A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Tislelizumab (BGB-A317) Versus Placebo in Combination With Concurrent Chemoradiotherapy in Patients With Localized Esophageal Squamous Cell Carcinoma
Phase: PHASE3
Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
Sponsor: BeiGene

BGB-A317-311 
BeiGene 
Protocol Amendment 4.0 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL TITLE PAGE 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of 
Tislelizumab (BGB-A317) Versus Placebo in Combination With Concurrent 
Chemoradiotherapy in Patients With Localized Esophageal Squamous Cell 
Carcinoma 
Brief Title: 
A Study to Investigate Tislelizumab (BGB-A317) Versus Placebo in Combination With Concurrent 
Chemoradiotherapy in Patients With Localized Esophageal Squamous Cell Carcinoma 
Protocol Number: 
BGB-A317-311 
Amendment Number: 
Amendment 4 Global 
Investigational Medicinal 
Product: 
Tislelizumab 
Regulatory Agency 
Identification Number(s): 
Clinical Drug Trials ID: 
ClinicalTrials.gov Identifier: 
CTR20190198  
Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
4th Floor, Building D  
780 Cailun Road  
China (Shanghai) Pilot-free Trade Zone 
Shanghai 201203, P.R. China  
Approval Date: 
See electronic signature 
Contact Information: 
BeiGene Medical Officer 
Phone: 1.877.828.5568 
Email: clinicaltrials@beigene.com 
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. 
Approved Date
9/30/2024
NCT03957590

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Protocol Amendment 4.0 
 
 
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FINAL PROTOCOL APPROVAL SHEET   
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Tislelizumab (BGB-A317) 
Versus Placebo in Combination With Concurrent Chemoradiotherapy in Patients With Localized 
Esophageal Squamous Cell Carcinoma 
 
 
BeiGene, Ltd., Approval: 
See electronic signature 
Sponsor Development Core Team Lead  
See electronic signature  
Date 
 
 
Approved Date
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Protocol Amendment 4.0 
 
 
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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title:   A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of 
Tislelizumab (BGB-A317) Versus Placebo in Combination With Concurrent Chemoradiotherapy 
in Patients With Localized Esophageal Squamous Cell Carcinoma 
 
Protocol Identifier:  
 
BGB-A317-311 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval from 
BeiGene, Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name of the 
center in which the study will be conducted. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
 
_______________________________   Date:  _____________ 
Printed Name:  
 
 
 
 
_______________________________ 
Investigator Title:  
 
 
 
_______________________________ 
Name/Address of Center:  
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________  
 
 
 
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DOCUMENT HISTORY  
Prior versions of the study protocol are listed in the table below. 
Amendment Version Number 
Approval Date 
Type of Protocol Amendment  
BGB-A317-311 Amendment 3.0 
18 October 2022 
Substantial 
BGB-A317-311 Amendment 2.0 
18 September 2021 
Substantial 
BGB-A317-311 Amendment 1.0 
29 December 2020 
Substantial 
Original protocol 
10 January 2019 
Not applicable 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
The primary purpose of amendment 4.0 is to ensure that the PFS final analysis could be 
performed within feasible time as event accumulation of PFS is significantly slowing down, 
incorporating the feedback from health authority. The key changes made in this amendment are 
described in the table below.  
A few clarifications, non-substantial updates, editorial and formatting changes have also been 
made but are not included in this summary. 
Protocol Amendment Summary of Changes Table 
Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 9.6 Sample Size 
Consideration 
Section 9.7 Interim Analyses 
• Added that the final analysis of 
PFS and OS will be performed 
concurrently when 
approximately 200 PFS events 
or approximately 191 OS 
events have been observed, 
whichever occurs first  
• Removed one interim analysis 
of OS and updated the 
statistical analysis power 
accordingly 
Ensure that the PFS final analysis 
could be performed within 
feasible time as event 
accumulation of PFS is 
significantly slowing down, 
incorporating the feedback from 
health authority 
Section 3.4 Safety Follow-up 
Section 3.6.3 End of Study 
Appendix 1 Schedule of 
Assessments 
• Added description of a long-
term extension study and 
posttrial continued access 
program  
• Updated the language 
regarding patients who may 
benefit from tislelizumab 
being offered the option to 
continue treatment after study 
completion 
• Added a requirement for 
patients to complete an 
End-of-Treatment/Safety 
Follow-up Visit before 
continuing in a long-term 
extension study or posttrial 
continued access program 
Clarify available options for 
patients to continue treatment 
after study completion 
 
 
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Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 5.5.5 Blinding 
• Added unblinding after PFS 
final analysis  
• Removed some duplicate 
statements  
• Provide guidance on 
unblinding after the PFS 
final analysis 
• Simplify guidance and 
avoid potential confusion   
Section 1.4.2 Toxicology 
Updated toxicology results 
Updated toxicology 
information with results from 
newly conducted studies 
Section 13.4 Patient and Data 
Confidentiality 
Updated language regarding 
patients’ privacy and 
confidentiality 
To be compliant with ICH 
Good Clinical Practice and 
local regulations 
Section 2.1.3 Exploratory Objectives 
Section 2.2.3 Exploratory Endpoints 
Section 7.7 Biomarkers 
Updated PBMC testing assay 
statement 
To keep consistent with 
future testing needs 
 
Title Page, DOCUMENT HISTORY 
(New Section), and PROTOCOL 
AMENDMENT SUMMARY OF 
CHANGES  
(New Section) 
Updated  
For consistency with new 
BeiGene protocol template 
 
