and 
those with important protocol deviations will be counted. The primary reason for study drug 
and/or 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.  
Important protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics of the ITT analysis set will be summarized using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial 
cancer diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables 
include, region (Asia [excluding Japan] vs Japan vs Rest of World), prior definitive therapy (yes 
vs no), choice of chemotherapy doublet (platinum plus fluoropyrimidine vs platinum plus 
paclitaxel), ECOG (0 vs 1), previous radiotherapy (yes vs no), previous surgery (yes vs no), age 
(≤ 65 vs > 65 years), gender (female vs male), number of metastatic sites (1 vs 2 vs > 2), 
metastatic site (eg, liver, lung, bone, lymph node, etc.), tumor location , smoking status, and 
alcohol use 
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9.1.5. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes. Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical (ATC) 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. Prior medications will be defined as medications that 
stopped before the day of first dose of study drug. Concomitant medications will be defined as 
medications that 1) started before the first dose of study drug and were continuing at the time of 
the first dose of study drug, or 2) started on or after the date of the first dose of study drug up to 
30 days after the patient’s last dose (as of Safety Follow-up Visit). In addition, telephone contacts 
with patients should be conducted to assess imAEs and concomitant medications (if appropriate, 
ie, associated with an imAE or is a new anticancer therapy) at 60 and 90 days (± 14 days) after the 
last dose of study drugs regardless of whether or not the patient starts a new anticancer therapy. 
9.2. 
Efficacy Analyses  
The primary endpoint of OS in the ITT analysis set will be tested at a one-sided alpha of 0.025. 
By using the graphic approach of Bretz et al (2009), if the null hypothesis for OS in the ITT 
analysis set is rejected, the corresponding alpha will be shifted to the hypothesis tests of the 
secondary endpoints PFS by the investigator in the ITT analysis set, ORR by the investigator in 
the ITT analysis set, OS in the PD-L1 vCPS ≥ 10% subgroup, and HRQoL in the ITT analysis set, 
which will be tested sequentially. The inferential test will be stopped at the first non-significant 
endpoint.  
9.2.1. 
Primary Efficacy Analysis  
OS in the ITT analysis set: 
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 primary analysis of OS will be carried out when approximately 488 OS events are reached. In 
absence of confirmation of death, patients will be censored either at the date that the patient was 
last known to be alive or the date of data cut-off, whichever comes earlier. 
OS will be compared between Arm A and Arm B in a one-sided, stratified log-rank test using the 
stratification factors of pooled geographic region (Asia [including Japan] vs Rest of World), prior 
definitive therapy (yes vs no), and the investigator choice of chemotherapy (ICC) option 
(platinum with fluoropyrimidine vs platinum with paclitaxel). A significance level of one-sided 
0.025 will be used in the OS testing. 
The median OS and the cumulative probability of OS at every 3 months including 9-month OS 
and 18-month OS, if estimable, will be calculated for each treatment arm and presented with 
2-sided 95% CIs. Kaplan-Meier survival probabilities for each arm will be plotted over time. OS 
rate at 9 and 18 months based on Kaplan-Meier estimate will be compared between the 2 
treatment arms for landmark analysis. 
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The treatment effect will be estimated by fitting a Cox regression model to the OS times including 
treatment arm as a covariate and geographical region and prior definitive therapy as strata. From 
this model, the HR of OS will be estimated and presented with a 2-sided 95% CI. 
Primary Analyses of OS 
There will be 1 interim analysis of OS utilizing the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. The interim analysis 
will be performed at the time when approximately 423 death events (87% of the target number of 
OS events) among the 2 treatment arms are observed. It is estimated that it will take 
approximately 33 months to observe 423 death events. An IDMC will oversee the interim analysis 
of OS. The final analysis of OS will take place after approximately 488 OS events have been 
observed. Stopping boundaries in p-value and Z score for primary analyses of OS are shown in 
Table 8. The boundaries will be updated according to the actual numbers of events in the interim 
and final analyses, and the revised alpha level due to alpha shifting as described above, using the 
above pre-specified alpha spending function. 
Table 8.  Stopping Boundaries (in p-Value and Z Score) of Primary Analysis of Overall 
Survival  
Endpoint 
Analysis 
Analysis 
Time 
(months) 
# Events 
p-value1 (Z score)  
for Efficacy 
Approximate HR 
Threshold 
OS 
Interim 
analysis 
33 
423 
< 0.0145 (> 2.18) 
0.809 
Final 
analysis 
40 
488 
< 0.0216 (> 2.02) 
0.833 
Abbreviations: HR = hazard ratio; OS = overall survival  
1one-sided 
Subgroup Analyses 
To determine if the treatment effect is consistent across various subgroups, the HR estimates of 
OS and their 95% CI will be estimated and plotted within each category of the following 
variables: region (Asia [excluding Japan] vs Japan vs Rest of World), region (Asia [including 
Japan] vs Rest of World), choice of chemotherapy doublet (platinum plus fluoropyrimidine vs 
platinum plus paclitaxel), ECOG (0 vs 1), age (≤ 65 vs > 65 years), gender (female vs male), 
smoking status, PD-L1 expression (vCPS ≥ 10% vs vCPS < 10%). 
9.2.2. 
Secondary Efficacy Analysis  
Progression Free Survival (PFS)  
There will be one analysis of PFS in the ITT analysis set, which will be carried out after 
superiority of OS in the ITT analysis set has been demonstrated. Similar statistical analysis 
methods used for the OS testing will be applied to PFS analysis. 
The p-value from one-sided, stratified log-rank test will be presented using the stratification 
factors of pooled geographic region, prior definitive therapy, and ICC option.  
PFS assessed by the investigator will be estimated using the Kaplan-Meier method in the ITT 
analysis set. The PFS censoring rule will follow United States (US) Food and Drug 
Administration (FDA) Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer 
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drugs and Biologics (FDA 2018). Data for patients without disease progression or death at the 
time of analysis will be censored at the time of the last tumor assessment. Data for patients who 
are lost to follow-up prior to documented disease progression will be censored at the last tumor 
assessment date when the patient is known to be progression-free. Data for patients who start to 
receive new anti-cancer therapy will be censored at the last tumor assessment date prior to the 
introduction of a new therapy.  
The median PFS and the cumulative probability of PFS at every 3 months, including 6-month 
PFS, if estimable, will be calculated for each treatment arm and presented with 2-sided 95% CIs. 
Kaplan-Meier estimates of PFS for each arm will be plotted over time. The PFS rate at 6 months 
based on the Kaplan-Meier estimate will be compared between the 2 treatment arms for landmark 
analysis. 
HR estimated from a Cox regression model will be presented with its 95% CI. 
OS in the vCPS ≥ 10% subgroup  
This analysis for the baseline vCPS ≥ 10% subgroup is similar to the OS analysis in the ITT 
analysis. 
Other secondary efficacy endpoints 
The null hypotheses of no difference in ORR per RECIST v1.1 by the investigator will be tested 
using Cochran-Mantel-Haenszel (CMH) method, adjusting for stratification factors of pooled 
geographic region, prior definitive therapy, and ICC options in the ITT analysis set. Patients with 
no post-baseline response assessment (for any reason) will be considered non-responders. The 2-
sided 95% CIs for the odds ratio in ORR will be calculated along with Clopper-Pearson 95% CIs 
of ORR for each treatment arm. 
DOR assessed by the investigator will be calculated similarly to PFS by the investigator in the 
responders. Median DOR per arm, if estimable, will be presented. 
HRQoL will be analyzed and compared between treatment arms via the post-baseline scores of 
QLQ-C30’s Global Health Status/QoL (GHS), functional scales and symptom scores and 
symptoms single item scores, QLQ-OES18’s index score and symptoms scales and single item 
scores, and EQ-5D-5L descriptive scale scores as well as the visual analogue scale (VAS) scores. 
Observed values and changes from baseline will be summarized using descriptive statistics. A 
mixed-effect model analysis for measuring clinically meaningful changes post-baseline will be 
performed using the key patient-reported outcome endpoints of GHS, physical functioning, and 
fatigue domains of QLQ-C30 and dysphagia, reflux, pain and eating of QLQ-OES18.  
Time to clinically meaningful deterioration in the aforementioned scales will be estimated using 
the Kaplan-Meier method and Cox regression model. Deterioration thresholds will be defined 
based on the published 10-point EORTC threshold utilizing key patient-reported outcome 
endpoints and a secondary deterioration threshold based on data may be explored. 
9.2.3. 
Exploratory Efficacy Analysis  
BOR is defined as the best response per RECIST v1.1 by the investigator recorded from 
randomization till data cut, progressive disease (PD) or start of new anti-cancer treatment. The 
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proportion and its corresponding Clopper-Pearson 95% CI for each of the response categories 
(CR, PR, SD, and PD) will be presented by treatment arm. 
DCR will be analyzed similarly as ORR in the ITT analysis set. 
To calculate PFS2, data from patients without disease progression after next line of treatment or 
death at the time of analysis will be censored at the last time known to be alive. Kaplan-Meier 
method as described in the PFS and OS analyses will be used in the analysis of PFS2. 
In addition, PFS, ORR, DOR, and DCR assessed by BIRC per RECIST v1.1 are summarized 
similarly as the data assessed by the investigator for exploratory analysis. 
Exploratory biomarkers may also be assessed. 
9.3. 
Safety Analyses  
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (eg, hematology, clinical chemistry, coagulation, and urinalysis), dosing, vital 
signs, ECGs, and physician examinations will also be evaluated in defining the safety profile of 
each treatment arm. Descriptive statistics will be used to analyze all safety data in the Safety 
analysis set. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of doses 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events  
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to MedDRA 
(Version 20.0 or higher) lower level term, preferred term, and primary 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 drug and up to 30 days following study drug 
discontinuation or initiation of new anti-cancer therapy, whichever occurs first. The TEAE 
classification also applies to imAEs that are recorded up to 90 days after discontinuation from 
tislelizumab or placebo, regardless of whether the patient starts a new anticancer therapy. Only 
those AEs that were treatment-emergent will be included in summary tables. 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 preferred term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v4.03 within an SOC and preferred term, even if the patient experienced more than 
1 TEAE within a specific SOC and preferred term. The number (percentage) of patients with 
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TEAEs will also be summarized by relationship to the study drug. Treatment-related AEs include 
those events considered by the investigator to be related to study treatment or with missing 
assessment of the causal relationship.  SAEs, deaths, TEAE with ≥ Grade 3 severity, imAE, 
infusion-related reactions, treatment-related TEAEs and TEAEs that led to treatment 
discontinuation, dose interruption, dose reduction, or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, 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 CSR for this protocol. Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, 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 visit. 
Laboratory parameters that are graded in NCI-CTCAE v4.03 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, glucose, potassium, sodium) will be 
summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
temperature) and changes from baseline will be presented by visit for all visits. Vital signs will be 
listed by patient and visit. 
9.3.5. 
Ophthalmologic Examination  
Ophthalmologic examination results will be listed by patient. 
9.4. 
Pharmacokinetic Analysis  
Individual tislelizumab concentrations will be tabulated by scheduled time of collection. 
Additional PK analyses such as population PK analysis may be conducted as appropriate. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
The results from these analyses will be reported separately from the main study report. 
9.5. 
Immunogenicity Analyses  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
9.6. 
Sample Size Consideration  
The initial sample size calculation was based on the primary efficacy analysis of PFS and OS in 
the comparison between tislelizumab in combination with chemotherapy arm and placebo plus 
chemotherapy arm in the ITT analysis set. Hazard ratios in PFS and OS were assumed as 0.65 and 
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0.73, respectively, with median PFS of 5 months and OS of 9 months in the comparator arm. A 
total of 480 patients would be enrolled in a 1:1 randomization over 17-month period at enrollment 
rates of 10 patients/month in the first month, 20 patients/month in the second month and 30 
patients/month in the next 15 months. Approximately 319 PFS events were planned in the PFS 
hypothesis testing to have a power of 90% with an alpha of 0.005. A group sequential testing of 
OS would be performed. The interim analysis was planned after approximately 67% of the total 
planned death events had occurred (241). The final analysis of OS would be performed when 
approximately 360 death events had been observed. The sample size calculation of OS was based 
on overall power of 82% and an alpha level of 0.02. 
The previous version of protocol amendment 3.0 was amended on 25 May 2020. The study 
sample size was increased from 480 to 622 to allow increased targeted numbers of events in the 
PFS and OS analyses, which was to account for the showed delayed treatment effect and 
increased usage of subsequent immunotherapies that were observed in the newly published 
immuno-oncology trials in the second-line ESCC (Kojima et al 2019; Kato et al 2019; Huang et al 
2019).  
By 24 November 2020, enrollment was completed with 649 randomized patients. In the current 
protocol amendment, BIRC-assessed PFS has been removed from the primary efficacy analysis 
based on the results from KEYNOTE-590 (Kato et al 2020) in the first-line treatment of ESCC. 
OS is the sole primary efficacy endpoint. The HR for OS is assumed to be 0.74 at the time of final 
analysis after an initial 1-month delayed treatment effect (e.g. assuming HR = 1 in the first 
month), the number of deaths required in the final analysis will be approximately 488 with 90% 
power by simulation. The planned interim analysis with a power of 81% will occur after 
approximately 423 events have been observed. A 5% annual dropout rate is assumed and one-
sided alpha of 0.025 is used in the sample size calculation. 
9.7. 
Interim Analyses  
An interim analysis of OS (see Section 9.2.1) will be performed by an independent statistician 
external to the Sponsor. The independent statistician will work with the blinded study statistician 
to provide statistical outputs to the IDMC as described in the IDMC charter and perform any ad-
hoc analyses requested by the IDMC. 
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Blinded Independent Review Committee  
A BIRC will be established to perform an independent review of all radiological images for the 
efficacy analysis, and to determine all instances of response and disease progression on the basis 
of the 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 on 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, 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 Imaging 
Manual and BIRC Charter. 
10.2. 
Independent Data Monitoring Committee  
As described in Section 3.8, enrollment of Japanese patients will be gated to monitor for 
unexpected or new safety concerns.  IDMC will review safety data of the safety cohort of 
approximately 10 Japanese patients after they complete 1 cycle of treatment or whenever there is a 
safety concerns.  Enrollment will continue only when the safety and tolerability are deemed 
acceptable by the IDMC. 
Regular safety monitoring (every 6 months or in longer, previously agreed on intervals after the 
first IDMC safety review if there are no significant safety concerns), and efficacy monitoring will 
be performed by an IDMC.  The first IDMC safety review will occur after approximately 50 
patients have been randomized to study treatment (ie, at least 25 patients per treatment arm) and 
have been on treatment for ≥ 1 month to determine if the proposed dosing schedule of 
tislelizumab is safe and tolerable.  The IDMC may recommend study modification including 
termination of the study due to safety and/or efficacy concerns. The IDMC will also be 
responsible for reviewing the results from pre-defined analyses, including final analysis of PFS 
and interim analysis of OS and making the recommendations for stopping the study based on pre-
defined efficacy boundaries.  The function and membership of the IDMC will be described in the 
IDMC charter. 
In addition to the planned IDMC review(s), ad hoc reviews may be performed based on new 
information.  
Following IDMC review and discussion, the sponsor will make all final decisions regarding any 
changes in study conduct. 
 