 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL TITLE PAGE ...........................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
DOCUMENT HISTORY.................................................................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................5 
TABLE OF CONTENTS .................................................................................................................7 
SYNOPSIS ....................................................................................................................................15 
LIST OF ABBREVIATIONS AND TERMS ................................................................................23 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Background Information on Esophageal Carcinoma ..................................................25 
1.2. 
Current Treatment of Esophageal Carcinoma and Unmet Clinical Needs .................25 
1.3. 
Anti-PD-1 Therapy for Esophageal Squamous Cell Carcinoma ................................28 
1.4. 
Background Information on Tislelizumab ..................................................................29 
1.4.1. 
Pharmacology .............................................................................................................29 
1.4.2. 
Toxicology ..................................................................................................................30 
1.4.3. 
Clinical Pharmacology ................................................................................................30 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................31 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies and Combination Studies 
With Chemotherapy ....................................................................................................31 
1.4.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................35 
1.5. 
Study Rationales .........................................................................................................35 
1.5.1. 
Rationale for Tislelizumab in the Treatment of Esophageal Carcinoma ....................35 
1.5.2. 
Rationale for Selection of Tislelizumab Dose ............................................................36 
1.5.3. 
Rationale for Tislelizumab in Combination With Chemoradiotherapy ......................36 
1.5.4. 
Rationale for Cisplatin and Paclitaxel Chemotherapy ................................................37 
1.5.5. 
Rationale for Radiotherapy Dose................................................................................38 
1.5.6. 
Rationale for Placebo as the Comparator ...................................................................38 
1.6. 
Benefit-Risk Assessment ............................................................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Study Objectives .........................................................................................................40 
2.1.1. 
Primary Objective .......................................................................................................40 
2.1.2. 
Secondary Objectives .................................................................................................40 
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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 
3. 
STUDY DESIGN .......................................................................................................43 
3.1. 
Summary of Study Design ..........................................................................................43 
3.2. 
Screening Period .........................................................................................................43 
3.3. 
Treatment Period ........................................................................................................44 
3.4. 
Safety Follow-up ........................................................................................................45 
3.5. 
Survival Follow-up .....................................................................................................45 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................46 
3.6.1. 
Patient Discontinuation from Study Treatment ..........................................................46 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........46 
3.6.3. 
End of Study ...............................................................................................................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. 
Placebo ........................................................................................................................52 
5.1.3. 
Chemotherapy Agents ................................................................................................52 
5.2. 
Dosage, Administration, and Compliance ..................................................................52 
5.2.1. 
Tislelizumab ...............................................................................................................53 
5.2.2. 
Matched Placebo .........................................................................................................54 
5.2.3. 
Chemotherapy .............................................................................................................54 
5.2.4. 
Radiotherapy ...............................................................................................................55 
5.2.5. 
Supportive Care ..........................................................................................................55 
5.3. 
Overdose .....................................................................................................................55 
5.4. 
Investigational Medicinal Product Accountability .....................................................55 
5.5. 
Dose Delay and Modification .....................................................................................56 
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5.5.1. 
General Guidance Regarding Dose Modifications .....................................................56 
5.5.2. 
Dose Delay or Modification for Tislelizumab or placebo ..........................................57 
5.5.3. 
Dose Delay or Modifications for Chemotherapy ........................................................58 
5.5.3.1. 
Dose Reduction Level and Dose Modification for Hematologic Toxicity .................58 
5.5.3.2. 
Dose Modifications for Renal and Hepatic Impairment .............................................59 
5.5.3.3. 
Chemotherapy Delay or Dose Modification for Other Toxicities ..............................59 
5.5.4. 
Dose Delay or Modifications for Radiotherapy ..........................................................60 
5.5.5. 
Blinding ......................................................................................................................60 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................62 
6.1. 
Prior Therapy ..............................................................................................................62 
6.2. 
Concomitant Therapy .................................................................................................62 
6.2.1. 
Permitted Concomitant Medications ..........................................................................62 
6.2.2. 
Prohibited Concomitant Medications .........................................................................63 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................63 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................63 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................65 
7.1. 
Screening ....................................................................................................................65 
7.1.1. 
Demographic Data and Medical History ....................................................................65 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................65 
7.1.3. 
Informed Consent and Screening Log ........................................................................66 
7.1.4. 
Pulmonary Function Tests ..........................................................................................66 
7.2. 
Enrollment ..................................................................................................................66 
7.2.1. 
Confirmation of Eligibility .........................................................................................66 
7.2.2. 
Patient Numbering ......................................................................................................66 
7.2.3. 
Enrollment/Randomization .........................................................................................66 
7.3. 
Tislelizumab or Placebo Drug Dispensation ..............................................................67 
7.4. 
Safety Assessments .....................................................................................................67 
7.4.1. 
Vital Signs ..................................................................................................................67 
7.4.2. 
Physical Examinations ................................................................................................67 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................67 
7.4.4. 
Laboratory Safety Tests ..............................................................................................67 
7.4.5. 
Electrocardiograms .....................................................................................................67 
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7.4.6. 
Adverse Events ...........................................................................................................68 
7.5. 
Tumor and Response Evaluations ..............................................................................68 
7.6. 
Pharmacokinetic and Anti-Drug Antibody Testing ....................................................69 
7.7. 
Biomarkers ..................................................................................................................70 
7.8. 
Patient-Reported Outcomes ........................................................................................71 
7.9. 
Visit Windows ............................................................................................................71 
7.10. 
Unscheduled Visits .....................................................................................................71 
8. 
SAFETY MONITORING AND REPORTING .........................................................72 
8.1. 
Risks Associated With Study Treatment ....................................................................72 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................72 
8.1.2. 
Risks Associated With Concurrent Chemotherapy ....................................................72 
8.1.3. 
Risks Associated With Radiotherapy .........................................................................73 
8.2. 
General Plan to Manage Safety Concerns ..................................................................74 
8.2.1. 
Eligibility Criteria .......................................................................................................74 
8.2.2. 
Safety Monitoring Plan ...............................................................................................74 
8.3. 
Adverse Events ...........................................................................................................74 
8.3.1. 
Definitions and Reporting ...........................................................................................74 
8.3.2. 
Assessment of Severity ...............................................................................................75 
8.3.3. 
Assessment of Causality .............................................................................................75 
8.3.4. 
Following Adverse Events ..........................................................................................76 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................77 
8.4. 
Definition of a Serious Adverse Event .......................................................................77 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................78 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................78 
8.6.1. 
Adverse Event Reporting Period ................................................................................78 
8.6.2. 
Reporting Serious Adverse Events .............................................................................78 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................78 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................79 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................79 
8.6.3. 
Eliciting Adverse Events ............................................................................................80 
8.6.4. 
Recording Disease Progression ..................................................................................80 
8.6.5. 
Deaths .........................................................................................................................80 
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8.6.6. 
Pregnancies .................................................................................................................80 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................81 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................81 
8.7. 
Management of AE of Special Interest .......................................................................81 
8.7.1. 
Infusion-Related Reactions .........................................................................................81 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................83 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................83 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................85 
9.1. 
Statistical Analysis ......................................................................................................85 
9.1.1. 
Randomization Methods .............................................................................................85 
9.1.2. 
Analysis Sets ...............................................................................................................85 
9.1.3. 
Patient Disposition ......................................................................................................85 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................85 
9.1.5. 
Prior and Concomitant Medications ...........................................................................85 
9.2. 
Efficacy Analyses .......................................................................................................86 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................86 
9.2.1.1. 
PFS Assessed by BIRC ...............................................................................................86 
9.2.2. 
Secondary Efficacy Analyses .....................................................................................87 
9.2.2.1. 
Key Secondary Endpoint - Overall Survival ..............................................................87 
9.2.2.2. 
HRQoL .......................................................................................................................87 
9.2.2.3. 
Objective Response Rate by the BIRC .......................................................................87 
9.2.2.4. 
Duration of Response .................................................................................................88 
9.2.3. 
Exploratory Efficacy Analyses ...................................................................................88 
9.2.3.1. 
1-Year PFS rate ...........................................................................................................88 
9.2.3.2. 
2-Year PFS rate ...........................................................................................................88 
9.3. 
Safety Analyses ..........................................................................................................88 
9.3.1. 
Extent of Exposure .....................................................................................................88 
9.3.2. 
Adverse Events ...........................................................................................................89 
9.3.3. 
Laboratory Analyses ...................................................................................................89 
9.3.4. 
Vital Signs ..................................................................................................................89 
9.4. 
Pharmacokinetic Analysis ..........................................................................................89 
9.5. 
Immunogenicity Analyses ..........................................................................................90 
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9.6. 
Sample Size Consideration .........................................................................................90 
9.7. 
Interim Analyses .........................................................................................................91 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................92 
10.1. 
Blinded Independent Review Committee ...................................................................92 
10.2. 
Independent Data Monitoring Committee ..................................................................92 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................93 
11.1. 
Access to Information for Monitoring ........................................................................93 
11.2. 
Access to Information for Auditing or Inspections ....................................................93 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................94 
12.1. 
Regulatory Authority Approval ..................................................................................94 
12.2. 
Quality Assurance .......................................................................................................94 
12.3. 
Study Site Inspections.................................................................................................94 
12.4. 
Drug Accountability ...................................................................................................94 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................96 
13.1. 
Ethical Standard ..........................................................................................................96 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................96 
13.2.1. 
Protocol Amendments ................................................................................................96 
13.3. 
Informed Consent .......................................................................................................96 
13.4. 
Patient and Data Confidentiality .................................................................................97 
13.5. 
Financial Disclosure ...................................................................................................99 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................100 
14.1. 
Data Collection and Management Responsibilities ..................................................100 
14.1.1. 
Data Collection .........................................................................................................100 
14.1.2. 
Data Management/Coding ........................................................................................100 
14.2. 
Data Integrity and In-house Blinding .......................................................................100 
14.3. 
Study Records Retention ..........................................................................................101 
14.4. 
Protocol Deviations ..................................................................................................102 
14.5. 
Publication and Data Sharing Policy ........................................................................102 
14.6. 
Study and Study Center Closure ...............................................................................103 
14.7. 
Information Disclosure and Inventions ....................................................................103 
15. 
REFERENCES .........................................................................................................105 
Appendix 1. Schedule of Assessments ......................................................................................110 
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Appendix 2. Blood Biomarker Analysis ...................................................................................116 
Appendix 3. Clinical Laboratory Assessments .........................................................................117 
Appendix 4. ECOG Performance Status ...................................................................................118 
Appendix 5. The Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, 
Version 1.1 ...........................................................................................................119 
APPENDIX 5.1 ESOPHAGEAL PRIMARY LESION ASSESSMENT AND 
RESPONSE EVALUATION...............................................................................129 
Appendix 6. Pre-existing Immune Deficiencies or Autoimmune Diseases ..............................130 
Appendix 7. New York Heart Association Functional Classification ......................................131 
Appendix 8. Immune-Mediated Adverse Event Evaluation and Management .........................132 
Appendix 9. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation ................................................................................................................142 
Appendix 10. Contraception Guidelines and Definitions of “Women of Childbearing 
Potential,” “No Childbearing Potential” ..............................................................143 
Appendix 11. EORTC-QLQ-C30 QUESTIONNAIRE ............................................................145 
Appendix 12. EORTC QLQ-OES18 QUESTIONNAIRE ........................................................147 
 
LIST OF TABLES  
Table 1:  Definitive CRT Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma ......................................................................................................................26 
Table 2:  Selection and Timing of Dose for Each Patient ..............................................................53 
Table 3:  Dose Reduction Level of Cisplatin and Paclitaxel .........................................................58 
Table 4:  Dose Modification based on Hematologic Nadir Values Prior to the Next Dose ..........58 
Table 5:  Dose Modifications of Cisplatin for Renal Impairment .................................................59 
Table 6:  Treatment Modification of Paclitaxel for Hepatic Impairment ......................................59 
Table 7:  Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .................................................................................79 
Table 8:  Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) .................................................................................................................82 
Table 9:  Immune-Mediated Adverse Events ................................................................................84 
Table 10:  The Analysis Timing and Efficacy Boundary for PFS in the Interim Analysis 
and Final Analysis ..........................................................................................................91 
 
 
 
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LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................43 
 