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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 International Conference on Harmonisation (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 BeiGene 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 
BeiGene 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 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 drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product.  Dispensation records will document quantities received from BeiGene’s 
designated depot or its designee and quantities dispensed to patients, including batch/lot number, 
date dispensed, patient identifier number, patient initials, and the initials of the person dispensing 
the medication. 
The Investigator and/or study personnel will keep accurate records of drug dispensed and used by 
each patient. This information must be captured in the source document at each patient visit. The 
Investigator is responsible for tislelizumab, cisplatin, oxaliplatin, 5-FU, capecitabine, and 
paclitaxel reconciliation, and record maintenance. In accordance with all applicable regulatory 
requirements, the Investigator or designated study center personnel must maintain tislelizumab, 
cisplatin, oxaliplatin, 5-FU, capecitabine, and paclitaxel accountability records throughout the 
course of the study. This person will document the amount of tislelizumab, cisplatin, oxaliplatin, 
5-FU, capecitabine, and paclitaxel received from the sponsor, the amount supplied, and/or 
administered (and returned by patients, if applicable). 
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At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction to ensure that it complies with BeiGene’s requirements specified in the 
Pharmacy Manual.  At appropriate times during the conduct of the study or at the end of the study, 
the study site will dispose of and/or destroy all unused study drug supplies following drug 
inventory reconciliation by the monitor.  These include empty containers, according to these 
procedures.  If the site cannot meet BeiGene’s requirements specified in the Pharmacy Manual for 
disposal, arrangements will be made between the site and BeiGene 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 PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the investigator and the study center in full conformance with the 
ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki or 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
Definitions and Standards for Expedited Reporting (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,  to the IRB/IEC by the investigator and 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. . 
The 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 the IRB/IEC.  Investigators may receive written investigational new drug (IND) 
safety reports or other safety-related communications from the sponsor.  Investigators are 
responsible for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/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 sponsor 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 reconsent 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, if the updated information may be relevant to the patient’s 
willingness to continue 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. All patients in the survival follow-up will reconsent to the updated ICF if the updates 
may be relevant to the patient’s willingness to continue participation in the study, either during 
on-site visits or by phone/video-call/mail, according to local regulations. The IRB/IEC submission 
letters, if applicable, should specify the approach taken (phone, video-call, or mail) according to 
local regulations. The process by which the consent is obtained from a patient during the survival 
follow-up should be documented in the patient’s case history or clinical records. 
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 investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study.  
The investigator must ensure that patients’ confidentiality will be strictly maintained and that their 
identities are protected from unauthorized parties.  Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to or collected by the sponsor or its service providers is: 1) required by the protocol, 
and 2) appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• Names or initials (full or partial); 
• Full dates of birth; 
• Contact information (such as phone numbers or home or email addresses);  
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• Numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• Geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• Information about marital status, family, or household members; employment, sex life, 
sexual preference, or other sensitive data that is not relevant to the study. 
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 US Food and Drug Administration (FDA), the China National Medical Products 
Administration, and all other national and local health authorities; by sponsor affiliates, 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 IB, this protocol, eCRFs, the 
investigational new drug, 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.  
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 the clinical investigators and/or disclose those financial 
interests, as required to the appropriate health authorities. This is intended to ensure financial 
interests and arrangements of the clinical investigators with BeiGene 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 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 investigator or designee as identified on Form FDA 1572 
must provide e-signature in the EDC system to attest to its accuracy, authenticity, and 
completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available in 
any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities.  
14.1.2. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored by BeiGene 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 study, a study monitor (clinical research associate) 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 with due consideration given to data protection and medical 
confidentiality. 
AEs will be coded using the MedDRA Version 20.0 or higher.  Concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary.  Concomitant 
diseases/medical history will be coded using the MedDRA Version 20.0 or higher. 
14.2. 
Data Integrity and In-House Blinding  
Due to the blinded design of the study, access to the patient level clinical data in the EDC system 
will be assigned to predefined study personnel only.  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 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. 
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Analyses or summaries generated by randomized treatment assignment and actual treatment 
received will be limited and documented. 
Bioanalytical labs may not be blinded as long as there are no means for the investigators or 
blinded sponsor team to know which samples will be analyzed or not. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least 1 the following categories: 1) investigator’s study file, and/or 2) 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, informed consent, 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 documents such as (although 
not be limited to) 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, screening and enrollment log, etc.  
Following 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 assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator must ensure 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 the 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 the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that they can be returned sealed 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. 
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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. 
The investigator is to document and explain any deviations from the approved protocol.  The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC policies 
and procedures.  
14.5. 
Publication and Data Sharing Policy  
A clinical study report will be prepared and provided to the regulatory agency(ies).  BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3).  Note that 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 
regulator 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.  As this is 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 Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
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 sponsor 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. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the investigator’s clinical study agreement. 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: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
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• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Return of treatment codes to the sponsor 
• Shipment of PK samples to assay laboratories 
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 reasons including, 
but not limited to, safety or ethical issues or severe noncompliance.  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 prior to it taking 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 IEC/IRB promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor.  In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which 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.  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 IEC/IRB solely for the 
evaluation of the study 
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• 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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immune activation in HCC. J Hepatol. 2015;62:1420-9.  
National Comprehensive Cancer Network (NCCN) guidelines version 1. (2017). Esophageal and 
esophagogastric junction cancers. 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#esophageal  
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.  
Oxaliplatin (Eloxatin®) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; 2014.  
Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular 
carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681-700.  
Shah MA. Update on metastatic gastric and esophageal cancers. J Clin Oncol. 
2015;33(16):1760-9.  
Shirasu H, Tsushima T, Furuta M, et al. Prognostic significance of nutritional risk index in 
patients with metastatic esophageal squamous cell cancer. J Clin Oncol. 2018;36(4):156.  
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.  
Soar J, Pumphrey R, Cant A, et al. Emergency treatment of anaphylactic reactions--guidelines for 
healthcare providers. Resuscitation. 2008;77(2):157-69.  
Stahl M, Oliveira J, ESMO Guidelines Working Group. Esophageal cancer: ESMO clinical 
recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20 Suppl 4: 32-3.  
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of 
chronic hepatitis B: AASLD 2018 hepatitis B guidance. Clin Liver Dis (Hoboken). 
2018;12(1):33-4.  
Vahle JL. Immunogenicity and Immune Complex Disease in Preclinical Safety Studies. Toxicol 
Pathol. 2018;46(8):1013-19.  
Worobec AS, Rosenberg AS. A risk-based approach to immunogenicity concerns of therapeutic 
protein products, part 1: considering consequences of the immune response to a protein. BioPharm 
Intl. 2004a;17(11). http://www.biopharminternational.com/risk-based-approach-immunogenicity-
concerns-therapeutic-protein-products-part-1-considering-conseque. Accessed 01 August 2017.  
Worobec AS, Rosenberg AS. A risk-based approach to immunogenicity concerns of therapeutic 
protein products, part 2: considering host-specific and product-specific factors impacting 
immunogenicity. BioPharm Intl. 2004b;17(12). http://www.biopharminternational.com/risk-
based-approach-immunogenicity-concerns-therapeutic-protein-products-part-2-considering-host-
spe. Accessed 01 August 2017.  
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screening1 
Treatment Cycles 
Safety Follow-up3 
Survival 
Follow-up4 
Cycles 1 to 3 
(every 21 days) 
Cycle 4 and 
Subsequent 
Cycles 
(Every 21 Days) 
End of Treatment  
Visit2 
Days (Window) 
-28 to ~ -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
1 (± 3) 
 
30 ± 7 Days After Last 
Dose 
Every 3 
Months 
(± 14 days) 
Informed consent 
x 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
Randomization5 
x 
 
 
 
 
 
 
Demographics/medical history/prior 
medications/ ongoing cancer symptoms6 
x 
 
 
 
 
 
 
Cancer diagnosis and treatment history6 
x 
 
 
 
 
 
 
Vital signs/height and weight7 
x 
x 
x 
x 
x 
x 
 
Physical examination8 
x 
x 
 
 
x 
x 
 
ECOG Performance Status 
x 
x 
 
 
x 
x 
 
12-lead ECG9 
x 
As clinically indicated 
x 
 
Optical coherence tomography (or 
equivalent diagnostic test) and visual 
acuity tests10 
x 
Approximately every 15 weeks 
x 
 
Adverse events11 
x 
x 
x25 
x25 
x 
x 
 
Concomitant medications12 
x 
x 
x25 
x25 
x 
x 
 
Hematology13 
x1 
x 
x 
x 
x 
x 
 
Serum chemistry13 
x1 
x 
x 
x 
x 
x 
 
Coagulation parameters 13 
x 
x 
 
 
x 
x 
 
Urinalysis13 
x 
As clinically indicated 
 
Pregnancy test14 
x 
x 
 
 
x 
x 
 
Thyroid function15 
x1 
 
 
 
x 
x 
 
HBV/HCV tests16 
x 
Every 4 cycles and as clinically indicated 
 
Pulmonary function tests17 
x 
As clinically indicated 
 
 
Pharmacokinetics18 
 
x 
 
 
x 
x 
 
Anti-tislelizumab antibodies19 
 
x 
 
 
x 
x 
 
Tumor assessment20 
x 
 
 
 
x 
x 
x 
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Assessment 
Screening1 
Treatment Cycles 
Safety Follow-up3 
Survival 
Follow-up4 
Cycles 1 to 3 
(every 21 days) 
Cycle 4 and 
Subsequent 
Cycles 
(Every 21 Days) 
End of Treatment  
Visit2 
Days (Window) 
-28 to ~ -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
1 (± 3) 
 
30 ± 7 Days After Last 
Dose 
Every 3 
Months 
(± 14 days) 
Archival tumor tissue21 
x 
 
 
 
 
 
 
Fresh tumor tissue22 
x 
 
x22 (when PD is assessed) 
 
Study drug administration23 
 
x 
 
 
x 
 
 
EQ-5D-5L24 
x 
x 
 
 
x 
x 
 
EORTC QLQ-C3024 
x 
x 
 
 
x 
x 
 
EORTC QLQ-OES1824 
x 
x 
 
 
x 
x 
 
Survival status 
 
 
 
 
 
 
x 
Blood sample collection 
 
x26 
x27 (when CR/PR and/or PD is assessed) 
 