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SYNOPSIS  
Name of Sponsor/Company:  BeiGene (Shanghai) Co., Ltd. 
Investigational Product:  Tislelizumab (BGB-A317)  
Title of Study:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Tislelizumab 
(BGB-A317) Versus Placebo in Combination With Concurrent Chemoradiotherapy in Patients With 
Localized Esophageal Squamous Cell Carcinoma 
Protocol Identifier:  BGB-A317-311 
Phase of Development:  3 
Number of Patients:  Approximately 366 patients 
Study Centers:  Approximately 30 centers  
Study Objectives: 
Primary: 
• 
To compare the progression-free survival (PFS) as assessed by the Blinded Independent 
Review Committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 (v1.1) in the Intent-to-Treat (ITT) Analysis Set between tislelizumab in 
combination with concurrent chemoradiotherapy (cCRT) and placebo in combination with 
cCRT. 
Secondary:  
Key Secondary 
• 
To compare the overall survival (OS) in the ITT Analysis Set between tislelizumab and 
placebo in combination with cCRT. 
Other Secondary 
• 
To compare the patient-reported outcomes of health-related quality of life (HRQoL) between 
tislelizumab and placebo in combination with cCRT. 
• 
To compare the overall response rate (ORR) as assessed by the BIRC per RECIST v1.1 in the 
ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• 
To compare the duration of response (DOR) as assessed by the BIRC per RECIST v1.1 in the 
ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• 
To evaluate the safety and tolerability of tislelizumab combined with cCRT. 
Exploratory: 
• 
To compare the 1-year PFS rate as assessed by the investigator per RECIST v1.1 in the ITT 
Analysis Set between tislelizumab and placebo in combination with cCRT. 
• 
To compare the 2-year PFS rate as assessed by the investigator per RECIST v1.1 in the ITT 
Analysis Set between tislelizumab and placebo in combination with cCRT. 
• 
To explore the potential predictive, prognostic biomarkers including but not limited to: 
programmed cell death protein ligand-1 (PD-L1) expression; gene expression profiling (GEP); 
tumor infiltrating lymphocytes (TILs); tumor mutational burden (TMB), gene mutation, and 
microsatellite instability (MSI); and/or blood-based biomarkers (flow cytometry, immune-
phenotyping [panel: A173, A167, A163, and A378], and circulating tumor DNA [ctDNA] 
alteration; and peripheral blood mononuclear cell [PBMC] immune cell profiling) in archival 
and/or fresh tumor tissue and blood samples obtained before and/or during study treatment, 
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and/or at disease progression, and the association with disease status, response to study 
treatment and mechanism of resistance. 
• 
To assess the pharmacokinetics (PK) of tislelizumab in combination with cCRT. 
• 
To assess host immunogenicity to tislelizumab. 
Study Endpoints: 
Primary: 
• 
PFS – defined as the time from randomization to the first documented disease progression as 
determined by BIRC per RECIST v1.1, or death from any cause, whichever occurs first.  
Secondary: 
Key Secondary 
• 
OS – defined as the time from the date of randomization to the date of death due to any cause. 
Other Secondary 
• 
HRQoL assessment defined as patients’ reported treatment effects using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) and European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Oesophageal Cancer Module (EORTC QLQ-OES18). 
• 
ORR – defined as the proportion of patients who had complete response (CR) or partial 
response (PR) as assessed by BIRC per RECIST v1.1. 
• 
DOR – defined as the time from the first occurrence of a documented objective response to the 
time of relapse, as determined by BIRC per RECIST v1.1 or death from any cause, whichever 
occurs first. 
• 
The incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, 
v5.0, 2017).  
Exploratory: 
• 
1-year PFS rate – defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 1 year from randomization, as determined by investigator per RECIST v1.1. 
• 
2-year PFS rate – defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 2 years from randomization, as determined by investigator per RECIST 
v1.1. 
• 
Status of PD-L1-related, immune-related, esophageal squamous cell carcinoma (ESCC)-
related, and other exploratory biomarkers (GEP, TILs, TMB/gene mutation/MSI, and/or blood-
based biomarkers [flow cytometry and immune-phenotyping (panel: A173, A167, A163, and 
A378), ctDNA alteration, and PBMC immune cell profiling]) in archival and/or fresh tumor 
tissues and blood samples obtained before and/or during study treatment and/or at disease 
progression, and the association with disease status and/or response to tislelizumab in 
combination with cCRT and placebo in combination with cCRT.  
• 
Assessments of PK of tislelizumab when given with cCRT. 
• 
Assessments of immunogenicity of tislelizumab by determining the incidence of anti-drug 
antibodies (ADA). 
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Study Design: 
This is a double-blind, placebo-controlled, randomized, multicenter, Phase 3 study designed to evaluate 
the efficacy and safety of tislelizumab versus placebo in combination with cCRT in approximately 
366 patients with localized ESCC. This study will be conducted in China. 
The primary outcome measure of the study is PFS as assessed by the BIRC in the ITT Analysis Set. 
Patients with pathologically confirmed localized ESCC who are considered suitable for cCRT 
(inoperable without prior radiotherapy) are eligible.  
Eligible patients will be stratified by the following two factors: 
• 
Eastern Cooperative Oncology Group (ECOG) performance status: 0 versus 1 
• 
Clinical stage: II/III vs IVa (AJCC version 8 [Rice et al 2017]) 
After 1:1 randomization, patients will begin double-blind treatment with one of the following regimens.  
• 
Arm A (study arm):  Tislelizumab + chemotherapy + radiotherapy (concurrent) 
• 
Arm B (control arm):  Placebo + chemotherapy + radiotherapy (concurrent) 
o Tislelizumab or placebo 
− 
200 mg intravenously on Day 1 of every 21-day cycle (every 3 weeks) up to 
24 months (about 35 cycles) (refer to Section 3.6.1 for details on treatment 
duration). 
o Chemotherapy consists of Cisplatin and Paclitaxel 
− 
Cisplatin 25 mg/m2 intravenously on Day 1 to 3 of every 21-day cycle (every 
3 weeks) for 2 cycles. 
− 
Paclitaxel 135 mg/m2 intravenously on Day 1 of every 21-day cycle (every 
3 weeks) for 2 cycles. 
o Radiotherapy 
− 
Radiotherapy will be delivered in both arms with the total dose of 50.4 Gy in 
28 fractions and 5 fractions per week. Radiotherapy based on computed 
tomography (CT) simulation planning system with 5 mm-thick scan slices 
throughout the entire neck and thorax is required. 
The safety of tislelizumab or placebo in combination with cCRT will be assessed by an Independent 
Data Monitoring Committee (IDMC) in the first 20 patients (approximately 10 patients per each arm) 
after they have had at least 6 weeks of follow-up after the last dose of radiotherapy and throughout the 
conduct of the trial. Enrollment will continue during the safety review. 
Study Assessments: 
PFS and tumor response will be assessed by BIRC and investigators. Tumor imaging (CT with or 
without contrast or magnetic resonance imaging [MRI]) and esophagography must be performed within 
28 days prior to randomization. On-treatment tumor assessments will occur approximately every 
9 weeks (± 7 days) for the first 54 weeks, every 12 weeks (± 7 days) during Years 2 and 3, every 
24 weeks (± 7 days) during Years 4 and 5, and then according to local standards with a minimum of 1 
tumor response assessment annually thereafter, regardless of treatment delays. If a patient discontinues 
study treatment due to the reasons other than disease progression, tumor assessments will continue to 
be performed as scheduled until the patient begins a new anticancer therapy, experiences disease 
progression (confirmed by the investigator or BIRC, whichever is later), lost to follow-up, withdraws 
consent, death, or until the study terminates, whichever occurs first. At the discretion of the 
investigator, patients may be treated beyond progression assessed by BIRC per RECIST v1.1 after 
obtaining agreement from the sponsors medical monitor. After agreement is reached, the treating 
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investigator 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 of HRQoL will be collected using the EORTC QLQ-C30 and EORTC 
QLQ-OES18 at screening or baseline, prior to dosing of every treatment cycle for the first 6 cycles, 
then after every other cycle afterwards and at end of treatment. 
After initiation of study treatment, all adverse events (AEs) and serious adverse events (SAEs), 
regardless of relationship to study treatment, will be reported until 30 days after last dose of study 
treatment (including chemoradiotherapy) or until the initiation of another anticancer therapy, whichever 
occurs first. Immune-mediated AEs (imAEs) will be recorded 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 believed to be related to tislelizumab treatment at any time after treatment 
discontinuation. 
Safety and efficacy monitoring will be performed by IDMC. The IDMC may recommend modifications 
to the study, including study termination due to safety and/or efficacy concerns. The functions and 
membership of the IDMC will be described in an IDMC Charter. 
Duration of Patient Participation: 
Duration of treatment will be up to 24 months for tislelizumab or placebo, including approximately 
6 weeks for concurrent administration of chemotherapy and radiotherapy. Each patient’s treatment 
course will include: 
• 
Screening period of up to 28 days 
• 
Treatment until disease progression (or any other reasons for discontinuation before 
progression) 
• 
Safety Follow-up Visit to occur within 30 days (± 7 days) after the last dose of study treatment 
of tislelizumab/placebo or chemoradiotherapy (whichever is later) 
Survival follow-up information will be collected every 3 months after the Safety Follow-up Visit until 
death (or withdraw of consent, loss to follow-up, or study completion by the sponsor). The end of study 
is defined as the timepoint when the final data for a clinical study were collected, which is after the last 
study patient has made the final visit to the study location.  
Study Population:  
Patients with histologically confirmed localized ESCC suitable for cCRT are eligible. 
Key Eligibility Criteria: 
Key inclusion criteria 
Patients with histologically confirmed diagnosis of ESCC and suitable for cCRT, including:  
• 
Patients with Stage II-IVa inoperable ESCC (medically unsuitable for surgery or 
refuses surgical intervention) are eligible. Patients who received prior ≤ 3 cycles of 
chemotherapy without radiotherapy can be enrolled.  
Key exclusion criteria 
• 
Except ≤ 3 cycles of chemotherapy, received any other prior antineoplastic therapy(ies) for 
ESCC (eg, therapies targeting programmed cell death protein-1 (PD-1), PD-L1, programmed 
cell death protein ligand-2 (PD-L2) or other immune-oncology therapies, radiotherapy, targeted 
therapies, ablation, or other systemic or local antineoplastic treatment) 
• 
History of fistula due to primary tumor invasion  
• 
Patients with high risk of fistula or sign of perforation 
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• 
Evidence of distant metastases (M1 disease) 
• 
Clinically uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage or medical intervention within 2 weeks prior to randomization 
• 
Indicators of severe malnutrition. 
Investigational Product, Dose, and Mode of Administration:   
Tislelizumab or placebo will be administered at a dose of 200 mg intravenously on Day 1 of every 
21-day cycle. Tislelizumab or placebo will be given concurrently with the chemotherapy doublet and 
radiotherapy.  
Reference Therapy, Dose, and Mode of Administration:   
Chemotherapy consists of Cisplatin and Paclitaxel for 2 cycles (approximately 6 weeks): 
• 
Cisplatin 25 mg/m2 intravenously on Day 1 to 3 of every 21-day cycle (every 3 weeks). 
• 
Paclitaxel 135 mg/m2 intravenously on Day 1 of every 21-day cycle (every 3 weeks). 
Radiotherapy: 
• 
A total dose of 50.4 Gy in 28 fractions (1.8 Gy/fraction and 5 fractions/week) 
Statistical Methods: 
PFS is the primary endpoint of the study with the one-sided alpha (α) type I error rate controlled under 
0.025. The initial α allocated to PFS will be transferred to secondary endpoints once the primary 
endpoint is statistically significant. The secondary endpoints will be tested sequentially, ie, starting 
with the key secondary endpoint (OS), and followed by HRQoL. Testing for the secondary endpoints 
will continue until the first failure of rejection occurs. 
Analysis Sets: 
• 
The ITT Analysis Set includes all randomized patients. It will be the primary analysis set for 
the efficacy analysis  
• 
Safety Analysis Set includes all patients who received at least 1 dose of study treatment. It will 
be the primary analysis set for safety analysis 
• 
The PK Analysis Set includes all patients who are randomized to the tislelizumab arm, and for 
whom postdose PK data are available 
• 
The ADA Analysis Set includes all patients who are randomized to the tislelizumab arm and 
have a baseline and at least 1 postbaseline ADA result 
Primary Efficacy Endpoint Analysis: 
PFS Assessed by BIRC 
PFS assessed by BIRC is defined as the time from randomization to the first documented disease 
progression as determined by the BIRC according to RECIST v1.1, or death by any cause, whichever 
occurs first. The actual tumor assessment visit date will be used to calculate PFS. 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 (Food and Drug Administration 
Center for Drug Evaluation Research and Center for Biologics Evaluation and Research, 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 anticancer therapy will be censored at the 
last tumor assessment date prior to the introduction of new therapy.  
The null hypothesis to be tested is: 
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H0:  PFS in Arm A ≤ PFS in Arm B 
against the alternative: 
H1:  PFS in Arm A > PFS in Arm B 
This will be the primary analysis once the targeted PFS event number assessed by BIRC is reached. 
The p-value from the stratified log-rank test will be presented using the stratification factors at 
randomization (ECOG: 0 versus 1 and stage: II/III versus IVa). The median PFS 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. The treatment effect in the form of hazard ratio 
(HR) and its 95% CI will be estimated using a Cox regression model incorporating the treatment arm as 
the independent variable and the prespecified stratification factors as the strata. These analyses will be 
performed in the ITT Analysis Set as the primary analysis.  
Secondary Efficacy Endpoint Analyses: 
Key Secondary Endpoint - Overall Survival 
The OS is defined as the time from the date of randomization to the date of death due to any cause.  
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 distribution of OS will be compared between the 2 treatment arms using a stratified log-rank test at 
one-sided 2.5% level of significance, the p-value from the stratified log-rank test will be presented 
using the stratification factors at randomization (ECOG: 0 versus 1 and stage: II/III versus IVa). The 
median OS 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. The treatment effect in the form of 
HR and its 95% CI will be estimated using a Cox regression model incorporating the treatment arm as 
the independent variable and the prespecified stratification factors as the strata. These analyses will be 
performed in the ITT Analysis Set. 
 