Abbreviations: ADA, antidrug antibodies; AE, adverse event; CT, computed tomography; DNA, deoxyribonucleic acid; ECG, electrocardiogram; ECOG, 
Eastern Cooperative Oncology Group; 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 Dimensions (health questionnaire); FFPE, formalin fixed paraffin-embedded; HBcAb, hepatitis B 
core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAb, hepatitis B surface antibody; 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; OCT, optical coherence tomography; PET, positron 
emission tomography; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; RNA, ribonucleic acid; SAE, serious adverse event; T3, 
triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; v, version. 
1. Written informed consent is required prior to performing any study-specific tests or procedures. Results of standard of care tests or examinations performed 
prior to obtaining informed consent and within 28 days prior to randomization may be used for screening assessments rather than repeating such tests (only 
applicable if the same radiographic procedure will be used throughout the study). 
2. The EOT/Safety Follow-up Visit is conducted when the Investigator determines that tislelizumab or chemotherapy will no longer be used. If routine 
laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the visit, tests need not be repeated. Tumor assessment is not required 
at the visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The EOT/Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of tislelizumab or chemotherapy, before the initiation of a 
new anticancer treatment, or before the first dose administration in the long-term extension/posttrial supply study for patients who are going to rollover to 
those studies, whichever occurs first. Patients receiving paclitaxel will need to be followed for safety and pregnancy for 180 days following the last dose. 
4. Survival Follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after the 
Safety Follow-up Visit until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor. All patients will be followed for survival and 
subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
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5. Patients will be randomized into either the tislelizumab with chemotherapy or placebo with chemotherapy arms via IRT. All patients are required to receive 
study treatment within 2 business days of randomization. 
6. Includes age or year of birth, gender, 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 prior to study entry may be collected for review by the 
Investigator. 
7. Vital signs collected on study include body temperature, pulse 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 within 30 minutes after the first infusion of 
tislelizumab. For subsequent infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 30 minutes after 
the infusion.  
8. Investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab 
treatment. For any change in vision, referral to an appropriate specialist will be made for further management guidance.   
9. The ECG recordings will be obtained during Screening, the Safety Follow-up Visit, and as clinically indicated at other time points. Patients should be resting 
in a for at least 10 minutes prior to each ECG collection. 
10. Eye exam, visual acuity test, and optical coherence tomography (OCT; or equivalent diagnostic test for retinal examination) captured as standard of care 
prior to obtaining written informed consent and within 28 days of randomization or first dose of study drug may be used rather than repeating tests. Eye 
exam, including visual acuity test, and optical coherence tomography (or equivalent diagnostic test) will be assessed by an appropriate specialist at the 
Screening visit. All patients will undergo repeat assessments approximately every 15 weeks (± 7 days) during study treatment and a final assessment at the 
EOT/Safety follow-up visit. 
11. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v4.03. All AEs will also be evaluated for seriousness. After the informed consent 
form has been signed, but prior to the administration of study drug, only SAEs should be reported. After initiation of study drug, all AEs and SAEs, 
regardless of relationship to study drug, will be reported until either 30 days after last dose of study drugs (including chemotherapy) or the initiation of new 
anticancer therapy, whichever occurs first. Immune-mediated AEs (serious or non-serious) should be reported until 90 days after the last dose of 
tislelizumab, regardless of whether the patient starts a new anticancer therapy. The investigator should report any SAEs that are assessed as related to 
tislelizumab treatment, at any time after treatment discontinuation. 
12. Concomitant medications include any prescription medications or over-the-counter medications. All concomitant medications received within 30 days before 
the first dose of study medication and 30 days after the last infusion of study medication should be recorded. At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded. Only new anti-cancer treatment will be collected at Survival 
Follow-up Visits. 
13. 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 2. If laboratory tests at screening are not performed within 7 days of Cycle 1, Day 1, these tests should be repeated and 
reviewed before study drug(s) administration. Hematology and serum chemistry (including liver function tests) will be performed weekly for the first 3 
cycles and then at the beginning of subsequent cycles (data collected as specified in Appendix 2). After Cycle 1, results are to be reviewed within 48 hours 
before study drug administration. Urinalysis is to be conducted during the treatment period only if clinically warranted.  Refer to Section 8.3.5 for additional 
information regarding clinical assessment and management of clinical laboratory abnormalities.  
14. 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. Serum pregnancy tests will be performed at each visit prior to dosing.  
15. Analysis of FT3, FT4, 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, et cetera), and at the Safety Follow-up Visit. 
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16. 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). If HBsAg or HBcAb is positive, then an HBV DNA test will be triggered. If HCV antibody is positive, an HCV RNA test will be 
triggered.  
17. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the underlying 
cancer or with a history of thoracic radiotherapy will have pulmonary function testing which may include, but is not limited to, spirometry and assessment of 
diffusion capacity done during the screening period to assist the determination of suitability on the study. 
18. 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 at Day 1 of Cycles 1, 2, 5, 9 and 17; A postdose (within 30 minutes after completing tislelizumab infusion) sample is required to be collected 
at Day 1 of Cycles 1 and 5. If IP treatment is not given, the predose PK samples are still recommended to be collected when patients are available at the 
study site. An additional PK sample is required to be collected at the 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. These tests are required when it is allowed by local 
regulations/IRBs/ECs. PK sample collection will stop after patients finish 3-year follow up.  
19. Blood used to test for anti-tislelizumab antibodies should be collected within 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 5, 9, and 17 and 
at the mandatory Safety Follow-up Visit. All samples should be drawn at the same time as blood collection for predose PK analysis. If IP treatment is not 
given, the predose ADA samples are still recommended to be collected when patients are available at the study site. These tests are required when it is 
allowed by local regulations/IRBs/ECs. ADA sample collection will stop after patients finish 3-year follow up. 
20. Radiological images captured as standard of care prior to obtaining written informed consent and within 28 days of randomization may be used rather than 
repeating tests (only applicable if the same radiographic procedure will be used throughout the study). All measurable and evaluable lesions are required to 
be assessed and documented at Screening and reassessed at each subsequent tumor evaluation. An MRI (or CT scan if MRI is contraindicated or not readily 
available) of the head may be required at screening based on clinical judgement; 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. During the study, tumor imaging will be performed every 6 weeks (± 7 
days) for the first 48 weeks, then every 9 weeks (± 7 days) after 48 weeks 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 on the planned schedule. The Investigator may perform additional scans or more 
frequent assessments if clinically indicated. See Section 7.5 for more information. Patients who discontinue study treatment early for reasons other than 
documented radiographic disease progression (eg, toxicity) will continue to undergo tumor assessments following the original plan until the patient 
experiences disease progression, withdraws consent, is lost to follow-up, dies, or until the study terminates, whichever occurs first. Tumor assessment should 
continue as planned in patients receiving study drug(s) beyond initial investigator-assessed progression. Tumor assessment in such patients should continue 
until study treatment discontinuation.  
21. Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 [≥ 6] unstained slides) for biomarker analysis. 
22. Fresh biopsy: In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 28 days before randomization) is needed (written 
informed consent is required prior to fresh tumor biopsies). An optional biopsy will be taken for patients with confirmed disease progression during the 
study. See Section 7.7 and Section 7.8 for more information. 
23. Tislelizumab will be administered first, followed by an approximate 30-minute observation period for safety surveillance, then the chemotherapy doublet 
will be administered (see Section 5.2). The chemotherapy doublet may be administered without regard to the sequence of chemotherapy (note that in 
Chemotherapy Doublet B, capecitabine is given orally daily). Platinum therapy may be stopped after 6 cycles, per site or investigator preference or standard 
practice. If platinum treatment is stopped, the non-platinum agent (fluoropyrimidine or paclitaxel) may continue at the regular schedule. 
24. To be completed prior to any clinical activities during on-study site visits. EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-OES18 will be completed at 
baseline, after randomization, prior to dosing or any clinical activities at every treatment cycle for the first 6 cycles, then every other cycle thereafter, and at 
the EOT Visit. Patient-reported outcome collection will stop after patients finish 3-year follow up. 
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25. Review of AEs and concomitant medications may be conducted by telephone on Days 8 and 15. 
26. Blood sample will be taken at baseline (predose on Day 1 of Cycle 1) for all randomized patients to explore the association of blood-based biomarkers with 
response and prognosis to tislelizumab in combination with chemotherapy or chemotherapy alone. Written patient consent is required for blood sample 
collection. 
27. Blood samples are highly recommended to be collected at first tumor response (CR/PR) and/or at confirmed disease progression to explore response and/or 
resistance mechanism to tislelizumab in combination with chemotherapy or chemotherapy alone. Written patient consent is required for optional blood 
sample collection. See Section 7.8 for more information. 
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
Function 
HBV and HCV 
Serology 
- Alkaline phosphatase 
- Alanine 
aminotransferase 
- Aspartate 
aminotransferase 
- Albumin 
- Total bilirubin 
- Direct bilirubin 
- Blood urea nitrogen or 
urea 
- Potassium 
- Sodium 
- Chloride 
- Magnesium 
- Phosphorous 
- Total calciuma 
- Creatinine 
- Glucose 
- Lactate 
dehydrogenase 
- Total protein 
- Creatine kinase (CK)b 
- CK-MBb 
- Lipase and/or 
Amylase 
- Hematocrit 
- Hemoglobin 
- Red blood cell 
count 
- Platelet counts 
- WBC count 
with automated 
differential 
- Lymphocyte 
count 
- Neutrophil 
count 
- Prothrombin time 
- Partial thromboplastin 
time or activated 
partial thromboplastin 
time 
- International 
normalized ratio 
- Glucose 
- Protein 
- Blood 
- Ketones 
- TSH 
- Free T3 
- Free T4 
- HBsAb 
- HBsAg 
- HBcAb 
- HBV DNAc 
- HCV Ab 
- HCV RNAc 
Abbreviations: Ab, antibody; CK-MB, creatine kinase cardiac isoenzyme; DNA, deoxyribonucleic acid; HBcAb, 
hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; pH, negative of the 
logarithm to base 10 of the activity of the (solvated) hydronium ion; RNA, ribonucleic acid; T3, triiodothyronine; 
T4, thyroxine; TSH, thyroid-stimulating hormone; WBC, white blood cells.  
a. 
For patients with hypoproteinemia, this value needs to be corrected, which means a corrected calcium is needed 
Formula to calculate the corrected calcium: Corrected Calcium = (0.8*(Normal Albumin-Pt’s Albumin)) + Serum Calcium  
Note: above formula assumes albumin units in g/dL. (online calculator is available at http://www.mdcalc.com/calcium-
correction-hypoalbuminemia#evidence) 
b. 
In the event CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
c. 
If HBsAg or HBcAb is positive, then an HBV DNA test will be triggered. If HCV antibody is positive, an HCV RNA test 
will be triggered. 
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APPENDIX 3. ECOG 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 house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
The text below was obtained from the following reference:  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (Version 1.1). Eur J Cancer. 2009;45:228-247. 
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 (v1.1).  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 exam (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 scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable 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 nonmeasurable 
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 
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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above 
• Blastic bone lesions are nonmeasurable 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) 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 
noncystic 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 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 nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological 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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Nontarget 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 nontarget 
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, since CT is more sensitive than X-ray, particularly in 
identifying new lesions.  However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• 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. 
• 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 
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where recurrence following complete response (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 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 progressive disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or nontarget) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• Progressive Disease (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 (SD): 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, SD and PD, 
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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 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 Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (<10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions.  
(Note: the appearance of 1 or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of 1 or more nontarget 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 nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
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target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable 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 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition: if all lesions are truly nonmeasurable) 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 nonmeasurable 
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 nonmeasurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must 
be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: 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 PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression.  An example of this is the 
patient who has visceral disease at baseline and while on trial has a CT or MRI brain ordered 
which 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 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 taking into account 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 nontarget 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 non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “best overall response”. 
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 time points (for example, a patient who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a BOR of PR).  
When SD 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 SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments.  For example, a 
patient who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after the first SD 
assessment would be considered unevaluable. 
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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
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”.  
In trials where confirmation of response is required, repeated ”NE” time point 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 time point responses of 
PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and unevaluability” 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 like 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. 
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 
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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 SD, measurements must have met the SD 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 or progressive disease is 
objectively documented (taking as reference for progressive disease 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 (in randomized trials, from date of 
randomization) 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 duration of response 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 take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice.  However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made. 
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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.  
Please contact the sponsor medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s 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’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) nephropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 6. 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. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the 
heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 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 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated AE 
(imAE) are intended as a 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, disease progression, 
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 tislelizumab and the adverse 
event? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the adverse event (AE) in the electronic case report form (eCRF) should be 
checked.  
For any adverse events not included in this appendix, please refer to the recent guidelines 
(Haanen et al 2017; Brahmer et al 2018) for further guidance on diagnostic evaluation and 
management of immune-mediated toxicities. 
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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 
culture, viral PCR, Clostridium difficile toxin, 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 Grade 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. 
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Recommended Diagnostic Tests in the Management of  
Possible Immune-Mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
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, and consider a muscle biopsy 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac enzyme; 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; HIV, human immunodeficiency 
virus; 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 study medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study 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 
 
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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-moderate 
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. 
3-4 
Severe or life-
threatening 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
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 at least 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 
N/A 
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. 
3-4 
Severe/life-threatening 
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. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
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. 
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. 
Continue study 
treatment. 
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. 
 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
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. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day. When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 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. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
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. 
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 or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
Diabetic Ketoacidosis 
Admit patient to hospital and follow 
procedures of admitting institution. 
Refer to endocrinologist for further 
diabetic management. 
Hold study treatment 
until blood glucose 
stabilized at baseline. 
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. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
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 3X 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 symptoms do not 
improve add immunosuppressant 
therapy.  Taper oral steroids over at 
least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. Discontinue 
if any evidence of 
myocardial 
involvement. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical Judgement) 
Study Drug 
Management 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2. 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin. 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; INR, 
international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; N/A, not 
applicable; 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 8. 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) 
equation1 and the Modification of Diet in Renal Disease (MDRD) Study equation. The National 
Kidney Disease Education Program (NKDEP) calculators rely on creatinine determinations 
which are isotope dilution mass spectrometry (IDMS) traceable.  All laboratories should be using 
creatinine methods calibrated to be IDMS traceable.   
This CKD-EPI equation calculator should be used when Scr reported in mg/dL.  This equation is 
recommended when eGFR 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. 
Sites may use a different equation than the one listed above if consistent with local guidance. 
 
1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-12). 
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APPENDIX 9. 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. 
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal). If oral (birth 
control pills with estrogen and/or progestogen, below) are selected, they must be used 
with a barrier form of contraception (see below) simultaneously. 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• 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, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, 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 a highly effective form of birth control 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) 
• Postmenopausal, defined as: 
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− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/mL 
and all alternative medical causes for lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc.  
If an FSH measurement is required to confirm postmenopausal state, concomitant 
use of hormonal contraception or hormonal replacement therapy should be 
excluded. 
 
Adapted from Clinical Trials Facilitation Group (CTFG).  Recommendations related to contraception 
and pregnancy testing in clinical trials.  September 15, 2014. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
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APPENDIX 10.  EORTC-QLQ-C30 QUESTIONNAIRE  
 
 
 
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APPENDIX 11.  EORTC QLQ-OES18 QUESTIONNAIRE  
 
 
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APPENDIX 12.  EQ-5D-5L QUESTIONNAIRE  
 
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APPENDIX 13. FLOW CHART  
 
Abbreviations: ESCC, esophageal squamous cell carcinoma; mets, metastasis; NCCN, National Comprehensive 
Cancer Network; TFI, treatment-free interval 
1. Combinations include any combination of surgery, chemotherapy and radiotherapy. 
2. TFI: treatment-free interval. Duration from the last day of prior treatment therapy. 
3. Patients who had surgery or radio therapy alone, local chemotherapy (e.g., intrathoracic chemotherapy), or any 
systemic chemotherapy (neoadjuvant, concurrent, or adjuvant) with a nonplatinum-based regimen (except for 
paclitaxel monotherapy), even if the TFI was ≤ 6 months, are eligible for platinum-based chemotherapy doublet 
and are appropriate for this study. 
4. Patients who had progression after receiving ≥ 2 definitive therapies are also allowed into this study as long as 
TFI > 6 mo. Patients with TFI ≤ 6 months with no prior platinum-based chemotherapy are also eligible. 
5. The chemotherapy in concurrent chemoradiotherapy is usually deemed as a chemosensitizer. In this case, 
patients may be enrolled into the study, even if the TFI is ≤ 6 months.  
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APPENDIX 14. AMERICAN JOINT COMMITTEE ON CANCER TNM 
CLASSIFICATION OF CARCINOMA OF THE 
ESOPHAGUS AND ESOPAGOGASTRIC JUNCTION (7TH 
ED, 2010)  
 
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Squamous-cell carcinoma stage groupings 
 
 
 
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APPENDIX 15. NUTRITIONAL RISK INDEX  
 
Recent weight loss history of the patient may not always be known and the body weight loss 
does not take the albumin level into consideration, so the Nutritional Risk Index (NRI) is 
referenced as an alternative per investigator’s choice to assess the patient’s nutritional status for 
the purpose of eligibility. The formula is provided below (Shirasu et al 2018): 
 
NRI = (1.489 × serum albumin) + (41.7 × present body weight / ideal body weight) 
 
The Ideal Body Weight (IBW) formula is based on the Peterson formula (Peterson, 2016):  
IBW (kg) = 2.2 x Target BMI + [3.5 x Target BMI x (Height (m) - 1.5 m)]. For the purpose of 
this study, we will use a Target BMI of 22, so the formula becomes: 
IBW (kg) = 48.4 + [77 x (Height (m) - 1.5 m)] 
 
Or you can use below online calculator to calculate the IBW, and please choose the calculation 
results of the Peterson formula: 
https://www.gigacalculator.com/calculators/ideal-weight-calculator.php 
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Signature Page 
Approval with eSignature
Development
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SAP_001.pdf: 
BeiGene USA, Inc 
    BGB-A317-306 
     (Statistical Analysis Plan) 
Version 2.0: Feb 2022 
Page 1 of 56 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-A317-306 
Study Protocol 
Title: 
A Randomized, Placebo-Controlled, Double-Blind Phase 3 Study to 
Evaluate the Efficacy and Safety of Tislelizumab (BGB-A317) in 
Combination with Chemotherapy as First-Line Treatment in Patients 
with Unresectable, Locally Advanced Recurrent or Metastatic 
Esophageal Squamous Cell Carcinoma 
Date: 
Feb 18, 2022 
Version: 
Version 2.0 
DocuSign Envelope ID: ACF023F5-E0D4-4B7F-BB45-9BBB2890726B
Version
.0
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7.5
Safety Analyses 
38
7.5.1
Adverse Events 
41
7.5.1.1
Treatment Emergent Adverse Event 
42
7.5.1.2
Immune-mediated Adverse Event 
45
7.5.1.3
Infusion-related Adverse Event 
45
7.5.2
Death 
45
7.5.3
Laboratory Values 
45
7.5.4
Vital Signs 
47
7.5.5
Ophthalmology Examination 
47
7.5.6
Electrocardiograms (ECG) 
48
7.5.7
ECOG 
48
7.6
Pharmacokinetic Analyses 
48
7.7
Immunogenicity 
48
7.8
Other Analysis 
49
8
INTERIM ANALYSIS 
49
9
CHANGES IN THE PLANNED ANALYSIS 
50
10
REFERENCES 
51
11
APPENDIX 
52
11.1
Impute partial dates for concomitant medication 
52
11.2
Impute partial dates for adverse events 
52
11.3
Impute partial dates for subsequent anti-cancer surgery/procedure 
53
11.4
Rules for identifying missing tumor assessments 
54
11.5
Immune-mediated Adverse Event Category List 
56
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Tracking Changes 
 
Update Content 
Update Impact 
Section (Current 
index) 
Cutoff -> cutoff 
Change TAP score to PD-L1 
score 
Change gender to sex 
minor 
overall 
Update prior definitive therapy 
criteria for clarity 
minor 
2.1 
Change biomarker wording  
minor 
3.2 
Clarity added for estimand 
Clarity added to “Asia”: i.e., 
including Asia (excluding Japan” 
and Japan as described in the 
protocol 
minor 
4 & overall 
Add clarity to safety analysis set 
minor 
7.1 
For prior definitive therapy, add 
cancer-related to surgery 
 Update summary items 
minor 
2.1 
7.3.5 
drop by indication table 
 
minor 
7.3.6  
Add clarity for sensitivity 
analysis, drop sensitivity analysis 
3(unpooled region as stratification 
factor), sensitivity analysis 4(PD-
L1 status as stratification factor) 
for post-hoc as needed 
minor 
7.4.1 
Estimated using Greenwood's 
formula update reference to  
Kalbfleisch and Prentice 1980 
Drop rank preserving and two-
stage supportive analysis 
minor 
7.4.2 
Clarify that Tradition Chinese 
Medicine are not considered as 
next line anticancer therapy for 
efficacy and safety 
minor 
7.4.3 
adding ND from IRC as valid 
assessment of PFS 
Add more clarity to PFS2 
censoring 
minor 
7.4.4 
Subsequent anti-cancer therapy 
also summarized by region, 
adding Asia(excluding Japan) vs. 
minor 
7.4.6 
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Japan vs. Rest of world for OS by 
subgroup analysis 
 
Add infusion rate decreased into 
the analyses of  
dose modification  
Add tislelizumab/placebo related 
TEAE leading to death occurring 
>=2 pts summary 
Add rationale of TEAE definition 
change 
Update AE summary 
Add clarity of exposure adjusted 
AE 
major 
7.5 & 7.5.1 
Add lab parameter 
Add by region tables 
minor 
7.5.3 
Update AE partial missing 
imputation 
minor 
11.2 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BCLC 
Barcelona Clinic Liver Cancer 
BGB-A317 
Code name for monoclonal antibody tislelizumab 
BID 
Twice daily 
BIRC 
Blinded Independent Review Committee 
BOR 
Best overall response 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
CP 
Child-Pugh 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
Ctrough 
Trough serum concentration 
DCR 
Disease control rate 
DOR 
Duration of response 
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ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQ-5D 
European Quality of Life 5-Dimensions 
EORTC QLQ-HCC 18 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Hepatocellular Carcinoma 18 Questions 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-position emission tomography 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HbcAb 
Hepatitis B core antibody 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
INR 
International Normalized Ratio 
imAE 
Immune-mediated adverse event 
ITT 
Intent-to-Treat 
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IV 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PO 
Orally 
PP 
Per-Protocol  
PR 
Partial response 
ROW 
Rest of world 
Q2W 
Once every 2 weeks 
Q3W 
Once every 3 weeks 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOC 
System Organ Class 
TACE 
Transarterial chemoembolization 
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TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
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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 A317-306: A Randomized, Placebo-
Controlled, Double-Blind Phase 3 Study to Evaluate the Efficacy and Safety of Tislelizumab 
(BGB-A317) in Combination with Chemotherapy as First-Line Treatment in Patients with 
Unresectable, Locally Advanced Recurrent or Metastatic Esophageal Squamous Cell Carcinoma. 
The focus of this SAP is for the planned interim analysis and the final analysis specified in the 
study protocol. This SAP is based on BGB-A317-306 Protocol Amendment 4.0 dated on 
 2021. 
The analysis details for Pharmacokinetic (PK), Pharmacodynamics, Pharmacogenomics and 
Biomarker analyses are not described within this SAP. Separate analysis plans will be completed 
for these analyses. 
2 
STUDY OVERVIEW 
2.1 
STUDY DESIGN 
This is a randomized, placebo-controlled, double-blind, global Phase 3 study comparing efficacy 
and safety following treatment with the anti-programmed cell death protein-1 (PD-1) monoclonal 
antibody tislelizumab in combination with standard chemotherapy compared to placebo in 
combination with chemotherapy when given as the first-line treatment in patients with 
unresectable, locally advanced recurrent or metastatic ESCC. 
The study design schema is as follows: 
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regimens.  
x Arm A:   
o Tislelizumab + chemotherapy doublet 
o The chemotherapy doublet will consist of: 
 Platinum (cisplatin or oxaliplatin) and a fluoropyrimidine (capecitabine or 
5-fluorouracil [5-FU]) 
OR 
 Platinum (cisplatin or oxaliplatin) and paclitaxel 
x Arm B:   
o Placebo + chemotherapy doublet 
o The chemotherapy doublet will consist of: 
 Platinum (cisplatin or oxaliplatin) and a fluoropyrimidine (capecitabine or 
5-FU) 
OR 
 Platinum (cisplatin or oxaliplatin) and paclitaxel 
 
The platinum agent may be cisplatin or oxaliplatin (except in China (including Taiwan) and 
Japan where oxaliplatin substitution is not permitted) according to site or investigator preference 
or standard practice as determined prior to randomization. 
Cross-over between treatment arms or switch between fluoropyrimidine and paclitaxel during the 
study treatment period will not be allowed. 
Study treatment will be administered until disease progression, intolerable toxicity, or another 
reason for treatment discontinuation criterion is met. Platinum therapy may be stopped after 6 
cycles, per site or investigator preference or standard practice. If platinum treatment is stopped, 
the non-platinum agent (fluoropyrimidine or paclitaxel) may continue at the regular schedule. 
2.2 
STUDY ASSESSMENTS 
Tumor response will be assessed by the investigator or by the BIRC for the assessment of the 
secondary endpoints and exploratory endpoints. Baseline tumor imaging (computed tomography 
[CT] with or without contrast or magnetic resonance imaging [MRI]) must be performed within 
28 days prior to randomization. Post-baseline tumor assessments will occur every 6 weeks 
(± 7 days) for the first 48 weeks after randomization, then every 9 weeks (± 7 days) based on 
RECIST v1.1, regardless of treatment delays, until disease progression. Patients who discontinue 
study treatment early for reasons other than documented radiographic disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original plan until the patient 
experiences radiographic disease progression, withdraws consent, is lost to follow-up, death, or 
until the study completes, whichever occurs first. Investigators must obtain written informed 
consent for treatment beyond radiologic disease progression and inform patients that this practice 
is not considered standard in the treatment of cancer. 
Patient Reported Outcomes (PROs) of HRQoL will be collected using the EORTC QLQ-C30, 
EORTC QLQ-OES18, and the EQ-5D-5L at baseline, prior to dosing of every treatment cycle 
for the first 6 cycles, then every other cycle afterwards, and at the Safety Follow-up Visit. 
All AEs will be reported during the study (AEs from the time of the first dose and SAEs from the 
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time of signing of informed consent) and for up to 30 days after the last dose of study drug(s) 
(including chemotherapy) or until initiation of another anticancer therapy, whichever occurs first. 
Immune-mediated AEs (which is equivalent to protocol defined immune-related AEs, serious or 
non-serious) should be reported up to 90 days after the last dose of tislelizumab, regardless of 
whether the patient starts a new anticancer therapy. The investigator should report any SAEs that 
are assessed as related to study treatment, at any time after treatment discontinuation. AEs will 
be graded according to NCI CTCAE v4.03. 
Safety and efficacy monitoring will be performed by an Independent Data Monitoring Committee 
(IDMC). The IDMC may recommend modifications to the study, including termination due to 
safety and/or efficacy concerns. The functions and membership of the IDMC will be described in 
an IDMC Charter. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
x To evaluate and compare the overall survival (OS) following treatment with 
tislelizumab in combination with chemotherapy compared to placebo in combination 
with chemotherapy when given as first-line treatment in patients with unresectable, 
locally advanced recurrent or metastatic ESCC 
3.2 
SECONDARY OBJECTIVES  
x To evaluate and compare the efficacy of tislelizumab in combination with 
chemotherapy compared to placebo in combination with chemotherapy as a first-line 
treatment in unresectable, locally advanced recurrent or metastatic ESCC as measured 
by PFS, ORR, and DOR assessed by the investigator per RECIST v1.1 
x To evaluate and compare the efficacy of tislelizumab in combination with 
chemotherapy with the efficacy of placebo in combination with chemotherapy as a 
first-line treatment in unresectable, locally advanced recurrent or metastatic ESCC as 
measured by OS in the PD-L1 score  10% subgroup.  PD-L1 expression is 
determined by PD-L1 score assessed by tumor area positive score (TAP) (previously 
referred to visually estimated Combined Positive Score [vCPS] in protocol), which is 
defined as the total percentage of the tumor area covered by tumor cells with any 
membrane staining above background and tumor-associated immune cells with any 
staining above background using Ventana PD-L1 (SP263) assay 
x To evaluate and compare health-related quality of life (HRQoL) based on patient-
reported outcomes (PROs) between tislelizumab in combination with chemotherapy 
and placebo in combination with chemotherapy 
x To compare the safety between tislelizumab in combination with chemotherapy and 
placebo in combination with chemotherapy 
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3.3 
EXPLORATORY OBJECTIVES  
x To characterize the DCR with tislelizumab in combination with chemotherapy 
assessed by the investigator per RECIST v1.1 
x To evaluate PFS, ORR, DOR and DCR assessed by BIRC per RECIST v1.1 
x To assess PFS after next line of treatment (PFS2) 
x To explore biomarkers in tumor tissues and/or blood samples before and after study 
treatment and/or at PD/reoccurrence, and the association between these biomarkers 
and clinical efficacy, disease status, and resistance. Biomarker assessment will consist 
of PD-L1 expression, gene expression profiling (GEP), tumor mutation burden 
(TMB)/microsatellite instability (MSI)/mutation profile, and tumor-infiltrating 
immune cells. Other assessments may be conducted as allowed by local regulations. 
x Assessments of pharmacokinetics of tislelizumab when given with chemotherapy 
x To assess host immunogenicity to tislelizumab in combination with chemotherapy 
4 
DEFINITION OF PRIMARY ESTIMAND  
The primary scientific question of interest is: will the addition of Tislelizumab to chemotherapy 
doublet treatment prolong survival in first line ESCC patients, regardless of  subsequent  anticancer 
therapy? 
   
The primary estimand is described by the following attributes:  
 
1. Treatment of interest:  
The treatment of interest is the randomized treatment (tislelizumab plus chemotherapy 
doublet as experimental regimen versus placebo plus chemotherapy doublet as control 
regimen). Doublets include platinum (Cisplatin or Oxaliplatin) with fluoropyrimidine (5-
Fluorouracil or Capecitabine) or Paclitaxel.  
2. Population:  
All subjects randomized in the study--Adult patients with unresectable, locally advanced recurrent 
or metastatic ESCC, who have not received prior systemic therapy for locally advanced 
unresectable or metastatic ESCC. Further details on the population characteristics are provided in 
the protocol eligibility criteria(Details refer to Section 4 in protocol). 
3. Primary variable:  
Overall survival (see Section 5.1.1), defined as the time from the date of randomization to 
the date of death due to any cause  
4. Handling of intercurrent events:  
x New anticancer therapy started prior to death: any new anticancer therapy will be 
ignored (treatment policy strategy)  
x Discontinuation of study treatment:  discontinuation of any component of study 
treatment will be ignored (treatment policy strategy).  
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x Any unforeseen intercurrent events (e.g., COVID-19 -related events): OS will take 
into account all deaths irrespective of any unforeseen intercurrent events (treatment 
policy strategy) 
 
5. Summary measure: 
Hazard ratio (HR) of OS comparing tislelizumab plus chemotherapy doublet versus placebo plus 
chemotherapy doublet, stratified by pooled geographic region* (Asia vs Rest of World), prior 
definitive therapy (yes vs no) and ICC option (Investigator choice of chemotherapy [platinum 
with fluoropyrimidine vs platinum with paclitaxel]). 
*: Pooled geographic region as   “Asia” include  “Asia [excluding Japan]” and “ Japan”  which 
are defined as geographic regions in study protocol. 
5 
STUDY ENDPOINTS 
5.1.1 Primary Endpoint 
x OS - defined as the time from the date of randomization until the date of death due to 
any cause 
5.1.2 Secondary Endpoints 
x PFS - defined as the time from the date of randomization to the date of first 
documentation of disease progression assessed by investigator per RECIST v1.1 or 
death, whichever occurs first 
x ORR - defined as the proportion of patients whose best overall response (BOR) is 
complete response (CR) or partial response (PR) assessed by investigator per 
RECIST v1.1 
x OS in the PD-L1 score  10% subgroup 
x DOR- defined as the time from the first determination of an objective response until 
the first documentation of progression assessed by investigator per RECIST v1.1 or 
death, whichever comes first 
x HRQoL assessment of the patient’s overall health status using European EORTC 
QLQ-C30 index, the European esophageal cancer specific module EORTC QLQ-
OES18, and the generic health state instrument EuroQol 5D (EQ-5D-5L) 
x The incidence and severity of treatment-emergent adverse events (TEAEs) according 
to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v4.03 
5.1.3 Exploratory Endpoints 
x DCR - defined as the proportion of patients whose BOR is CR, PR, and stable disease 
(SD) assessed by investigator per RECIST v1.1 
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x PFS, ORR, DOR and DCR assessed by the BIRC per RECIST v1.1 
x PFS2 - defined as the time from randomization to the objective disease progression 
after next line of treatment or death from any cause, whichever occurs first. 
x 
To explore biomarkers including but not limited to PD-L1 expression, gene 
expression profiling (GEP), tumor-infiltrating lymphocytes (TIL), tumor mutation 
profile/tumor mutation burden (TMB)/microsatellite instability-high (MSI-H) status 
in tumor tissue and/or blood sample before, after study treatment, and/or at 
progressive disease (PD)/reoccurrence, and the association between these biomarkers 
and clinical efficacy, disease status, and resistance 
x Assessments of pharmacokinetics of tislelizumab when given with chemotherapy 
x Assessments of immunogenicity of tislelizumab to determine the incidence of anti-
drug antibodies (ADA) 
6 
SAMPLE SIZE CONSIDERATIONS 
The initial sample size calculation was based on the primary efficacy analysis of PFS and OS in 
the comparison between tislelizumab in combination with chemotherapy arm and placebo plus 
chemotherapy arm in the ITT analysis set. The Type I error was strongly controlled by initially 
assigning a one-sided alpha of 0.005 to the PFS hypothesis and 0.02 to the OS hypothesis. 
Hazard ratios in PFS and OS were assumed as 0.65 and 0.73, respectively, with median PFS of 5 
months and OS of 9 months in the comparator arm. A total of 480 patients would be enrolled in a 
1:1 randomization over a 17-month period at enrollment rates of 10 patients/month in the first 
month, 20 patients/month in the second month and 30 patients/month in the next 15 months. 
Approximately 319 PFS events were planned in the PFS hypothesis testing to have a power of 
90% with an one sided alpha of 0.005. A group sequential testing of OS would be performed. 
The interim analysis was planned after approximately 67% of the total planned death events had 
occurred (241). The final analysis of OS would be performed when approximately 360 death 
events have been observed. The sample size calculation of OS was based on overall power of 
82% and an one-sided alpha level of 0.02. 
The protocol amendment 3.0 was amended on 25 May 2020.The PFS and OS hazard ratio 
assumptions was updated after reviewing the recently published results of anti-PD-1 therapies in 
the second line treatment of ESCC (Kojima et al 2019, Kato et al 2019, Huang et al 2019) which 
showed delayed treatment effect and increased usage of subsequent immunotherapies. Using a 
more conservative OS HR assumption of 0.76 around the time of final analysis after an initial 3-
month delayed treatment effect (e.g. assuming HR=1 in the first 3 months), the number of deaths 
required in the final analysis is increased from approximately 360 to 467 events for an 81% power 
using simulation. The updated number of deaths planned in the interim analysis with the 
aforementioned statistical methodology is increased from approximately 241 to 313 events. 
Similarly, with a PFS HR assumption of 0.68 around the time of interim analysis after an initial 3-
month delayed treatment effect, the PFS events are increased from approximately 319 to 423 
events to achieve an estimated power of 92% in the interim analysis (final analysis for PFS) using 
simulation. The interim analysis will be carried out after both targeted PFS and death events are 
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met. The sample size is increased to 622 patients who will be enrolled over an estimated 26-month 
period. A 5% annual dropout rate is assumed in the sample size calculation. 
By Nov 24, 2020, enrollment was completed with 649 randomized patients. In the current 
protocol amendment 4.0, PFS per BIRC is dropped from the primary efficacy analysis as it is no 
longer considered as approvable endpoint given the positive OS results from KEYNOTE-590 
(Kato et al 2020) in the 1st line treatment of ESCC. OS is kept as the sole primary efficacy 
endpoint. OS HR is assumed to be 0.74 at the time of final analysis after an initial 1-month 
delayed treatment effect (e.g. assuming HR=1 in the first month), the number of deaths required 
in the final analysis will be approximately 488 with 90% power by simulation. The planned 
interim analysis with a power of 81% will occur after 423 events have been observed.  A 5% 
annual dropout rate is assumed and one-sided alpha of 0.025 is used in the sample size 
calculation. 
7 
STATISTICAL METHODS 
7.1 
ANALYSIS POPULATIONS 
x The Intention-to-Treat (ITT) analysis set includes all randomized patients. It will be the 
primary analysis population for the efficacy analysis  
x The Safety analysis set includes all patients who received at least 1 dose of study drug. It 
will be the primary analysis population for safety analysis.  
x The Pharmacokinetics (PK) analysis set includes all patients who are receive at least 1 
dose of tislelizumab per the protocol, for whom any post-dose PK data are available 
x The ADA analysis set includes all patients who have a baseline and at least 1 post-
baseline ADA result 
 