Other Secondary Endpoints 
HRQoL 
HRQoL is an assessment of a patient’s overall health status using the EORTC QLQ-C30 index and the 
EORTC QLQ-OES18. The postbaseline scores will be compared between the 2 treatment arms, and the 
changes from the baseline scores will be summarized descriptively.   
Objective Response Rate by the BIRC 
The ORR is the proportion of patients who had a CR or PR as determined by BIRC per RECIST v1.1 
in the ITT Analysis Set. Patients without any postbaseline assessment will be considered 
nonresponders. The 2-sided 95% CIs for the odds ratio in the ORR will be calculated, as well as 
Clopper-Pearson 95% CIs of ORR for each treatment arm. 
Duration of Response 
The DOR assessed by BIRC per RECIST v1.1 will be analyzed only in responders. The statistical 
methods applied to DOR is similar to the analysis described in the above section for PFS analysis. 
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Exploratory Efficacy Analyses: 
1-Year PFS Rate 
The 1-year PFS rate is defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 1 year after randomization. The 1-year PFS rate and the 2-sided CIs for the 2 arms 
will be estimated using the Kaplan-Meier estimator. 
2-Year PFS Rate 
The 2-year PFS rate is defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 2 years after randomization. The 2-year PFS rate and the 2-sided CIs for the 2 arms 
will be estimated using the Kaplan-Meier estimator. 
Distribution of PD-L1 expression in tumor tissue will be examined in the ITT Analysis Set. The 
association between PD-L1 expression and tislelizumab treatment effect over the control (PFS, OS, 
ORR, DOR and disease control rate [DCR]) will be explored. 
Status of PD-L1 expression in tumor tissue will be examined in the ITT Analysis Set. The association 
between PD-L1 expression and study treatment will be explored. 
Other immune, ESCC-related and exploratory biomarkers including but not limited to gene expression 
profiling and tumor mutational profile and their association with disease status and/or response to study 
treatment will also be explored. 
Safety Analyses: 
Extent of exposure to each treatment will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA) terms and graded per NCI-CTCAE v5.0. All TEAEs will be summarized. A TEAE is 
defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or 
after the first dose of study treatment up to 30 days following study treatment discontinuation or 
initiation of new anticancer therapy, whichever occurs first. SAEs, deaths, TEAEs with Grade 3 or 
above, treatment-related TEAEs, TEAEs that lead to treatment discontinuation, dose reduction, dose 
interruption or dose delay, and imAE 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.  
Pharmacokinetic Analyses: 
Tislelizumab postdose and trough serum concentration (Ctrough) data will be tabulated and summarized 
by visit/cycle at which these concentrations are collected. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses, including population PK analyses and exposure-response (efficacy, safety 
endpoints) analyses may be conducted as appropriate and the results of such analysis may be reported 
separately from the clinical study report (CSR). 
Immunogenicity Analysis: 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs. The incidences of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
Sample Size Considerations: 
The sample size calculation is based on the number of events required to demonstrate the PFS 
superiority of Arm A over Arm B in the ITT Analysis Set. Exponential distribution is assumed for PFS. 
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The estimates of the number of events required to demonstrate efficacy of PFS in the primary 
comparisons are based on the following assumptions: 
• 
Median PFS of 14 months in Arm B. 
• 
1.5-month delayed treatment effect (ie, assuming HR = 1 in the first 1.5 months; and 
HR = 0.65 thereafter, corresponding to an improvement in median PFS from 14 months to 21.5 
months). 
• 
One-sided α of 0.025. 
• 
1-year drop-out rate of 5% for both treatment arms. 
• 
Randomization ratio of 1:1. 
With these assumptions, approximately 200 PFS events are required to occur in the ITT Analysis Set 
for the PFS final analysis to obtain approximately 80% power.  Approximately 366 patients will be 
enrolled, with enrollment duration of 24.0 months. The interim PFS analysis will be performed at 
25.5 months after the first patient was randomized, when 115 PFS events occurred, with error spent 
from a Lan-DeMets O'Brien-Fleming approximation spending function. The boundaries for PFS 
interim and final analysis could be found in Table 10. 
To demonstrate the OS superiority of Arm A over Arm B in the ITT Analysis Set, the following 
assumptions are made: (1) median OS of 35 months in Arm B, (2) HR of 0.65, corresponding to an 
improvement in median OS from 35 months to 53.8 months. Approximately 191 death events will 
provide approximately 85% power using a 1-sided α of 0.025, with interim analysis for OS at the time 
of the interim PFS analysis.  
The final analysis of PFS and OS will be performed concurrently when approximately 200 PFS events 
or approximately 191 OS events have been observed, whichever occurs first. 
Interim Analysis: 
PFS 
The PFS interim analysis was planned when 115 target PFS events were reported. 
The stopping boundaries (p-values from stratified log-rank test) of the test for PFS at the interim and 
final analyses are shown in Table 10. The boundaries will be updated according to the actual number of 
events during analysis, to ensure overall type I error controlled. 
OS 
The key secondary endpoint of OS will be tested only after the primary endpoint is statistically 
significant. If the test of PFS is significant, the total α = 0.025 will be allocated to OS interim and final 
analyses to test for significance. The interim analysis of OS was planned at the time of the PFS interim 
analysis, with a fixed 1-sided α level of 0.0001 allocated, and the remaining fixed 1-sided α = 0.0249 
will be allocated for the final analysis of OS.   
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BIRC 
Blinded Independent Review Committee 
BOR 
best overall response 
cCRT 
concurrent chemoradiotherapy 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
CT 
computed tomography 
DCR 
disease control rate 
dCRT 
definitive chemoradiation therapy 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
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-Oesophageal Cancer Module 
ESCC 
esophageal squamous cell carcinoma 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FOLFOX 
5-fluorouracil, leucovorin, and oxaliplatin 
HBV 
hepatitis B 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 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
ORR 
overall response rate 
OS 
overall survival 
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 
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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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 (GLOBOCAN v1.0 2012). The incidence, prevalence, and histologic 
type of esophageal cancer varies between geographic regions, particularly between Western 
countries (United States 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). Approximately 75% of all cases occur in Asia with 
China bearing the largest burden, accounting for about 50% of total cases and cancer specific 
deaths (GLOBOCAN v1.0 2012). In China, esophageal cancer is the third most common cancer 
and the fourth leading cause of death from cancer, based on an estimation of 477,900 new 
esophagus cancer cases and 375,000 deaths from this disease expected in 2015 (Chen et al 2016). 
Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type (90% to 95%) 
among esophageal cancer (Arnold et al 2015; Wang et al 2014).  
Most patients with esophageal cancer are in the mid-advanced disease at their first diagnosis and 
more than half of them are medically unfit for surgery, hence concurrent chemoradiotherapy 
(cCRT) is an accepted alternative standard treatment to surgery. Approximately 70% to 80% of 
resected specimens harbor metastases in the regional lymph nodes. Thus, clinicians are often 
dealing with an advanced-stage, incurable cancer in newly diagnosed patients. However, 
prognosis for these patients remains poor and the 5-year overall survival (OS) is approximately 
20% (Stahl and Budach 2017; Meng et al 2013; McNamara et al 2012; NCCN Guidelines, v2, 
2018). 
1.2. 
Current Treatment of Esophageal Carcinoma and Unmet Clinical 
Needs  
The treatment of esophageal cancer 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, v2, 2018; Stahl et al 2009). Concurrent 
chemoradiation therapy may be given to those with larger tumors in the neo-adjuvant, adjuvant, 
locoregional recurrence from surgery or inoperable localized esophageal cancer. Postoperative 
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 therapy regimens are recommended for advanced 
esophageal and esophagogastric junction adenocarcinoma. Regimens should be chosen in the 
context of performance status, comorbidities, and toxicity profile (Lordick et al 2016; NCCN 
Guidelines, v2, 2018; Japanese Gastric Cancer Association Gastric Cancer, 2017; Stahl et al 
2009).  
A multimodality approach plays a key role in the treatment of patients with localized ESCC. In 
1992, the RTOG 8501 trial established definitive chemoradiotherapy as a standard treatment for 
localized esophageal cancers. The combination of 5-fluorouracil plus cisplatin (CDDP) is most 
commonly used, with a median survival time of 16 months. However, the standard regimen 
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remains controversial as more radiosensitive chemotherapeutic drugs, such as paclitaxel (PTX), 
have been investigated in esophageal cancer (Herskovic et al 1992; Minsky et al 2002; Cooper et 
al 1999; Zhu HT et al 2017; NCCN Guidelines, v2, 2018). Definitive chemoradiation therapy 
(dCRT), using the FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) regimen, cisplatin plus 
paclitaxel and docetaxel plus cisplatin regimen, has also been proved effective (Table 1). Anti-
epidermal growth factor receptor antibodies have been evaluated in combination with dCRT. 
However, the SCOPE and RTOG 0436 trials failed to show any survival benefits with the 
addition of cetuximab to chemoradiotherapy in esophageal cancer, which means this 
combination does not any additive benefits (Crosby et al 2017; Suntharalingam et al 2017). To 
date, there has been no demonstration that anti-epidermal growth factor receptor antibodies have 
any additional benefit in combination with dCRT. 
Although long-term survival and cure have been observed in some patients with dCRT, most 
patients experience local failure or distant metastasis and eventually die from the disease, which 
represents a large unmet medical need. Several studies have confirmed dCRT in esophageal 
carcinoma with survival rates of 35% to 40% at 2 years and about 20% at 5 years (Stahl and 
Budach 2017).  
A locoregional recurrence after dCRT occurs in about 50% of patients with inoperable 
esophageal cancer. In addition, the majority of patients (86%) experience a locoregional 
recurrence within the radiation field (primary tumor alone in 57%) (Stahl and Budach 2017; 
Hirano et al 2018). 
Table 1:  Definitive CRT Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma 
Reference 
Sample 
Size by 
Histology 
(n) 
Stage 
 