7.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
7.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first dose of study drug 
(for safety analysis) or randomization date (for efficacy analysis).  For assessments conducted on 
or after the date of the randomization date/first dose of study drug, study day will be calculated 
as (assessment date – randomization date/date of first dose of study drug + 1).  For assessments 
conducted before the date of the randomization date/first dose of study drug, study day is 
calculated as (assessment date – randomization date/date of first dose of study drug). 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 11. 
Baseline Measurements: 
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x Baseline characteristics and efficacy analysis including HRQol:  a baseline value is 
defined as the last non-missing value collected up to the randomization.  
x Safety analysis: a baseline value is defined as the last non-missing value up to the first 
study drug administration. 
Study Follow-up Duration (SFD): Study follow-up duration is defined as the duration from the 
randomization date to death date if the patient died prior to data cutoff, or the study discontinuation 
date if the patient discontinued from study prior to data cutoff, otherwise to the data cutoff date. 
Minimum study follow up (MinFU) is defined as a difference between the date of cutoff and the 
date of last patient randomized. 
All calculations and analyses will be conducted using SAS version 9.4 or higher. 
7.2.2 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 Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
x P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
x Time-to-event or duration of event endpoints will be based on the actual date the 
radiograph was obtained rather than the associated visit date. 
x Missing efficacy or safety data will not be imputed unless otherwise specified. 
x For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
x For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator, unless otherwise specified. 
x For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
7.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. This included 
withdraw from study by subjects which have no further data collection.  Missing dates or 
partially missing dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures.  
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Specific rules for handling of missing or partially missing dates for adverse events, 
prior/concomitant medications/procedures, and subsequent anti-cancer therapy are provided in 
Appendix 11.1, 11.2, 11.3 and 11.4 
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.  
7.2.4 Adjustments for Covariates / Stratification 
The stratification factors used for randomization (IRT recorded), including pooled geographic 
region (Asia vs Rest of World), prior definitive therapy (yes vs no) and ICC option 
(Investigator choice of chemotherapy [platinum with fluoropyrimidine vs platinum with 
paclitaxel]), will be used in stratified log-rank test and stratified Cox proportional hazard model 
for primary endpoint OS and secondary endpoints PFS and other secondary endpoints. 
Similarly these stratification factors will be used in Cochran-Mantel-Haenszel method to 
analyze ORR. 
 
7.2.5 Multiplicity Adjustment 
The type I error will be strongly controlled at 0.025 (1-sided) in the primary analysis of OS in the 
ITT analysis set.  
There will be 1 interim analysis of OS utilizing the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. Details may refer to 
Section 8. 
 By using the graphical approach of Bretz et al 2009, if the null hypothesis for OS in the ITT 
analysis set is rejected, the corresponding alpha will be shifted to the hypothesis tests of the 
secondary endpoints, PFS by investigator in ITT, ORR by investigator in ITT, OS in PD-L1 
score10% subgroup and HRQoL in ITT, which will be tested sequentially. The inferential test 
will be stopped at the first non-significant endpoint. For HRQoL, Bonferroni method will be 
applied to the test of OES 3 symptoms dysphagia, eating and reflux using an alpha of 0.0083. To 
control overall type I error in the secondary endpoint testing, all secondary endpoints will be 
tested only once using data from the interim analysis with an alpha of 0.025 (0.0083 for each of 
the beforementioned OES symptoms), no matter when the null hypothesis of OS in the primary 
analysis is rejected (IA or final). Therefore, if OS superiority is demonstrated only at the final 
analysis, the results of secondary endpoints from the interim analysis will be used for hypothesis 
testing, while those data from the final analysis will be summarized for descriptive purpose 
only.  
The data set for analysis should be an accurate and complete representation of the subjects' 
relevant outcomes from the clinical database.  All data should be complete and reviewed up to a 
pre-specified cutoff date.  Consistency checks and appropriate source data verification should be 
complete. 
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7.3 
SUBJECT CHARACTERISTICS 
7.3.1 Subject Disposition 
The number (percentage) of patients who signed informed consent, randomization, screen 
failures, and screened previously will be summarized. The number (percentage) of screen failure 
reason will also be summarized. 
The number (percentage) of subjects randomized, treated, discontinued from treatment and 
discontinued from the study will be summarized. The primary reason for end of treatment (study 
drug discontinuation) and end of study will be summarized by categories in the eCRF. Study 
follow-up duration will be summarized descriptively.  
Patient disposition and reasons for discontinuation will also be summarized by region (Asia vs 
Rest of World) for ITT analysis set. 
7.3.2 Protocol Deviations 
Protocol deviation criteria will be established together with its category/term of important or not 
important. Patients with important protocol deviations will be identified and documented before 
the database lock.  Important protocol deviations will be summarized for all patients in the ITT 
analysis set.  
Patient data listings of important and non-important protocol deviation will be provided. A 
separate list of patients with critical protocol deviation will also be provided. 
Important and non-important protocol deviations related to COVID-19 will be summarized. 
7.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the ITT Population using 
descriptive statistics.  
   
Demographic and other baseline characteristics include: 
 
x Age 
x Age group (<65 vs >= 65 years) 
x Sex 
x Race 
x Ethnicity 
x Height (cm) 
x Weight (kg) 
x BMI (kg/m2) 
x Region: (Asia: Japan, ex-Japan); Rest of World 
x Tobacco use status 
x Alcohol consumption status 
x ECOG status 
. 
The demographic summary will also be repeated by region (Asia and Rest of World) and by 
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baseline PD-L1 status in ITT population. 
In addition, the stratification factors per IRT and per eCRF will be summarized based on ITT 
population: 
 
x Prior definitive therapy (yes vs no) 
x Geography (Asia [excluding Japan] vs Japan vs Rest of World)  
x Choice of chemotherapy doublet (platinum plus fluoropyrimidine vs platinum plus 
paclitaxel) 
 
7.3.4 Disease History and Baseline Disease Characteristics 
Following disease history and characteristics at study entry will be summarized using ITT 
analysis set: 
x Time since initial cancer diagnosis to Study Entry (month) 
x Time since metastatic disease diagnosis to date of Study Entry (month) 
x Primary site of esophageal cancer  
x Histological Tumor differentiation grade and type  
x Disease stage at diagnosis 
x Metastatic disease status at study entry 
x  Metastatic location at study entry 
x Number of metastatic sites involved (0, 1, 2, 3) at study entry 
x Target lesions sum of diameters by investigator 
x PD-L1 status (PD-L1 score  10%, < 10 %, Unknown) 
Histology Grade Cancer associated symptoms at baseline will be coded by MedDRA version 
24.0 and summarized by system organ class, preferred term, and NCI CTCAE 4.03 grade using 
ITT analysis set. 
Disease history and characteristics at study entry will also be summarized by region (Asia and 
Rest of World) and baseline PD-L1 status in ITT analysis set 
Patient data listings of disease history and cancer associated symptoms at baseline will be 
provided. 
7.3.5 Prior Anti-Cancer Therapies and Surgeries 
The number of subjects receiving prior anti-cancer drug therapies, prior anti-cancer radiation 
therapy including prior chemo-radiation therapy, prior anti-cancer surgeries will be summarized. 
The therapies with the same sequence/regimen number are counted as one prior therapy. The 
number of subjects with at least one prior definitive therapy, and its subcategories, definitive 
surgery with/without adjuvant/neo-adjuvant treatment and definitive radiotherapy with/without 
chemotherapy, will also be summarized. In addition, time from end of last anti-cancer therapy to 
study entry will be summarized. 
The prior anti-cancer therapy will also be summarized by region (Asia and Rest of World) and 
by baseline PD-L1 status for ITT analysis set. 
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7.3.5.1 Prior Anti-Cancer Systemic Therapy 
The number (percentage) of patient with at least one prior anti-cancer systemic therapy, platinum 
based prior systemic therapy, treatment setting of prior anti-cancer systemic therapies, and 
duration of last prior anti-cancer systemic therapy (months) will be summarized by using ITT 
analysis set.   
The prior anti-cancer systemic will also be summarized by Anatomical Therapeutic Chemical 
(ATC) class and preferred term). 
Patient data listings of prior anti-cancer systematic therapy, radio therapy and surgeries will be 
provided.  
7.3.6 Prior and Concomitant Medication and Therapy 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes, and will be further classified to the appropriate Anatomical 
Therapeutic Chemical (ATC) code.  
The number (percentage) of subjects reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term by phase in the safety 
population. Prior medications are defined as medications that received within 30 days before 
randomization and stopped before the first dose date. Concomitant medications will be defined as 
medications that (1) started before the first dose of study drug and were continuing at the time of 
the first dose of study drug, or (2) started on or after the date of the first dose of study drug up to 
30 days after the subject’s last dose. 
 In addition, systemic corticosteroid/immunosuppressant received between the first dose of study 
drug and up to 90 days after last dose will be summarized. 
 Medication to treat COVID-19-related adverse events will also be summarized separately. A 
listing of prior and concomitant medications will be provided 
 
 
7.3.7 Medical History 
Medical History will be coded using MedDRA (version 24.0 or newer). The number (percentage) 
of subjects reporting a history of any medical condition, as recorded on the CRF, will be 
summarized by system organ class and preferred term in the safety population. A listing of medical 
history will be provided. 
7.4 
EFFICACY ANALYSIS 
7.4.1 Primary Efficacy Endpoint 
7.4.1.1 Primary Estimand 
Primary estimand is defined in Section 4. 
7.4.1.2 Primary analysis for primary estimand  
Overall survival is defined as time from randomization date to the documented death date for 
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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 (LKADT). 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 cutoff date whichever comes first for other alive patients.  
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 patients 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. Any deaths after missing visits are still considered as events. 
 
Overall Survival in ITT 
The null and alternative hypotheses to be evaluated for OS are: 
H0 : HR  1, 
Ha : HR< 1, 
where HR represents the hazard ratio between the treatment and the control groups, assuming a 
proportional hazard. The null hypothesis will be tested using a log-rank test stratified by pooled 
geographic region (Asia vs Rest of World), prior definitive therapy (yes vs no) and ICC option 
(Investigator choice of chemotherapy).  If the one-sided p-value is less than significance level 
threshold specified in table 7 for interim or final analysis, it will be concluded that the null 
hypothesis is rejected and the superiority of treatment group over the control group in OS is 
demonstrated at the significance level. 
The HR and its 2-sided 95% CI will be estimated from a stratified Cox regression model with the 
same stratification factors above. The stratified hazard ratio will be the main estimator for the 
primary estimand of OS. The exact method will be used for handling the tied events. 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. Ninety-five percent 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 (Kalbfleisch and Prentice 1980). Kaplan-Meier survival curve for each arm 
will also be provided.  
OS Sensitivity analyses and supportive analysis: 
¾ Analysis 1 “Unstratified OS sensitivity analysis”: To assess the impact of stratification, the 
unstratified HR together with the associated 95% confidence interval obtained using the 
unstratified Cox regression model will be presented. 
¾ Analysis 2 “OS sensitivity analysis with stratification factors from the eCRF”: To assess the 
impact of mis-stratification,  the HR together with the associated 95% confidence interval 
obtained using the stratified Cox regression model with stratification factors collected in the 
eCRF will be presented.  
¾ Analysis 3 ”OS Supportive analysis of Proportional hazard assumption”: Analyses to assess 
proportional hazard assumption including Schoenfeld residual plot and time dependent 
covariate using treatment by time interaction in the cox model will be explored.  
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Supplementary analyses related to OS 
Supplementary analysis 1 ”OS analysis based on Restricted mean survival time method”: This 
analysis targets an estimand which has the same attributes as the primary estimand except for the 
summary measure will be difference in Restricted mean survival time (RMST) between two 
treatment groups.  In order to account for the possible non-proportional hazard effect, the restricted 
mean survival time (RMST) (RMST, Uno H, Claggett B, Tian L, Inoue E, et al. 2014) will be 
computed for OS using the area under the curve from baseline to the minimum of the largest 
observed time on each of the two treatment groups. RMST will be computed for each treatment 
arm and the difference with its 95% CI will be displayed.  
 
Supplementary analysis 2 ”OS analysis based on Max-Combo method”: This analysis targets an 
estimand which has the same attributes as the primary estimand except for the summary 
measure which will be hazard ratio from combination of Fleming and Harrington weighted log-
rank test (FH) test (Max-Combo) based on the Gȡ,Ȗ family between two treatment groups.  In 
order to account for the possible non-proportional hazard effect, combination of G0,0, G0,1, G1,1 , 
G1,0  will be computed  which allows possibility for  different NPH type. 
 