Regimen 
ORR 
(%) 
PFS 
(median 
months 
OS 
(median 
months) 
Cisplatin + 5-FU 
Herskovic 
et al 1992 
Cooper et 
al 1999 
ESCC (51) 
T1-3N0-1 
M0 
Cisplatin 75 mg/m2 intravenously Day 
1  
5-FU 1000 mg/m2 intravenously 
infusion Days 1-4 Q4W 
RT:50.4 Gy 
NA 
NA 
14.1 
Conroy et 
al 2010 
ESCC (38) 
Ⅱ-Ⅳa 
Cisplatin 75 mg/m2 intravenously day 
1  
5-FU 1000 mg/m2 intravenously 
infusion Days 1-4 Q4W 
RT: 50 Gy 
68.3 
9.2 
15.1 
Zhao et al 
2012 
ESCC (45) 
Ⅱ-Ⅳa 
Cisplatin 75 mg/m2 intravenously Day 
1  
5-FU 250 mg/m2 intravenously 
infusion Days 1-4 Q4W 
RT:50.4 Gy 
53.3 
14 
22.3 
Conroy et 
al 2014 
ESCC 
(115) 
Ⅱ-Ⅳa 
Cisplatin 75 mg/m2 intravenously Day 
1  
5-FU 1000 mg/m2 intravenously 
infusion Days 1-4 Q4W 
RT: 50Gy 
65 
9.4 
17.5 
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Reference 
Sample 
Size by 
Histology 
(n) 
Stage 
 
Regimen 
ORR 
(%) 
PFS 
(median 
months 
OS 
(median 
months) 
Zhu Y et al 
2017 
ESCC (41) 
Ⅱ-Ⅳa 
Cisplatin 80 mg/m2 intravenously Day 
1  
5-FU 1000 mg/m2 intravenously 
infusion Days 1-4 Q3W 
RT: 60-64 Gy 
84.4 
NA 
NR 
FOLFOX 
Conroy et 
al 2010 
ESCC (42) 
Ⅱ-Ⅳa 
Oxaliplatin 85 mg/m2 intravenously 
Day 1 
leucovorin 200 mg/m2 intravenously 
Day 1 
5-fluorouracil 400 mg/m2 
intravenously followed by  
600 mg/m2 in 22h days 1, 2 Q2W 
RT:50 Gy 
78.7 
15.2 
22.7 
Conroy et 
al 2014 
ESCC 
(114) 
Ⅱ-Ⅳa 
oxaliplatin 85 mg/m2 intravenously 
Day 1 
leucovorin 200 mg/m2 intravenously 
Day 1 
5-fluorouracil 400 mg/m2 
intravenously followed by  
600 mg/m2 in 22h days 1, 2 Q2W 
RT:50 Gy 
67 
9.7 
20.2 
Cisplatin + docetaxel 
Zhao et al 
2012 
ESCC (45) 
Ⅱ-Ⅳa 
Cisplatin 75 mg/m2 intravenously Day 
1  
docetaxel 75 mg/m2 intravenously 
Day 1 
Q4W 
RT:50.4 Gy 
73.3 
25.3 
43.2 
Zhu Y et al 
2017 
ESCC (45) 
Ⅱ-Ⅳa 
Cisplatin 80 mg/m2 intravenously Day 
1  
docetaxel 60 mg/ m2 intravenously 
Day 1 
Q3W 
RT: 60-64 Gy 
84.4 
NA 
NR 
5-FU + paclitaxel 
Xia et al 
2017 
ESCC (50) 
Ⅱ-Ⅳa 
(62%) 
Postoperat
ive 
recurrent 
paclitaxel 50 mg/m2, 5-FU 300 mg/m2 
days 1, 8, 15, 22, 29; 
paclitaxel 135 mg/ m2, 5-FU 1800 
mg/m2 days 57, 85 
RT: 50.4 Gy/28 fractions or 
61.2 Gy/34 fractions 
NA 
12.4 
 
17.9 
Cisplatin + paclitaxel 
Tu et al 
2013 
ESCC (36) 
Ⅱ-Ⅳa 
Cisplatin 75 mg/m2 intravenously Day 
1 Q3W 
Paclitaxel 135 mg/m2 intravenously 
Day 1 Q3W 
RT: 60 Gy 
50 
12.0 
18.0 
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Reference 
Sample 
Size by 
Histology 
(n) 
Stage 
 
Regimen 
ORR 
(%) 
PFS 
(median 
months 
OS 
(median 
months) 
Tang et al 
2016 
ESCC (76) 
Ⅱ-Ⅳ 
Cisplatin 25 mg/m2 intravenously Day 
1-3 Q3W 
Paclitaxel 175 mg/m2 intravenously 
Day 1 Q3W 
RT: 61.2Gy/34 fractions or 
68.4 Gy/44 fractions 
NA 
14.7 
28.5 
Zhu HT et 
al 2017 
ESCC (76) 
Ⅱ-Ⅳa 
Cisplatin 25 mg/m2 intravenously Day 
1-3 Q4W 
Paclitaxel 175 mg/m2 intravenously 
Day 1 Q4W 
RT: 61.2 Gy/34 fractions 
NA 
13.3 
23.7 
Abbreviations: CRT, chemoradiotherapy; 5-FU, 5-fluorouracil; ESCC, esophageal squamous cell carcinoma; 
FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; Gy, gray; NA, not available; NR, not reached; ORR, overall 
response rate; OS, overall survival; PFS, progression-free survival; Q2W, once every 2 weeks; Q3W, once every 3 
weeks; Q4W, once every 4 weeks; RT: radiotherapy.  
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. There are no data with 
checkpoint inhibitors given in the chemoradiotherapy treatment setting in patients with 
esophageal carcinoma. Nevertheless, all data described below are supportive of the safety and 
antitumor activity of anti-PD-1 (programmed cell death protein-1) monoclonal antibodies in 
esophageal carcinoma. 
Tislelizumab 
Please refer to Section 1.4.4.2 for details regarding efficacy data of tislelizumab. 
Nivolumab 
An open-label, single-arm, multicenter Phase 2 study with ESCC patients treated with nivolumab 
(a PD-1 monoclonal antibody) was conducted (Kudo et al 2017). This study enrolled 65 patients 
with ESCC 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 intravenously once every 2 weeks. 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 
overall response rate (ORR) was 17.2% (95% confidence interval [CI]: 9.9% to 28.2%) by 
central radiology assessment and 21.9% (95% CI: 13.5% to 33.4%) by investigator assessment. 
The disease control rate (DCR), defined as the proportion of patients who achieve complete 
response (CR), partial response (PR), or stable disease, was 42% (95% CI: 31% to 54%) by 
central assessment and 53% (95% CI: 41% to 65%) 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 duration of progression-free survival (PFS) was 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. 
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Pembrolizumab  
KEYNOTE-028 (NCT02054806), a multicohort, Phase 1b trial, recruited patients with advanced 
ESCC and adenocarcinoma with disease progression following standard therapy. Patients 
received pembrolizumab 10 mg/kg once every 2 weeks. Response was assessed every 8 weeks 
for the first 6 months and every 12 weeks thereafter. Primary endpoint was ORR per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 by investigator review. In this cohort of 23 
patients, 87% received ≥ 2 prior therapies for advanced/metastatic disease and 78% (17 patients) 
had ESCC. With a median follow-up of 7 months (range: 1 to 33 months), ORR was 30% (95% 
CI: 13-53%), 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). ORR was 28% for patients with 
ESCC (Doi et al 2018). 
KEYNOTE-180 (NCT02559687), a phase 2, open-label study, recruited 121 patients with 
metastatic esophageal cancer and ≥ 2 prior lines of therapy; 53% of these patients had ESCC. In 
this study, patients received pembrolizumab 200 mg once every 3 weeks for up to 2 years. As of 
18 September 2017, median duration of follow-up was 5.8 months (range: 0.2 to 18.3) and ORR 
(CR+PR) was 10% (95% CI: 5% to 17%). PR and stable disease were observed in 12 (10%) and 
25 (21%) patients, respectively. Median DOR was not reached, and median PFS was 2 months 
(95% CI: 1.9 to 2.1 months) with a 6-month PFS rate of 16% (95% CI: 10% to 23%). Median OS 
was 5.8 months (95% CI: 4.5 to 7.2 months) with a 12-month OS rate of 28% (95% CI: 20% to 
37%). ORR was 14% (95% CI: 7 to 25) in patients with ESCC and 5% (95% CI: 1 to 14) in 
patients with esophageal adenocarcinoma. ORR was 14% (95% CI: 6 to 25) in patients with 
programmed cell death protein ligand-1 (PD-L1) positive (+) cancer and 6% (95% CI: 2 to 16) in 
patients with PD-L1 negative (-) cancer. As of 18 September 2017, 15 (12%) patients had at least 
1 treatment-related treatment-emergent adverse event (TEAE) with severity ≥ Grade 3. Five 
(4%) patients discontinued due to a treatment-related TEAE. There was 1 treatment-related death 
from pneumonitis (Shah et al 2018). 
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 and is being developed for the treatment of several human 
malignancies. The IgG4 variant antibody has very low binding affinity to gamma fragment 
crystallizable region (Fc) receptor IIIA (FcγRIIIA) and complement 1q, a subunit of complement 
1, by in vitro assays, suggesting either low or no antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity effects in humans (Labrijn et al 2009). 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant = 0.15 nM). It competitively blocks binding efforts by 
both PD-L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated 
negative signaling in T cells. In in vitro cell-based assays, tislelizumab was observed to 
consistently and dose-dependently enhance the functional activity of human T cells and pre-
activated, primary peripheral blood mononuclear cells. In addition, tislelizumab has 
demonstrated antitumor activity in several allogeneic xenograft models, in which peripheral 
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blood mononuclear cells were co-injected with human cancer cells (A431 [epidermoid 
carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into immunocompromised mice. 
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 in the 13-week repeated-dose 
study. However, immunogenicity-related changes due to formation of antidrug antibodies 
(ADAs) and immune complex formation in nonhuman primates are 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. 
No tissue cross-reactivity was found in either human or monkey tissues, nor was any effect 
on cytokine release observed in a 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-A317-311. 
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 and Study BGB-A317-102, interim pharmacokinetics 
(PK) analysis (data cutoff date 28 August 2017) was conducted using noncompartmental 
methods, using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, and 10 
mg/kg once every 2 weeks, and 2.0 mg/kg, 5.0 mg/kg, and 200 mg once every 3 weeks (Phase 1a 
Parts 1, 2, and 3, and Phase 1b in BGB-A317_Study_001), and patients who received doses of 
200 mg once every 3 weeks 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, both 
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after single-dose administration at steady state. Preliminary PK data from 28 patients who were 
administered 1 dose of 200 mg once every 3 weeks (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. 
Preliminary population PK analysis using a 2-compartment model with first-order elimination 
shows a systemic plasma clearance 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 (t1/2) of 
approximately 19 days. Race, gender, and body weight were not significant covariates on the 
clearance of tislelizumab, which supports fixed-dosing across different ethnic groups. 
Non-compartmental analysis is available for Studies 001 and 102. Comparison of intensive PK 
data after a single intravenous infusion of tislelizumab indicated that dose-normalized exposure 
(AUC0-14day) was consistent between Study 001 with non-Chinese patients (n=91 mostly 
Caucasian) and Study 102 with Chinese patients (n=20). This shows that the PK of tislelizumab 
is comparable between Chinese and non-Chinese patients. Additionally, dose-normalized 
exposure (AUC0-14day) was also consistent across Asian patients (n=27, including 20 Chinese and 
7 non-Chinese Asian) and Caucasian patients (n=80). This finding is consistent with the evidence 
that ethnic differences in PK are not expected for therapeutic monoclonal antibodies (Chiba et al 
2014, Matsushima et al 2015, Zhou et al 2012). 
Similarly, comparison of trough (predose) and peak (end-of-infusion) concentration data after 
multiple intravenous infusions of 200 mg Q3W tislelizumab between Chinese (Studies 102 and 
203) and non-Chinese (Study 001) patients, and between advanced solid tumors (Studies 001 and 
102) and classical Hodgkin lymphoma (Study 203) showed that the levels are generally similar 
between the 2 ethnic groups and between different tumor types. 
1.4.4. 
Prior Clinical Experience of Tislelizumab  
As of 20 May 2020, there are 28 ongoing studies with tislelizumab. Of these, 15 studies have 
preliminary data available in the Investigator’s Brochure version 8, 10 September 2020: 7 
monotherapy studies, 2 chemotherapy combination therapy studies; and 6 targeted therapy 
combination studies. 
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on 
tislelizumab efficacy and safety when given as monotherapy or in combination with 
chemotherapy. 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies and Combination Studies 
With Chemotherapy  
Monotherapy Studies 
A pooled analysis of 7 monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy. 
Overall, there were 1328 patients in the pooled monotherapy studies: 1181 patients treated in 5 
solid tumor studies and 147 patients treated in 2 hematologic malignancies studies.   
Of the 1328 patients enrolled, 368 patients (27.7%) remained on study as of 20 May 2020; and 
189 patients (14.2%) were still receiving tislelizumab treatment. 
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Combination Studies With Chemotherapy 
A pooled analysis of 2 chemotherapy combination therapy studies was conducted to provide a 
comprehensive safety assessment separately from other combination therapy studies. 
Overall, there were 84 patients in the pooled chemotherapy combination studies. Of the 84 
patients enrolled, 13 patients (15.5%) remained on study as of 20 May 2020; and 7 patients 
(8.3%) were still receiving tislelizumab treatment. 
Refer to the tislelizumab Investigator’s Brochure for more detailed information on tislelizumab 
safety data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1.1. Pooled Demographics and Baseline Characteristics  
Monotherapy Studies 
Overall, the 1181 patients in the pooled solid tumor monotherapy analysis had a median 
treatment exposure duration of 3.68 months (range: 0.13 to 55.26) and median study follow-up 
duration of 9.89 months (range: 0.07 to 58.91). The pooled solid tumor monotherapy population 
had a median age of 60 years and was 67.1% male. 
Combination Studies With Chemotherapy 
Overall, the 84 patients in the pooled chemotherapy combination analysis had a median 
treatment exposure duration of 7.805 months (range: 0.66 to 30.88) and median study follow-up 
duration of 21.225 months (range: 0.10 to 31.24). The pooled chemotherapy combination 
population had a median age of 61 years and was 77.4% male. 
1.4.4.1.2. Treatment-Emergent Adverse Events Assessed as Related to Treatment  
Monotherapy Studies 
Of the 1181 patients in the solid tumor group of the pooled monotherapy studies, 788 (66.7%) 
experienced at least one treatment-related TEAE. The most commonly occurring TEAEs 
assessed as related to tislelizumab were aspartate aminotransferase increased (136 patients, 
11.5%), alanine aminotransferase increased (125 patients, 10.6%), hypothyroidism (106 patients, 
9.0%), rash (97 patients, 8.2%), and fatigue and pruritis (95 patients each, 8.0%). 
Of the 1181 patients in the solid tumor group of the pooled monotherapy studies, 167 (14.1%) 
experienced at least one ≥ Grade 3 TEAE assessed as related to tislelizumab. The only ≥ Grade 3 
TEAEs that occurred in ≥ 1% (≥ 12 patients) in the solid tumor group were aspartate 
aminotransferase increased (21 patients, 1.8%), alanine aminotransferase increased (17 patients, 
1.4%), and anaemia (13 patients, 1.1%). 
Combination Studies With Chemotherapy 
Of the 84 patients in the pooled chemotherapy combination studies, 69 (82.1%) experienced at 
least one treatment-related TEAE. The most commonly occurring TEAEs assessed as related to 
tislelizumab were asthenia (17 patients, 20.2%), alanine aminotransferase increased (12 patients, 
14.3%), and aspartate aminotransferase increased (11 patients, 13.1%). 
Of the 84 patients in the pooled chemotherapy combination studies, 18 (21.4%) experienced at 
least one ≥ Grade 3 TEAE assessed as related to tislelizumab. The only ≥ Grade 3 TEAEs that 
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occurred in ≥ 2 patients were aspartate aminotransferase increased and hepatic function abnormal 
(2 patients each, 2.4 %). 
1.4.4.1.3. Treatment-Emergent Serious Adverse Events  
Monotherapy Studies 
Of the 1181 patients in the solid tumor group of the pooled monotherapy studies, 415 (35.1%) 