Supplementary analysis 3 ‘OS analysis adjusted for baseline covariates’: The target population, 
the primary variable, the treatment of interest, intercurrent events are the same as for the primary 
estimand. A Cox regression model stratified by randomization stratification factors will be fitted 
to evaluate the effect of other baseline demographic and disease characteristics on the estimated 
hazard ratio. The fitted model adjusting the treatment difference for key baseline and prognostic 
factors will include as covariates the following: baseline PD-L1 status (PD-L1 score  10%, PD-
L1 score < 10%), age(<65, >=65), sex, race, smoking, ECOG status, metastatic (yes or no)   
Supplementary analysis 4 “COVID-19 OS supplementary analysis”: This analysis may be 
performed when there are sufficient patients (i.e., 5% of ITT) meeting the criteria below regarding 
COVID-19. This analysis will aim at assessing the treatment effect based on OS had COVID-19 
pandemic not occurred will also be conducted. The target population, treatment of interest and the 
summary measure of this endpoint are the same as for the primary estimand. The primary variable 
is defined as the time from the date of randomization to the date of death due to non-COVID-19 
pandemic reasons. The remaining intercurrent events will be handled as follows:  
o Discontinuation of study treatment due to any non-COVID-19 pandemic reasons: 
OS will take into account all deaths irrespective of the study treatment discontinuation 
reasons (treatment policy) 
o Discontinuation of study treatment due to COVID-19 pandemic reasons: OS will 
be censored on the date of discontinuation of treatment due to COVID-19 pandemic 
(hypothetical strategy). The discontinuation reason due to COVID-19 pandemic will 
be identified from the defined COVID-19 protocol deviations. 
o Medications used for treating COVID-19 cases: OS will be censored on the date of 
administration of COVID-19 medication (hypothetical strategy). The medications will 
be identified by drug class of aminoquinolines, protease inhibitors, glucocorticoids, 
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macrolides, antiviral or antiretroviral OR drug names that contain key word of 
“hydroxychloroquine” or “chloroquine”. 
o Death due to COVID-19: OS will be censored on the date of death due to COVID-19 
(hypothetical strategy) 
 
 
 
 
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Supplementary analyses targeting different estimands are described in Table 1. 
Table 1 Supplementary analyses for OS  
 
Primary 
estimand 
Supplementary 
estimand 1 
Supplementary 
estimand 2 
Supplementary 
estimand 3 
Supplementary 
estimand 4 
Scientific question of 
interest  
Will the 
addition of 
Tislelizumab 
to 
chemotherapy 
doublet 
treatment 
strategy 
prolong 
survival in 
first line 
ESCC 
patients  
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
Will the 
addition of 
Tislelizumab 
to 
chemotherapy 
doublet 
treatment 
strategy 
prolong 
survival due to 
non-COVID-
19 pandemic 
reasons in 
first line 
ESCC patients  
Treatment  
 
Arm A and  
Arm B 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
Population  
Unresectable, 
Locally 
Advanced 
Recurrent or 
Metastatic 
Esophageal 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
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Squamous 
Cell 
Carcinoma 
 
Intercurrent events 
 
 
 
 
 
- 
New anticancer 
therapy 
Ignored 
(treatment 
policy 
strategy) 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
- 
Discontinuation 
of treatment; 
 
Ignored 
(treatment 
policy 
strategy) 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
same as 
primary 
estimand 
Summary measure 
Hazard ratio 
of OS from 
stratified cox 
model 
Difference in 
Restricted 
mean survival 
time   
Weighted 
hazard ratio of 
OS from Max-
combo test 
 
Hazard ratio of 
OS from 
stratified cox 
model 
adjusted by 
covariates  
same as 
primary 
estimand 
Methods used for 
analysis 
Stratified Cox 
regression 
analysis 
RMST 
Max-combo 
Multivariate 
analysis 
Stratified Cox 
regression 
analysis 
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7.4.2 Secondary Efficacy Endpoints 
Progression Free Survival (PFS) by investigator in ITT 
The null and alternative hypotheses to be evaluated for PFS are: 
H0 : HR  1, 
Ha : HR< 1, 
where HR represents the hazard ratio between the treatment and the control groups, assuming a 
proportional hazard. After superiority of OS in the ITT analysis set has been demonstrated, the 
null hypothesis will be tested using a log-rank test stratified by pooled Geographic region (Asia  
vs Rest of World), prior definitive therapy (yes vs no) and ICC option (Investigator choice of 
chemotherapy [platinum with fluoropyrimidine vs platinum with paclitaxel]). If the one-sided p-
value is less than 0.025, it will be concluded that the null hypothesis is rejected and the 
superiority of treatment group over the control group in PFS is demonstrated at the significance 
level. 
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 PFS, 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. Ninety-five percent CIs for median and 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 (Kalbfleisch and Prentice 
1980). Kaplan-Meier survival curve for each arm will also be provided.  
Progression-Free survival is defined as the time from the date of randomization to the date of 
first documentation of disease progression assessed by the Investigators per RECIST v1.1 or 
death, whichever occurs first. Progression-free survival censoring rule for PFS primary and 
supportive analysis are described in Table 2.  
Table 2: The primary and secondary censoring rules for the derivation of PFS 
No. 
Situation 
Date of Progression or 
Censoring 
Primary 
Analysis 
Supportive 
Analysis 1 
Supportive
Analysis 2 
1 
No baseline or any 
post-baseline tumor 
assessments and 
without death within 
13 weeks after 
randomization  
Randomization date 
Censored 
Censored 
Censored 
2 
Progression 
documented 
Date of first radiologic 
PD assessment  
Event 
Event 
Event*** 
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between scheduled 
visits 
3 
No progression at 
the time of data 
cutoff or withdrawal 
from study 
Date of last adequate 
radiologic assessment 
prior to or on date of data 
cutoff or withdrawal from 
study 
Censored 
Censored 
Censored 
4 
New anticancer 
treatment started 
Date of last adequate 
radiologic assessment 
prior to or on date of new 
anticancer treatment 
Censored 
NA 
Censored 
5 
Death before first 
PD assessment 
Date of death 
Event 
Event 
Event*** 
6 
Death between 
adequate assessment 
visits* 
Date of death 
Event 
Event 
Event*** 
7 
Death or 
progression after 
more than one 
missed visit** 
Date of last adequate 
radiologic assessment 
before missed tumor 
assessments 
Censored 
Censored 
Event 
8 
No baseline or any 
post-baseline tumor 
assessments and 
died within 13 
weeks after 
randomization 
Date of death 
Event 
Event 
Event*** 
 
*Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD 
or PD as determined by the investigators. 
** More than one missed visit is defined if the duration between the last tumor 
assessment and death or PD is longer than D2. The D2 is defined as two times protocol 
specified interval between tumor assessments (TAs) plus the protocol allowed window 
around the assessments.  Since tumor assessment is scheduled as once every 6 weeks for 
first 48 weeks and once every 9 weeks afterwards with one-week window, D2 is 12 
weeks + 1 week in the first 48 weeks and 18 weeks + 1 week afterwards.  
*** Progression date for PFS event will be the earliest date of events defined in 2,4,5,6,8. 
The priority of the censoring rules in the primary analysis is as follows: 
1. If the patient had PD or death, the following sequence will be applied: 
a. If a patient did not have baseline tumor assessment (No. 1), the patient will be 
censored on the randomization date.  However, if the patient died within two 
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consecutive tumor assessments specified in protocol after randomization and did not 
receive new anticancer treatment, the date of death will be the PFS event date (not 
censored).  
b. If a patient had new anticancer treatment before PD or death (No. 4), the patient will 
be censored on the date of the last adequate tumor assessment prior to or on the date 
of new anticancer treatment. 
c. If a patient missed more than one assessment before PD or death (No. 7), the patient 
will be censored on the date of the last tumor assessment before PD or death.  Note 
that if a patient is censored by both this criterion and the anticancer treatment criteria, 
the earliest censoring date will be used.  
d. Otherwise, if a patient has event (No. 2, No. 5, or No. 6), the earliest event date will 
be used.  
2. If a patient did not have PD or death, the censoring date will be the earliest censoring date 
if the patient met multiple censoring criteria (No. 1, No. 3, No. 4). 
3. In supportive analysis 1 in table 2, the PFS event date will be derived ignoring new anti-
cancer therapy. 
4. In supportive analysis 2 in table 2, any PD or death after more than one missing tumor 
assessment will be considered as a PFS event. 
Objective Response Rate (ORR) by investigator in ITT  
The null and alternative hypotheses for ORR are set as follows: 
H0 : ORRT  ORRC’ 
Ha : ORRT > ORRC’ 
where ORRT and ORRC represent ORR of the Tislelizumab treatment and Control groups, 
respectively. The null hypothesis will be tested using the Cochran-Mantel-Haenszel method 
stratified by pooled Geographic region (Asia vs Rest of World), prior definitive therapy (yes vs 
no) and ICC option (Investigator choice of chemotherapy [platinum with fluoropyrimidine vs 
platinum with paclitaxel]) at the one-sided significance level of  0.025. If the null hypothesis can 
be rejected, it will be concluded that the superiority of treatment group over the control group in 
ORR is demonstrated at the significance level. 
Patients with no post-baseline response assessment (for any reason) will be considered non-
responders. The 2-sided 95% CIs for the odds ratio in ORR will be calculated, as well as 
Clopper-Pearson 95% CIs of ORR for each treatment arm. 
Best overall response, defined as the best response recorded from randomization until data cut or 
the start of new anticancer treatment. Patients with no post-baseline response assessment (due to 
any reason) will be considered non-responders for BOR. The proportion and its corresponding 
Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be 
presented by treatment arm.  
 
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Overall Survival in ITT PD-L1 (PD-L1 score  10%) subgroup 
The null and alternative hypotheses to be evaluated for OS are: 
H0 : HR  1, 
Ha : HR< 1, 
where HR represents the hazard ratio between the treatment and the control groups in ITT PD-L1 
score  10% subgroup, assuming a proportional hazard. 
The PD-L1 score  10% subgroup includes patients whose baseline PD-L1score  10% using 
VENTAN A PD- L1 (SP263) CDx Assay.  
The overall survival analysis by other baseline PD-L1 status (PD-L1 score  < 10 %) are analyzed 
similarly as in ITT analysis set. 
 
Duration of Response (DOR) assessed by investigator in ITT 
Duration of Response (DOR) is defined in Section 4.2 as progression/death event free time 
counted from the first objective response date to the first documented radiological PD date/or 
death date, whichever occur first.  All the censoring rules for PFS primary analysis (Table 2 
Table ). should be applied to DOR as well.   
 Median of DOR with 95% confidence interval, if estimable, will be constructed with a 
generalized Brookmeyer and Crowley method.  The cumulative probabilty of DOR at 3 and 6 
months, if estimable will be caculated and presented with two-sided 95% confidence interval by 
using Greenwood’s formula.   
 
7.4.3 Subsequent Anti-Cancer Therapy 
To assess the subsequent anti-cancer therapy within two treatment groups which potentially 
impact patient overall survival, subsequent anti-cancer therapy is defined as the anti-cancer 
therapy started after the last dose date of study drug. A summary of number and pecentage of 
patients who received subsequent systematic anticancer therapy/immunotherapy by arm will be 
provided based on ITT and by baseline PD-L1 status (PD-L1 score  10%, <10%, Unknown). 
Separate flags of start date of new anti-cancer therapy for efficacy and safety analyses are derived 
individually.   
-       As for efficacy analysis, start date of new anti-cancer therapy could be the earlist of date of the 
new anti-cancer therapy taken during treatment, date of the post-treatment systemic anti-cancer 
therapy and date of other anti-cancer therapy such as post-treatment surgery and radiotherapy as 
deem appropriate.   
-       The start date of new anti-cancer therapy in defining TEAE for safety analyses is always the first 
date of new systemic anti-cancer 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 medicine(TCM). ORR, PFS or OS benefit of Chinese 
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herbal medicines or Chinese patent medicines has not yet been established. Therefore, they will 
not be taken into account as new anti-cancer therapy in the efficacy and safety analyses. 
Patient data listings of subsequent anti-cancer therapy will be provided. 
7.4.4 Exploratory Analysis 
Disease control rate (DCR) assessed by investigator. 
Disease control rate (DCR) defined as the proportion of patients whose best overall response 
(BOR) is CR, PR, Non-CR/Non-PD or SD.  DCR assessed by investigators will be analyzed 
similarly to ORR in the ITT 
PFS, ORR, DOR assessed by BIRC in ITT  
PFS, ORR, DOR, and DCR assessed by BIRC per RECIST v1.1 will be summarized using the 
same approach as by investigator in the exploratory analysis. No formal testing will be performed 
for BIRC assessed endpoints.  
The concordance/discordance of PFS by BIRC and investigators will be assessed by comparing 
PFS event type/censor between BIRC and investigators, as well as summary of gap time in months 
for PFS as per BIRC and as per investigators.  
It is worth noting that if the independent radiologists are not able to identify any disease at 
baseline (target or non-target lesions), they will be required to confirm that no lesions were 
identified at baseline. The overall tumor response assessment will be no disease (ND) at 
subsequent tumor assessment, provided the criteria for PD or NE are not met. In that case, ND or 
PD will be considered as valid tumor assessment when performing the analysis of PFS. 
 
PFS2 assessed by investigator in ITT 
Analysis of progression-free survival after next line of treatment (PFS2) is defined as the time 
from randomization to second/subsequent disease progression, or death from any cause, whichever 
occurs first. To calculate PFS2, data from patients without disease progression after next-line of 
treatment or death at the time of analysis will be censored at the last time known to be alive. 
Kaplan-Meier (KM) method as described in the PFS analyses will be used in the analysis of PFS2. 
x       Next-line therapy is defined as the first new (systemic) anti-neoplastic therapy initiated after 
discontinuation of study treatment regardless of EOT reason. Drugs given as part of the same 
regimen should be grouped as one line (i.e., part of the next-line therapy). In addition, 
continuation of the study treatment after the initial radiologic disease progression will not be 
considered as next-line therapy.  
x       PFS2 will be censored if no PFS2 event (progression or death) is observed during next-line 
therapy before the analysis cut-off date; the censoring date will be the date of last known to be 
alive.    
x       In case a second new anti-cancer therapy is introduced without progression on the first next 
anti-cancer therapy, then PFS2 will be censored at the end date of the first new anti-cancer 
therapy (i.e., next line therapy).  
x       PFS2 will be censored at the date of last known to be alive.  if a patient is still ongoing on study 
treatment irrespective of the disease progression status or second progression while being on 
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study treatment, or patient has discontinued study treatment but has not started next-line 
therapy and is still alive.  
x       Any death prior to initiation of next-line therapy will be considered as an event for PFS2 
 
7.4.5 Health-Related Quality of Life 
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 items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties). A high derived score for a functional scale represents a 
high/healthy level of functioning, a high derived score for global health status/QoL represents a 
high QoL, but a high derived score for a symptom scale/item represents a high level of 
symptomatology/problems. 
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). 
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 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. 
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 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 
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 
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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. 
OES18 index- score= (DS of Dysphagia, DS of Eating, Reflux, Pain, Trouble swallowing 
saliva, Choked when swallowing, Dry mouth, Trouble with taste, Trouble with coughing, 
Trouble talking) ÷ # non-missing of DS 
C30 index- score= [(100-DS of Physical functioning, 100-DS of Role functioning, 100-DS of 
Emotional functioning, 100-DS of Cognitive functioning, 100-DS of Social functioning, 100-DS 
of global QOL, DS of Fatigue, Nausea, Vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, 
Constipation, Diarrhea, Financial Difficulty] ÷ # non-missing of DS  
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 
Appetite loss 
AP 
1 
3 
13 
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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 
1,2,3* 
Eating 
EA 
4 
3 
6,7,8,9 
Reflux 
RE 
2 
3 
14,15 
Pain 
PA 
3 
3 
16,17,18 
 
 
 
 
 
Single Items 
 
 
 