experienced at least one treatment-emergent serious adverse event (SAE). The most commonly 
occurring treatment-emergent SAEs in the solid tumor group were pneumonia (41 patients, 
3.5%), and ascites and pyrexia (15 patients each, 1.3%). 
Combination Studies With Chemotherapy 
Of the 84 patients in the pooled chemotherapy combination studies, 29 (34.5%) experienced at 
least one treatment-emergent SAE. The most commonly occurring treatment-emergent SAEs 
occurring in ≥ 2 patients in the pooled analysis were pneumonitis (4 patients, 4.8%), platelet 
count decreased and thrombocytopenia (3 patients each, 3.6%), blood bilirubin increased, 
anaemia, hepatic function abnormal, dysphagia, and fatigue (2 patients each, 2.4%). 
1.4.4.1.4. Immune-Mediated Adverse Events  
Anti-PD1 therapies are known to cause immune-mediated adverse events (imAEs) in some 
patients and therefore have been defined as AEs of special interest in tislelizumab clinical 
studies. 
Immune-mediated AEs are consistent with an immune-related mechanism or immune-related 
component for which non-inflammatory etiologies (eg, infection or tumor progression) have 
been ruled out. Immune-mediated AEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. There is a potential temporal relationship 
between the initiation of treatment with tislelizumab and onset of an imAE that spans a window 
of days to several months. 
All adjudicated imAEs presented in the tislelizumab Investigator’s Brochure were adjudicated by 
clinical team from the identified potential imAEs based on clinical information in the clinical 
database and the safety database. Certain imAEs have multiple Medical Dictionary for 
Regulatory Activities (MedDRA) terms associated with the same category. Special categories 
have been created to group patients experiencing these events. 
Monotherapy Studies 
Of the 1113 patients in the adjudicated solid tumor group for the Pooled Monotherapy studies, 
233 (20.9%) experienced at least one imAE. The most commonly occurring imAEs were 
hypothyroidism (69 patients, 6.2%), hyperthyroidism (37 patients, 3.3%), and rash (34 patients, 
3.1%). Analysis of the total patients with ≥ 1 imAE that also was ≥ Grade 3 in severity showed 
that 52 patients (4.7%) experienced such events.  The most commonly occurring imAEs ≥ Grade 
3 in severity were alanine aminotransferase increased (9 patients, 0.8%),aspartate 
aminotransferase increased, and pneumonitis (7 patients each, 0.6%). 
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Combination Studies With Chemotherapy 
ImAEs were adjudicated and collected for Study BGB-A317-206 only. Of the 54 patients treated 
in this study, 17 (31.5%) experienced at least one imAE. The most commonly occurring imAEs 
of any grade were hypothyroidism (7 patients, 13.0%), pneumonitis (4 patients, 7.4%), and 
hyperthyroidism (3 patients, 5.6%). Analysis of the total patients with ≥ 1 imAE that also was 
≥ Grade 3 in severity showed that 3 patients (5.6%) experienced such events (immune-mediated 
pneumonitis, bilirubin conjugated increased, hepatic function abnormal, immune-mediated 
hepatitis myocarditis, and rhabdomyolysis). 
1.4.4.1.5. Infusion-Related Reactions  
Infusion-related reactions, including high-grade hypersensitivity reactions, following 
administration of tislelizumab are uncommon. 
Monotherapy Studies 
Of the 1181 patients in the solid tumor group within the pooled monotherapy studies, 45 (3.8%) 
experienced ≥ 1 infusion-related reaction. The most commonly occurring infusion-related 
reactions that occurred in the solid tumor group were infusion-related reaction (28 patients, 
2.4%), pyrexia (10 patients, 0.8%), and nausea (4 patients, 0.3%). Two patients experienced ≥ 
Grade 3 infusion-related reactions in the solid tumor group of the pooled monotherapy studies 
and all other ≥ Grade 3 events occurred in single instances. 
Combination Studies With Chemotherapy 
Of the 84 patients in the pooled chemotherapy combination studies, 3 (3.6%) experienced ≥ 1 
infusion-related reaction. The infusion-related reactions that occurred in single instances 
included pruritis, rash, chills, palpitations, pyrexia, and flushing (all < Grade 3). No severe 
infusion-related reactions were observed in this study. 
1.4.4.1.6. Fatal Adverse Events  
Monotherapy Studies 
A total of 104 patients (8.8%) in the solid tumor studies died ≤ 30 days from the last study drug 
dose as of 20 May 2020. Of these 104 patients, there were 18 patients (1.5%) who had an AE 
with a fatal outcome ≤ 30 days from the last study drug dose. Of 683 patients (57.8%) who 
died > 30 days after the last study drug dose, 8 patients (0.7%) died as a result of an AE (refer to 
the Investigator’s Brochure Edition 8, Section 5.2.1.10). 
Combination Studies With Chemotherapy 
One patient (1.2%) died ≤ 30 days from the last study drug dose due to an AE in the Pooled 
Chemotherapy Combination Studies as of 20 May 2020. Of 35 patients (41.7%) who died > 30 
days after the last study drug dose, 1 patient (1.2%) died as a result of an AE, 26 patients 
(31.0%) died as a result of progressive disease, and 8 patients (9.5%) died as a result of “other” 
causes of death (refer to the Investigator’s Brochure Edition 8, Section 5.2.2.9). 
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1.4.4.2. 
Efficacy Assessment of Tislelizumab  
Efficacy data are available from 3 of the ongoing studies in solid tumors, BGB 
A317_Study_001, BGB-A317-102, and BGB-A317-205, which are summarized below. 
1.4.4.2.1. Study BGB-A317_001 (Data Cutoff 27 October 2018)  
This is a 2-stage study. Phase 1a consists of a dose-escalation and dose-finding component, and 
Phase 1b investigates efficacy and safety in select tumor types. 
There were 451 patients treated in the study. Of the 53 esophageal carcinoma patients included in 
the Efficacy Evaluable Analysis Set, there were 6 patients (11.3%) with a confirmed response 
and 14 patients (26.4%) with a best overall response (BOR) of stable disease. 
1.4.4.2.2. Study BGB-A317-102 (Data Cutoff 01 December 2018)  
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. 
There were 300 patients treated in the study. Of the 17 esophageal carcinoma patients included in 
the Efficacy Evaluable Analysis Set, there was 1 patient (5.9%) with a confirmed response and 7 
patients (41.2%) with a BOR of stable disease. 
1.4.4.2.3. Study BGB-A317_205 (Data Cutoff 31 Mar 2019)  
This is a multicohort, Phase 2 study of tislelizumab in combination with standard chemotherapy 
as first-line treatment in Chinese patients. An ESCC cohort and a gastric and gastroesophageal 
junction adenocarcinoma (GAC/GEJ adenocarcinoma) cohort have been enrolled concurrently. 
In the ESCC cohort, patients are treated with tislelizumab 200 mg intravenously on Day 1, 
cisplatin 80 mg/m² IV on Day 1, and 5-fluorouracil (5-FU) 800 mg/m²/day intravenously using 
continuous pumping system on Days 1 through 5 during each 21-day cycle.  
There were 30 patients treated in the study and 26 patients were included in the Efficacy 
Evaluable Analysis Set. Of the 13 patients in the ESCC cohort, there were 7 patients (53.8%) 
with a confirmed response and 5 patients (38.5%) with a BOR of stable disease. 
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) 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 
cellular cytotoxicity or antibody-dependent cellular phagocytosis (ADCP) depletion of effector 
T-cells (Gül and Egmond 2015; Prieto et al 2015; Makarova-Rusher et al 2015; Beers et al 2016; 
Dahan et al 2015). As a non or low-FcγR-binding agent (thus causing minimal antibody-
dependent cellular cytotoxicity/ADCP effect), tislelizumab may 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, has shown that the drugs have both 
manageable safety profiles and promising antitumor activity in patients with esophageal 
carcinoma (Section 1.3). 
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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 1.3). 
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 intravenously 
once every 3 weeks was selected for further evaluation. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear dose-
dependence across these regimens. Similarly, confirmed ORRs in patients treated with 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared 
to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once every 3 weeks. 
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 the 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 BOR of PR, 4 patients (31%) had a 
BOR of stable disease, and 6 patients (46%) had a BOR of progressive disease. Therefore, 
clinical activity with a manageable and tolerable safety profile is expected to be maintained in 
patients receiving tislelizumab 200 mg once every 3 weeks. 
In conclusion, tislelizumab 200 mg once every 3 weeks is the recommended dose for pivotal 
studies. 
1.5.3. 
Rationale for Tislelizumab in Combination With Chemoradiotherapy  
Radiotherapy is an important nonsurgical treatment in management of esophageal cancer. 
Concurrent chemoradiotherapy has become the standard of care for the treatment of localized 
ESCC. As shown by the RTOG 8501 study, cCRT significantly improved OS compared to 
radiotherapy alone. But there was no substantial improvement subsequently with cCRT alone 
despite exploration of different treatment options such as dose escalation of radiation, induction 
chemotherapy, and various chemotherapy of cCRT (Stahl and Budach 2017; Hirano and Boku 
2018). 
There is strong evidence that not only can there be synergy of checkpoint inhibitors with 
chemotherapy; this can occur with cCRT as well. It is now known that both chemotherapy and 
radiotherapy can up-regulate the expression of PD-L1 (Zhang et al 2008; Deng et al 2014) due to 
the release of cytokines and other inflammatory molecules, which could make such tumors 
sensitive to a PD-1/PD-L1 directed therapy. In this setting, chemotherapy and radiotherapy act as 
priming agents for immunotherapy; elimination of cancer cells by chemotherapy and/or 
radiotherapy triggers release of antigens, which can turn poorly immunogenic or 
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immunosuppressive tumors into an immunogenic environment (Vanneman and Dranoff 2012). 
In addition, radiotherapy has an impact on the immune system by engaging both the innate and 
the adaptive arms, eliciting tumor-specific T-cells and establishing an immune memory against 
the tumor. This prolongs the effect of radiation, improving locoregional control, decreasing 
metastatic spread, and increasing OS (Formenti and Demaria 2013).  
The results from a preclinical model of ESCC showed that anti-PD1 treatment works 
synergistically with chemoradiation to increase tumor control and increase tumor-infiltrating 
lymphocytes while decreasing the number of anergic tumor-infiltrating lymphocytes. This may 
prove an effective strategy to improve combination therapy in localized ESCC (Oh et al 2016). 
The utility of combined immunotherapy and radiotherapy has been demonstrated in the clinical 
setting. A Phase 3 trial (PACIFIC trial) was conducted to compare durvalumab with placebo as 
consolidation therapy after platinum-based dCRT in patients with stage III non–small cell lung 
cancer (Antonia et al 2017). The PFS was significantly longer in the durvalumab group as 
compared with the placebo group (median PFS: 16.8 months versus 5.6 months; hazard ratio 
[HR]: 0.52, P < 0.001). No significant difference was observed in the incidence of Grade 3/4 
pneumonitis or radiation pneumonitis. This trial demonstrated the efficacy and manageable 
toxicity of durvalumab as consolidation therapy after dCRT. A secondary analysis of the 
KEYNOTE-001 trial revealed that previous radiotherapy might improve PFS and OS in patients 
with advanced non-small cell lung cancer (Shaverdian et al 2017). The PFS was significantly 
longer in patients who received any radiotherapy compared with patients who received no 
radiotherapy (median PFS: 4.4 months versus 2.1 months; HR: 0.56, P = 0.019). The OS was 
also significantly improved in patients who received any radiotherapy compared with patients 
who did not receive any radiotherapy (median OS: 10.7 months versus 5.3 months; HR: 0.58, P 
= 0.026). As with non-small cell lung cancer, a combination of immunotherapy and 
chemoradiotherapy may be beneficial in patients with unresectable localized ESCC. The interim 
safety analysis of a Phase 1b study (LA-SCCHN), analyzing pembrolizumab in combination 
with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head 
and neck, supported that pembrolizumab can be safely delivered with weekly cisplatin and 
radiotherapy with no new toxicity signals observed (Powell et al 2017). To address any potential 