 
Trouble swallowing saliva 
SA 
1 
3 
4 
Choked when swallowing 
SW 
1 
3 
5 
Dry mouth 
DM 
1 
3 
10 
Trouble with taste 
TA 
1 
3 
11 
Trouble with coughing 
CO 
1 
3 
12 
Trouble talking 
TA 
1 
3 
13 
*: Reversing scoring items. 
All HRQoL measures will be summarized in ITT analysis set  
Completion rates for the EORTC-QLQ-C30, QLQ-OES18, and EQ-5D-5L will be summarized 
separately at each visit.  A questionnaire module is considered complete if at least one question 
is answered.  In addition, the adjusted completion rate which defined as number of patients 
complete all questions divided by the number of patients still on study at relevant visit will also 
be summarized. 
For the EORTC-QLQ-C30, EORTC-QLQ-OES18 at each visit, raw score for functional scales 
and symptom scales will be calculated based on questionnaire items. Raw scores for the 
functional scale/symptom scale/single items will be transformed into 0-100 scale via linear 
transformation. The derived score (functional scales/symptom scales/single items and the global 
scale) of EORTC-QLQ-C30, and index score and symptom scales’ scores of EORTC-QLQ-
OES18 will be summarized as well as change from baseline using descriptive statistics.  
For EQ-5D-5L, descriptive modules 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 
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visit in a continuous scale using descriptive statistics. 
In addition, a mixed effect model analysis for measuring clinically meaningful changes post-
baseline adjusted for baseline will be performed using the GHS, physical function and fatigue 
domains of QLQ-C30 and index score, dysphagia, reflux, pain and eating of QLQ-OES18.  
Treatment effect of change from baseline will be evaluated at cycle 6. Bonferrroni method will 
be applied to the test of OES 18 symptoms dysphagia, eating and reflux using an alpha of 
0.0083. 
Time to clinically meaningful worsening in a HRQoL domains (for functional scales and global 
health status/) is defined as the time from randomization to the first time the difference between 
the current derived score and baseline was  10 in the worsening direction. A deterioration is not 
counted as an event if a subsequent improvement returned the overall worsening from baseline to 
less than 10 points. Patients without clinically meaningful worsening will be censored at the last 
time the HRQoL domain was assessed. And a secondary deterioration threshold based on data may 
be explored. 
Time to clinically meaningful worsening will be analyzed for comparing the difference between 
the two treatment arms using Cox model for selected domains, hazard ratio and its 95% confidence 
interval will be provided, and a forest plot for selected domains will be provided. Time to clinically 
worsening for a selected number of domains of major interest will be tested for comparing the 
difference between tislelizumab and ICC arms. The domains of major interest include: the global 
scale and physical function scale of QLQ-C30 and four symptom scale (dysphagia, eating, reflux, 
pain) from QLQ-OES18. 
KM estimates by treatment arm, the hazard ratio estimates and their 95% CI will be provided. 
Hazard ratio is based on a Cox regression model including treatment as covariate and stratified by 
pooled Geographic region (Asia  vs Rest of World), prior definitive therapy (yes vs no) and ICC 
option (Investigator choice of chemotherapy [platinum with fluoropyrimidine vs platinum with 
paclitaxel]).  
Country-specific subgroups may also be summarized per local regulatory requirements. 
7.4.6 Subgroup Analyses 
The following exploratory subgroup analyses may be conducted on the primary efficacy endpoint 
for OS in ITT analysis set. 
x 
ICC options 
x 
Geographic region 
o Asia vs.  Rest of World 
o Asia (excluding Japan) vs. Japan vs.  Rest of World 
x 
ECOG Performance status (0/1) 
x 
Age group (<65 years, >= 65 years) 
x 
Sex 
x 
Smoking status (former/current smoker, non-smoker) 
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x 
Race (White, Asian and Other) 
x 
Locally advanced vs. metastatic 
x 
Prior definitive therapy (yes/no) 
x 
Baseline PD-L1 expression category: PD-L1 score>= 10%, PD-L1 score< 10%, Unknown 
KM estimates by treatment arm, the unstratified hazard ratio estimates and their 95% CI will be 
provided.  The treatment effect will be estimated by fitting a Cox regression model to OS times 
only including treatment arm as a factor. 
Country-specific subgroups may also be summarized per local regulatory requirements. For the 
secondary endpoints, PFS, ORR, DOR, HRQoL and subsequent anti-cancer therapy will be 
summarized by region (Asia vs Rest of World) in ITT analysis set. 
PFS, ORR, DOR assessed by investigator will be summarized by baseline PD-L1 status (PD-L1 
score  10%, < 10 %, Unknown) using the same approach in ITT analysis set. 
7.5 
SAFETY ANALYSES 
Safety will be assessed by monitoring and recording of all TEAEs graded by NCI-CTCAE v4.03. 
Laboratory values (e.g., hematology, clinical chemistry), vital signs, ECGs, PEs and their changes 
from baseline will also be used in determining safety. Descriptive statistics (e.g., n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum for continuous variables; n [%] for categorical 
variables) will be used to analyze all safety data in the Safety analysis set.  
Extent of Exposure 
Extent of exposure will be summarized by treatment arm in ITT. 
For control arm, extent of exposure will be summarized by study drug. 
Extent of exposure will be summarized descriptively as the number of cycles received, duration of 
exposure (days), cumulative total dose received per patient, dose intensity and relative dose 
intensity. The number of patients (if any) treated beyond radiological progression (as per 
investigator) will also be presented. 
The number (percentage) of patients requiring infusion related infusion interruption/infusion rate 
decreased, dose delay, and dose reduction (in the Chemotherapy doublets only) due to AEs will be 
summarized for each study drug. Consecutive dose omission/skips will only be counted once. 
Frequency of the above dose adjustments will be summarized by category.  
x The number of cycles taken will be calculated as the sum of numbers of non-missing doses 
(dose>0) within each cycle for each study drug. 
x Cumulative total dose per subject will be computed as the sum of all of the doses received 
in each cycle for each study drug. The dose unit is mg for tislelizumab and mg/m2 for the 
Chemotherapy doublets. 
x Actual dose intensity is defined as 21*total cumulative dose (mg) / (last dose date up to 
cutoff date+ 21 - first dose date). Relative dose intensity is defined as Actual dose intensity 
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/ planned dose intensity. The planned dose intensity is the total planned dose in a cycle. 
For a patient in the tislelizumab/Placebo arm, the planned dose intensity is 200 mg Q3W.   
x In case there are some patients received the study drug different from assigned treatment 
group in safety analysis set, dose summary will only include the data as planned.   
 
 
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The derivations of ADI, planned dose and RDI for Chemotherapy are shown in Table5.   
Table 5  ADI, planned dose and RDI for Chemotherapy 
 
                                          ADI(mg/m2/cycle) 
PDI(Planned dose per 
cycle ) 
RDI 
Paclitaxel 
σ
ܽܿݐݑ݈ܽ ݀݋ݏ݁ (݉݃)
ܤܵܣכ (݉2)
× 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 െ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
 
First non-missing 
planned dose level 
collected in CRF 
 
ܣܦܫ
ܲܦܫ 
 
Cisplatin** 
σ
ܽܿݐݑ݈ܽ ݀݋ݏ݁ (݉݃)
ܤܵܣכ (݉2)
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 ݋ݎ 19 െ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
 
First non-missing 
planned dose level 
collected in CRF 
 
Oxaliplatin 
σ
ܽܿݐݑ݈ܽ ݀݋ݏ݁ (݉݃)
ܤܵܣכ (݉2)
× 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 െ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
       
First non-missing 
planned dose level 
collected in CRF 
 
5-FU 
σ
ܽܿݐݑ݈ܽ ݀݋ݏ݁ (݉݃)
ܤܵܣכ (݉2)
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 17 െ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
,
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
       
First non-missing 
planned does level 
collected in CRF*5 
 
capecitabine 
σ
ܽܿݐݑ݈ܽ ݀݋ݏ݁ (݉݃)
ܤܵܣכ (݉2)
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 8 െ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
,
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
 
 
First non-missing 
planned does level 
collected in CRF*14 
 
ܣܦܫ
28000 
 
*BSA: sqrt(height(cm)*weight (kg)/3600) or sqrt(height(cm)*weight (lb)/3131) 
** Cisplatin:  apply 21 if value of CRF field “Cisplatin administrated days number” value is “1 day” and 19 if value is “3 days”. 
 
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Treatment duration  
If patients discontinued treatment (with non-missing EOT date): 
• 
For the tislelizumab arm, Treatment duration (days) = minimum of (date of the last dose 
+ 20, death date, cutoff date) – date of first dose + 1.  
• 
For patients taking cisplatin or oxaliplatin or Paclitaxel   on a Q3W schedule,  
Treatment duration = minimum of (date of the last dose +20, death date, cutoff date) – date 
of first dose + 1. 
o For Chemotherapy Doublet C, cisplatin may be administered on Days 1 or 2, or in 3 
divided doses on Days 1, 2, and 3 depending on local guidelines.  
o Treatment duration = minimum of (date of the last dose + 20 (for Day 1 or Day 2   
schedule) or 18 (for 3 days schedule), death date, cutoff date)– date of first dose + 
1respectively. 
• 
For patients taking 5-Fluorouracil,  
Treatment duration = minimum of (date of the last dose + 16, death date, cutoff date) –date of 
first dose + 1. 
• 
For patients taking capecitabine,  
Treatment duration = minimum of (date of the last dose +7, death date, cutoff date) – date of 
first dose + 1. 
Otherwise if patient has treatment ongoing: Treatment duration = Cutoff date– date of first dose + 
1       
7.5.1 Adverse Events  
The AE verbatim descriptions (Investigator’s description from the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be coded to MedDRA (Version 24.0 or higher) lower level term closest to the 
verbatim term. The linked MedDRA System Organ Class (SOC) and Preferred Term (PT) are also 
classified. All adverse event summaries are based on safety analysis set. 
In this trial, a treatment emergent adverse event (TEAE) is defined as an AE that had an onset date 
or a worsening in severity from baseline (pre-treatment) on or after the first dose of study drug up 
to 30 days following study drug discontinuation or initiation of new anti-cancer therapy, whichever 
occurs first. Only those AEs that were treatment emergent will be included in summary tables.  
All AEs, treatment emergent or otherwise, will be presented in patient data listings. COVID-19 
related adverse events will be summarized separately. 
 
It is noteworthy that the definitions of TEAE in the protocol is different from the one in this SAP, 
while the definition of imAE remains the same. The update of TEAE window streamlines the 
TEAE derivation so all TEAEs can be identified programmatically instead of relying on the 
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manual medically review of imAE. imAE occurs outside of the above mentioned TEAE window 
will not be classified as treatment-emergent adverse events. All imAE will be reported separately. 
7.5.1.1 Treatment Emergent Adverse Event 
An overall summary of TEAEs will summarize the number (%) of patients with  
x At least one TEAE 
x At least one TEAE with NCI-CTCAE grade 3 
x At least one TEAE related to any component of study drug 
x At least one TEAE related to Tislelizumab 
x At least one TEAE related to Tislelizumab and grade 3 
x At least one TEAE with grade 3 and related to any component of study drug 
x At least one serious TEAE 
x At least one serious TEAE related to tislelizumab 
x At least one serious TEAE related to any component of study drug 
x At least one TEAE leading to death including death due to disease under study  
x At least one TEAE leading to death  
x At least one TEAE leading to permanent discontinuation of any component of study drug 
x At least one TEAE leading to dose modification of any component of study drug 
x At least one immune-mediated adverse event 
x At least one immune-mediated adverse event with NCI-CTCAE grade 3 
x At least one infusion-related reaction 
x At least one infusion-related reaction with NCI-CTCAE grade 3 
Summaries of the following TEAEs will be provided:  
x All TEAEs  
o All TEAEs by SOC 
o All TEAEs by PT 
o All TEAEs by SOC and PT* 
o Most frequently reported (incidence  10% in any treatment arm) TEAEs by SOC 
and PT 
o Treatment-related TEAEs by SOC 
o Treatment-related TEAEs by PT 
o Treatment-related TEAEs by SOC and PT* 
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o Most frequently reported (incidence  5% in any treatment arm) Treatment-related 
TEAE by SOC and PT 
o Tislelizumab/Placebo Related TEAEs by PT 
o Tislelizumab/Placebo Related TEAEs by SOC and PT* 
o Most frequently reported (incidence  10% in any treatment arm) 
Tislelizumab/Placebo Related TEAE by SOC and PT 
o Any Chemotherapy Component Related TEAEs by PT 
o Any Chemotherapy Component Related TEAEs by SOC and PT* 
x Serious TEAEs by SOC and PT* 
o Serious TEAEs by PT 
o Most frequently reported (incidence  2% in any treatment arm) serious TEAE by 
SOC and PT 
o Treatment-related Serious TEAE by SOC and PT* 
o Tislelizumab/Placebo Related Serious TEAE by SOC and PT* 
o Most 
frequently 
reported 
(incidence 
 
2% 
in 
any 
treatment 
arm) 
Tislelizumab/Placebo -related serious TEAE by SOC and PT 
o Any Chemotherapy Component Related Serious TEAE by SOC and PT* 
x TEAEs with NCI-CTCAE grade 3 by SOC and PT* 
o Most frequently reported (incidence  5% in any treatment arm) TEAE with NCI-
CTCAE grade  3 by SOC and PT 
o Treatment-related TEAE with NCI-CTCAE grade  3 by SOC and PT* 
o Tislelizumab/Placebo Related TEAE with NCI-CTCAE grade  3 by SOC and PT* 
o Most 
frequently 
reported 
(incidence 
 
1% 
in 
any 
treatment 
arm) 
Tislelizumab/Placebo Related  TEAE with NCI-CTCAE grade  3 by SOC and PT 
o Any Chemotherapy Component Related TEAE with NCI-CTCAE grade  3 by 
SOC and PT* 
o Tislelizumab/Placebo Related TEAEs leading to death by SOC and PT* 
o Tislelizumab/Placebo Related TEAEs leading to death by SOC and PT including 
death due to disease under study* 
o Any Chemotherapy Component Related  TEAE Leading to Death by SOC and PT* 
o Any Chemotherapy Component Related TEAE Leading to Death by SOC and PT 
including death due to disease under study 
x TEAEs leading to treatment discontinuation by SOC and PT* 
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o TEAE Leading to Treatment Discontinuation of Tislelizumab/Placebo by SOC and 
PT* 
o Most frequently reported (incidence  2 patients in any treatment arm) TEAE 
Leading to Treatment Discontinuation of Tislelizumab/Placebo by PT 
o Treatment-related TEAE Leading to Treatment Discontinuation of Any 
Chemotherapy Component by SOC and PT* 
o Most frequently reported (incidence  2 patients in any treatment arm) TEAE 
Leading to Treatment Discontinuation of Any Chemotherapy Component by PT 
o TEAE Leading to Treatment Discontinuation of All Treatment Components by 
SOC and PT* 
o TEAE Leading to Treatment Discontinuation of Tislelizumab/Placebo Excluding 
Treatment Discontinuation Due to Progressive Disease Progression by SOC and 
PT* 
 
x TEAEs leading to dose modification by SOC and PT 
o Treatment-related TEAE Leading to Dose Modification by SOC and PT 
o TEAE Leading to Dose Modification of Tislelizumab/Placebo by SOC and PT* 
o Most frequently reported (incidence  2% in any treatment arm) TEAE Leading to 
Dose Modification of Tislelizumab/Placebo by SOC and PT 
o TEAE Leading to Dose Modification of Any Chemotherapy Component by SOC 
and PT* 
o Most frequently reported (incidence  2% in any treatment arm) TEAE Leading to 
Dose Modification of Any Chemotherapy Component by SOC and PT 
The types of Dose modification include dose delayed, infusion interruption, infusion rate 
decreased and dose reduction for chemotherapy doublets; dose delayed and infusion interruption, 
infusion rate decreased for tislelizumab arm. 
*: Summaries will be provided by region (Asia vs.  Rest of World) in addition to safety analysis 
set. 
For exposure adjusted event rate (EAER), overall summary (at least one (serious) TEAE, (serious) 
treatment-related TEAE, grade 3 TEAE, grade 3 treatment-related TEAE, TEAE leading to 
death, treatment-related TEAE leading to death); summary by System Organ Class and Preferred 
Term will be provided for safety analysis set and by Region.   
EAER was calculated as event count*100 / person-months of exposure (longest treatment duration 
of all study medication components in treatment regimen defined by treatment duration in Section 
7.5). 
In addition, different cutoff of AE summary may be provided. 
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7.5.1.2 Immune-mediated Adverse Event 
Immune-mediated adverse events are of special interest and summarized by category within a pre-
defined list in Appendix 11.5. 
For immune-mediated adverse events, a summary of incidence based on the number of patients 
dosed or within the immune-mediated adverse event follow up period will be presented by 
category in the descending order of incidence based on the tislelizumab/placebo column.  
Summaries of the following incidence of immune-mediated adverse events will be provided: 
x Immune-mediated adverse events by category and by PT 
x Immune-mediated adverse events by category and by PT by region  
x Immune-mediated adverse events with NCI-CTCAE grade 3 by category  
x Immune-mediated adverse events by category and worst grade 
x Immune-mediated adverse events leading to treatment discontinuation by category 
x Immune-mediated adverse events leading to death by category 
x Immune-mediated adverse events leading to dose modification by category 
Exposure-adjusted event rate (EAER) per 100 subject years are provided. The EAER per 100 
subject -years/months is defined as 100 times the number of specific events divided by the total 
exposure time (in years/months) among subjects included in the analysis. Subjects with multiple 
occurrences of the specific event in the specific analysis period will be counted multiple times in 
the numerator. The exposure time for a subject with/without the specific event is the treatment 
duration. The total exposure time in years/months is calculated by dividing the sum of exposure 
time in days over all subjects included in the analysis by 365.25/30.4375. The EAER per 100 
subject-years/months is interpreted as expected number of specific event per 100 subject-
years/months of exposure to the study dru g. 
 
7.5.1.3 Infusion-related Adverse Event 
For IRRs, a summary of incidence by SOC, PT and maximum severity will be provided, sorted 
by descending order of incidence within each SOC and PT based on tislelizumab/placebo 
column. Summaries of IRRs, IRRs with NCI-CTCAE grade 3, IRRs of tislelizumab/placebo 
leading to treatment discontinuation, and IRRs of tislelizumab/placebo leading to dose 
modification will also be provided by PT only, in descending order. 
7.5.2 Death 
Number and causes of deaths, classified by deaths within 30 days of last dose of study drug and 
deaths more than 30 days after the last dose, will be summarized based on safety analysis set  
Patient data listings of death and reason will be provided.  
7.5.3 Laboratory Values 
Hematology, serum chemistry, thyroid function, will be summarized/listed for selected 
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parameters described in Table 6.  The coagulation, urinalysis, HBV/HCV serology, and 
pregnancy test results will be listed only. For thyroid function, summaries will be provided by 
region (Asia vs.  Rest of World). 
Laboratory results will be summarized/listed using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Table  6 , Error! Reference source not found.the actual v
alue and the change from baseline will be summarized by visit and worst post-baseline visit using 
descriptive statistics. Summaries will be provided by region (Asia vs.  Rest of World). Plots of 
laboratory values/change from baseline over time will be provided for selected lab parameters. 
The summary tables will report lab assessments up to 30 days of the last dose date. 
Laboratory parameters are also graded according to CTCAE v4.03 and will be summarized by 
shifts from baseline CTCAE grades to maximum post-baseline grades. Laboratory parameters 
(e.g., glucose, potassium, sodium) with CTCAE grading in both high and low directions will be 
summarized separately. Shift tables will be used to summarize the grade change from baseline to 
worst post baseline value with counts and percentages for hematology and serum chemistry. The 
lab parameters with grades increased in more than 2 from baseline to worst post baseline will 
also be summarized. Summaries will be provided by region (Asia vs. Rest of World). 
In addition, Hy’s law for liver injuries, hepatic function laboratory test and thyroid laboratory 
test are summarized. 
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Table 6˖Clinical Laboratory Assessments  
Serum 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
function  
HBV and 
HCV 
serology 
glucose, blood 
urea nitrogen 
[BUN] [or serum 
urea], creatinine, 
sodium, 
potassium, 
chloride, total 
and direct 
bilirubin, ALT, 
AST, alkaline 
phosphatase, 
lactate 
dehydrogenase 
[LDH] 
[optional], total 
protein, albumin, 
creatine kinase 
(CK), creatine 
kinase-cardiac 
muscle 
isoenzyme (CK-
MB) and 
amylase, 
calcium, 
magnesium and 
lipase 
complete blood 
count [CBC], 
including red 
blood cell [RBC] 
count, 
hemoglobin, 
Hematocrit,white 
blood cell 
[WBC] count 
with automated 
differential 
[neutrophils, 
lymphocytes, 
and], and platelet 
count 
 
Prothrombin time 
(PT),International 
Normalized Ratio 
(INR), Partial 
thromboplastin 
time or activated 
partial 
thromboplastin 
time 
 
complete 
[including, 
but not 
limited to 
glucose, 
protein, 
ketones, and 
blood] 
and/or 
microscopic, 
if clinically 
indicated 
 
TSH 
Free T3 
Free T4 
HBsAg, 
HBcAb and 
HCV 
antibody 
HBsAb, 
HBV DNA 
and HCV 
RNA 
 
7.5.4 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], pulse 
rate, and weight) and changes from baseline will be presented by visit. For tislelizumab, the 
change from post-dose (end of infusion) to pre-dose also need to be summarized for all vital sign 
parameters except for weight. Vital signs will be listed by patients and visits. Descriptive 
statistics for vital sign parameters. 
7.5.5 Ophthalmology Examination 
Ophthalmology abnormality will by summarized. In addition ophthalmology examination 
findings will be listed by patients and visits. 
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7.5.6 Electrocardiograms (ECG) 
12-lead ECG recordings are required at Screening, End of Treatment and as clinically indicated. 
Patient listing of ECG will be provided for all ECG recordings. 
The actual value and the change from baseline for QTc intervals will be summarized by visit and 
treatment arm using descriptive statistics.  
Abnormal post-baseline QTcF results will be summarized with the following categories: increase 
of >30 msec, increase of > 60 msec, value of > 450 msec, value of > 480 msec, value of > 500 
msec by treatment arm. 
7.5.7 ECOG 
A shift table from baseline to worst post baseline will be provided.  
7.6 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic samples were collected in this study as outlined in Appendix 1 in Protocol 
Amendment v4.0 and only from patients randomized to receive tislelizumab and in sites that are 
able to adequately perform sampling, handling and processing procedures outlined in the 
laboratory manual.  
Tislelizumab (as well as by region and race) serum concentration data, including but not limited 
to Ctrough, will be tabulated and summarized for each cycle at which pharmacokinetics are 
collected. Descriptive statistics will include means, medians, ranges, standard deviations and 
coefficient of variation (CV), and geometric mean, geometric CV as appropriate.  
Additional PK analyses such as population PK analysis may be conducted as appropriate. 
Exposure – response (efficacy and safety endpoints) analysis may be carried out if supported by 
data. The results from these analyses will be reported separately from the main study report.  
7.7 
IMMUNOGENICITY 
Samples to assess anti tislelizumab antibodies will be collected only in patients randomized to 
receive tislelizumab and in sites that are able to adequately perform sampling, handling and 
processing procedures outlined in the laboratory manual. 
ADA attributes: 
x 
Treatment boosted ADA is defined as ADA positive at baseline that was boosted to a 4-
fold or higher-level following drug administration.  
x 
Treatment-induced ADA is defined as ADA negative at baseline and ADA positive 
post-baseline.  
x 
Transient ADA response is defined as Treatment-emergent ADA detected only at 1 
time point during treatment or follow-up, excluding last time point; or detected at 2 or 
more time points during treatment or follow-up, where the first and last positive samples 
are separated by less than 16 weeks and the last time point is negative. 
x 
Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more 
time points during treatment or follow-up, where the first and last ADA positive samples 
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are separated by 16 weeks or longer; or detected only in the last time point or at a time 
point less than 16 weeks before a negative last sample. 
x 
Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological 
activity. 
ADA response endpoints: 
x ADA incidence is defined as sum of treatment-induced and treatment-boosted ADA-
positive patients as a proportion of the ADA evaluable population.  
x ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow, and may be reported separately from the main 
study report.  
7.8 
OTHER ANALYSIS 
Gene expression profile, tumor mutation burden (tumor tissue and/or blood), MSI and tumor-
infiltrated immune cells may be examined in the ITT analysis set Same analysis may be 
examined in on-progression samples (collected from patients after confirmed disease 
progression) if any collected. BOR, ORR, and PFS may be present by biomarker categories. 
Other potential predictive markers may be assessed with the same approach. 
Detailed information about biomarker analysis for exploratory endpoints will be in separate 
statistical analysis document and will not be described in the clinical study report. 
The impact of COVID-19 to patient disposition, adverse events, exposure with dose 
modification, protocol violation/deviation will be summarized.  
8 
INTERIM ANALYSIS 
An interim analysis for OS superiority test will be performed by an independent statistician 
external to the Sponsor. The independent statistician will work with the blinded study statistician 
to provide statistical outputs to the IDMC as described in the IDMC charter and perform any ad-
hoc analyses requested by the IDMC.  
The aim of this interim analysis is to stop the study early for efficacy if there is convincing evidence 
of outstanding OS benefit. An IDMC will be responsible for making the recommendation 
regarding stopping the study early based on predefined criteria for OS, as well as results from ORR 
and other secondary efficacy endpoints. More details will be given in the IDMC charter. Patients 
will continue to be treated per protocol at the time of interim analysis and until a final decision is 
made by the Sponsor after considering the recommendation provided by the IDMC.  
Timing and Stopping Boundary in the Interim and final Analyses of Overall Survival: 
There will be 1 interim analysis of OS utilizing the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. The interim analysis 
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will be performed at the time when approximately 423 death events (87% of the target number of 
OS events) among the 2 treatment arms are observed. It is estimated that it will take 
approximately 33 months (from first patient enrolled in study) to observe 423 death events. The 
IDMC will oversee the interim analysis of OS. The final analysis of OS will take place after 
approximately 488 OS events have been observed. Stopping boundaries in p-value and Z score 
for primary analyses of OS are shown in the table below. The boundaries will be updated 
according to the actual numbers of events in the interim and final analyse using the above pre-
specified alpha spending function. 
Table 7: Stopping Boundaries (in p-value and Z score) of Primary Analysis of  
Overall Survival 
Endpoint 
Analysis 
Analysis 
Time 
(month) 
# Events 
p-value1 
(Z score) for 
Efficacy 
Approximate 
HR Threshold 
OS 
Interim 
analysis 
33 
423 
< 0.0145 
(> 2.18) 
0.809 
Final 
analysis 
40 
488 
< 0.0216 
(> 2.02) 
0.833 
Abbreviations: HR = hazard ratio; OS = overall survival 
1one-sided 
 
9 
CHANGES IN THE PLANNED ANALYSIS 
If the SAP needs to be revised after the study starts, 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 JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F. The European Organisation for Research and Treatment of 
Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. 
Journal of the National Cancer Institute 1993; 85: 365-376. 
Eisenhauer EA, et al. (2009). New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 45(2), 228-47. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published 
by European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Hwang IK, Shih WJ, and DeCani JS. Group sequential designs using a family of type 1 error 
probability spending functions. Statistics in Medicine, 9:1439–1445, 1990. 
National Comprehensive Cancer Network (NCCN) Guidelines Version 1. (2017). Esophageal and 
Esophagogastric Junction Cancers. Retrieved from  
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#esophageal  
U.S. Food and Drug Administration Cencer for Drug Evaluation Research (CDER) and Center for 
Biologics Evaluation and Research. (2007). Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 
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. 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley 
& Sons; 1980. 
 
 
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11 APPENDIX 
11.1 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 
If the imputed end date > min (death date, data cutoff date, study discontinuation date), 
then set it as min (death date, data cutoff date, study discontinuation date) 
x  
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. Impute end date first if both  start and end dates are partially missing. 
If the imputed start date > end date, set to end date. 
11.2 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 > death date, then set to death date 
If year of the end date is missing or end date is completely missing, if subject dies and set to 
death date, otherwise 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 
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x If day is missing and month and year  month and year of treatment start date, the set 
to first of the month 
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. If the imputed end date > 
death date or end of study date, then set to death date or end of study date. 
11.3 IMPUTE PARTIAL DATES FOR SUBSEQUENT ANTI-CANCER SURGERY/PROCEDURE 
When the start date of subsequent anti-cancer therapy is partially missing, the following rules 
will be applied to impute partial dates. 
If start date of 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 subsequent anti-cancer therapy is collected from CRF “post-treatment 
discontinuation anti-cancer systemic therapy” or “post-treatment discontinuation anti-
cancer procedure” page, and the imputed date is prior to the last dosing date, then set 
to last dosing date + 1 
x         If the imputed date > min (death date, data cutoff date, study discontinuation date), 
then set it as min (death date, data cutoff date, study discontinuation date) 
x         The imputed start date must be before or equal to the end date 
         
If stop date of 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 stop date > min (death date, study discontinuation date, data cutoff 
date), then set to min (death date, study discontinuation date, data cutoff date) 
If year of the start date/stop date is missing, do not impute. Impute partial dates for prior 
anti-cancer 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. 
x If start date of a disease history or prior therapy 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 
 
If end date of a disease history or prior therapy is partially missing, impute as follows: 
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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 
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. If imputed start date/end date is after 
randomization date - 14, then set to randomization date - 14.  
11.4 RULES FOR IDENTIFYING MISSING TUMOR ASSESSMENTS  
Identifying two missing tumor assessment 
1) Input scheduled TA visit list for each study 
2) every 6 weeks till 48 weeks and every 9 weeks after week 48.Identify last evaluable TA 
before PD or death (--LPTADT) and map it to the closest scheduled visit (--
LPTADT_WK). 
a. In the event of unscheduled TA, choose the closest scheduled visit number (e.g. 
6wk or 27wk) as –LPTADT_WK. It can be achieved programmatically by 
following the classification rule (e.g. defining thresholds) depicted in table 8 
below.   
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 < earliest of PD/death date, then censor PFS at the –
LPTADT 
Table 8 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 Thredshold for Week 42. Assuming it is SD and the subsequent TA of the patient is 
PD after Week 58, PFS will be censored at LPTADT (Week 44); had the PD occurred prior to 
Week 58, it would be counted as an PFS event 
 
Table 8 Example of scheduled tumor assessments with time window  
 
Weeks 
Scheduled week -1 
Scheduled week 
Scheduled week+1 Thredshold  
Baseline 
  
Baseline 
  
  
Every 6 weeks 
for the first 48 
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 52 
Week 56 
Week 57 
Week 58 
Week 61 
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 Every 9 weeks 
afterwards 
  
Week 65 
Week 66 
Week 67 
Week 70 
Week 74 
Week 75 
Week 76 
… 
  
  
  
  
 
 
 
 
 
 
 
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BeiGene USA, Inc 
                      BGB-A317-306 
              (Statistical Analysis Plan) 
 
 
Version 2.0: Feb 2022 
Page 56 of 56  
CONFIDENTIAL 
 
11.5 IMMUNE-MEDIATED ADVERSE EVENT CATEGORY LIST 
 
Category 
Immune-mediated adrenal insufficiency 
Immune-mediated anaemia 
Immune-mediated colitis 
Immune-mediated hepatitis 
Immune-mediated hyperthyroidism 
Immune-mediated hypothyroidism 
Immune-mediated myocarditis 
Immune-mediated myositis/rhabdomyolysis 
Immune-mediated nephritis and renal dysfunction 
Immune-mediated nervous system disorder  
Immune-mediated ocular disorder 
Immune-mediated pancreatitis 
Immune-mediated pituitary dysfunction 
Immune-mediated pneumonitis 
Immune-mediated skin adverse reaction 
Immune-mediated thrombocytopenia 
Immune-mediated thyroiditis 
Immune-mediated type 1 diabetes mellitus 
Other immune-mediated reactions 
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