toxicities of administering anti-PD-1 treatment particularly when given simultaneously with 
cCRT, a rigorous safety assessment will be implemented with Independent Data Monitoring 
Committee (IDMC) reviewing early safety signals. 
1.5.4. 
Rationale for Cisplatin and Paclitaxel Chemotherapy  
Although Study RTOG 8501 showed a better OS in the cCRT group with the 
cisplatin/5-fluorouracil (PF) regimen, the results revealed that the PF regimen was not an optimal 
regimen with only 30% patients surviving over 3 years and 44% and 20% patients developing 
severe and life-threatening side effects, respectively. In 1994, paclitaxel (PTX) was proved to be 
one of the effective agents in the treatment of esophageal carcinoma, with the response rate of 
28% in squamous cell carcinoma (Ajani et al 1994; Ilson et al 2007). Thereafter, many 
institutions have conducted numerous studies using PTX combined with other agents, among 
which PTX plus cisplatin were the most common combinations used in the treatment of 
advanced esophageal carcinoma, with a response rate of 39% to 60% (van de Gaast et al 1997; 
Kelsen et al 1997; Polee et al 2002; Huang et al 2004). In 2008, the Radiation Therapy Oncology 
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Group reported a phase 2 randomized control study called RTOG 0113, which compared 2 PTX-
based regimens used in induction chemotherapy followed by cCRT to determine which regimen 
could achieve a better 1-year OS and surpass the historical result of Study RTOG 9405 (Ajani et 
al 2008; Minsky et al 2002). The results of RTOG 0113 demonstrate that such intense therapies 
are associated with considerable morbidity and neither of the two treatments proved to be 
sufficiently superior to the historical control of RTOG 9405 (Ajani et al 2008). A retrospective 
study of comparison of taxane and fluorouracil-based chemoradiotherapy in patients with 
inoperable ESCC showed that chemoradiation with taxane-based regimens was well tolerated 
with potentially promising efficacy which could become a good alternative treatment in these 
patients (Sun et al 2016). A phase 2 study of cCRT with cisplatin and paclitaxel for inoperable 
ESCC showed that cCRT with cisplatin 25 mg/m2 day 1 to 3 once every 3 weeks and paclitaxel 
175 mg/m2 day 1 once every 3 weeks resulted in an encouraging overall survival rate (Tang et al 
2016). 
1.5.5. 
Rationale for Radiotherapy Dose  
RTOG 8501 trial established cCRT as a standard treatment for localized esophageal carcinoma 
with a total radiotherapy dose of 50.4 Gy. However, the incidence of locoregional recurrence is 
over 50% (Cooper et al 1999). The recommended dose of radiotherapy remains controversial. A 
meta-analysis showed that a total dose of ≥ 60 Gy might improve patients’ OS, especially those 
in Asia (Chen et al 2017). But further attempts to improve outcomes were unsuccessful. INT-
0123 trial, the only randomized controlled trial that compared different radiation doses (64.8 Gy 
versus the standard 50.4 Gy) in combination with chemotherapy for nonsurgical esophageal 
carcinoma patients, showed that a 14.4 Gy dose escalation did not result in either OS or 
locoregional control benefit. For curative purposes, 50.4 Gy is the optimal radiation dose while 
minimizing toxicities such as acute radiation esophagitis and pneumonitis as much as possible. 
1.5.6. 
Rationale for Placebo as the Comparator  
In this blinded, Phase 3 study, the comparator arm will consist of a matched placebo in 
combination with chemoradiotherapy doublet. 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 chemoradiotherapy doublet for 
this patient population, minimizing the risk generally associated with placebo-alone arms in 
controlled studies.  
1.6. 
Benefit-Risk Assessment  
Patients with localized ESCC suitable for chemoradiotherapy represent a population with a great 
unmet medical need.  
As discussed in Section 1.3, checkpoint inhibition with tislelizumab has been shown to have 
antitumor activity in esophageal carcinoma patients, with an ORR of 11% (95% CI: 4.3% to 
23.0%) and a DCR of 38% (95% CI: 24.8% to 52.1%). A Phase 2 study, BGB-A317-205, as 
discussed in Section 1.4.4.2.3, which enrolled 15 patients treated with tislelizumab in 
combination with chemotherapy in the ESCC cohort (13 of them were included in the Efficacy 
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Evaluable Analysis Set), demonstrated that tislelizumab in combination with chemotherapy has a 
manageable safety profile. Among the 15 patients, 1 patient experienced a Grade 5 hepatic 
dysfunction (possibly from progressive disease and underlying hepatitis) which was possibly 
related to study treatment according to the investigator. Four patients discontinued study 
treatment due to adverse events (AEs) (Grade 3 tracheal fistula, Grade 3 lung infection, Grade 2 
pneumonitis, and Grade 3 increase in aspartate aminotransferase) (Xu et al 2019). 
More than 1300 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (2 to 5 mg/kg) or in combination. The safety profile is consistent with known class effects 
of anti-PD-1 antibodies and includes mostly mild/moderate AEs. Grade 3/4 imAEs have been 
observed and have been generally reversible and manageable with study drug interruption and/or 
steroid treatment. Fatal imAEs are rare. 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 combined with the published data from 
both nivolumab and pembrolizumab clinical trials, is considered favorable. To assess the 
potential benefit and safety of tislelizumab in combination with chemoradiotherapy over 
chemoradiotherapy alone, a randomized, blinded trial comparing tislelizumab to placebo will be 
conducted.  
An IDMC will be established to assess the preliminary safety for the first 20 patients, given that 
there is no direct safety data on this combination, and to regularly monitor the safety of 
tislelizumab when compared with placebo. An interim analysis for PFS superiority test was 
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 compare the progression-free survival (PFS) as assessed by the Blinded Independent 
Review Committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 in the Intent-to-Treat (ITT) Analysis Set between tislelizumab in combination with 
concurrent chemoradiotherapy (cCRT) and placebo in combination with cCRT. 
2.1.2. 
Secondary Objectives  
Key Secondary Objective 
• To compare the overall survival (OS) in the ITT Analysis Set between tislelizumab and 
placebo in combination with cCRT. 
Other Secondary Objectives 
• To compare the patient reported outcomes of health-related quality of life (HRQoL) 
between tislelizumab and placebo in combination with cCRT. 
• To compare the overall response rate (ORR) as assessed by the BIRC per RECIST v1.1 
in the ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• To compare the duration of response (DOR) as assessed by the BIRC per RECIST v1.1 
in the ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• To evaluate the safety and tolerability of tislelizumab in combination with cCRT. 
2.1.3. 
Exploratory Objectives  
• To compare the 1-year PFS rate as assessed by the investigator per RECIST v1.1 in the 
ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• To compare the 2-year PFS rate as assessed by the investigator per RECIST v1.1 in the 
ITT Analysis Set between tislelizumab and placebo in combination with cCRT. 
• To explore the potential predictive, prognostic biomarkers including but not limited to 
programmed cell death protein ligand-1 (PD-L1) expression; gene expression profiling 
(GEP); tumor infiltrating lymphocytes (TIL); tumor mutational burden (TMB), gene 
mutation, and microsatellite instability (MSI); and/or blood-based biomarkers (flow 
cytometry and immune-phenotyping [panel: A173, A167, A163, and A378], and 
circulating tumor DNA [ctDNA] alteration and peripheral blood mononuclear cell 
[PBMC]immune cell profiling) in archival and/or fresh tumor tissue and blood samples 
obtained before and/or during the study treatment and/or at disease progression, and the 
association with disease status, response to study treatment and mechanisms of 
resistance. 
• To assess the pharmacokinetics (PK) of tislelizumab in combination with cCRT. 
• To assess host immunogenicity to tislelizumab. 
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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• PFS – defined as the time from randomization to the first documented disease 
progression, as determined by BIRC per RECIST v1.1, or death from any cause, 
whichever occurs first.  
2.2.2. 
Secondary Endpoints  
Key Secondary Endpoint 
• OS – defined as the time from the date of randomization to the date of death due to any 
cause. 
Other Secondary Endpoints 
• HRQoL assessment defined as patients’ reported treatment effects using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 
30 (EORTC QLQ-C30) and the European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Oesophageal Cancer Module (EORTC QLQ-
OES18). 
• ORR – defined as the proportion of patients who had complete response (CR) or partial 
response (PR) as assessed by BIRC per RECIST v1.1. 
• DOR – defined as the time from the first occurrence of a documented objective response 
to the time of relapse, as determined by the BIRC per RECIST v1.1, or death from any 
cause, whichever occurs first. 
• The incidence and severity of TEAEs graded according to National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, v5.0, 2017). 
2.2.3. 
Exploratory Endpoints  
• 1-year PFS rate – defined as the Kaplan-Meier estimator of proportion of patients alive 
and progression free at 1 year from randomization, as determined by investigator per 
RECIST v1.1. 
• 2-year PFS rate – defined as the Kaplan-Meier estimator of proportion of patients alive 
and progression free at 2 years from randomization, as determined by investigator per 
RECIST v1.1. 
• Status of PD-L1-related, immune-related, esophageal squamous cell carcinoma (ESCC)-
related, and other exploratory biomarkers (GEP, TILs, TMB/gene mutation/MSI, and/or 
blood based biomarkers [flow cytometry and immune-phenotyping (panel: A173, A167, 
A163, and A378), ctDNA alteration, and PBMC immune cell profiling]) in archival 
and/or fresh tumor tissues and blood samples obtained before and/or during study 
treatment and/or at disease progression, and the association with disease status and/or 
response to tislelizumab in combination with cCRT and placebo in combination with 
cCRT.  
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• Assessments of PK of tislelizumab when given with cCRT. 
• Assessments of immunogenicity of tislelizumab by determining the incidence of anti-
drug antibodies (ADAs). 
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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: AE, adverse event; cCRT, concurrent chemoradiotherapy; DOR, duration of response; ECOG, 
Eastern Cooperative Oncology Group; ESCC, esophageal squamous cell carcinoma; HRQoL, health-related quality 
of life; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; vs, versus.  
*Safety of tislelizumab or placebo in combination with cCRT will be assessed by an Independent Data Monitoring 
Committee in the first 20 patients (approximately 10 patients per each arm) after they have had at least 6 weeks of 
follow-up after the last dose of radiotherapy. Enrollment will continue during the safety review. 
For all study procedures, see Section 7 and Appendix 1. 
3.2. 
Screening Period  
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate in this study will sign the informed consent form (ICF) prior to undergoing 
any screening procedure. All patients will take a pulmonary function test (refer to Section 7.1.4 
and Appendix 1 for details). Screening evaluations may be repeated as needed within the 
screening period; the investigator is to assess preliminary patient eligibility according to the 
latest screening assessment results. 
Study Population: 
ESCC suitable for cCRT 
include stage II-IVa 
inoperable candidate  
Arm A 
Tislelizumab in 
combination with cCRT 
Screening 
• Treatment of tislelizumab/placebo 
up to 24 months, or until disease 
progression, or intolerable 
toxicity, or withdrawal for other 
reasons  
• Safety Follow-up & Survival 
Follow-up 
Primary endpoints:  
• PFS 
Secondary endpoints: 
Key Secondary 
• OS 
Other Secondary 
• HRQoL 
• ORR 
• DOR 
• AEs 
Exploratory endpoints: 
• 1-year PFS rate 
• 2-year PFS rate 
• Correlation of biomarker results 
to response and/or resistance to 
treatment  
• Pharmacokinetics 
• Assessment of Immunogenicity 
Arm B 
Placebo in combination 
with cCRT  
Randomization & 
Stratification: 
n=366 
• 1:1 randomization to 
tislelizumab+cCRT or 
placebo+cCRT  
Stratification  
• Clinical stage II/III vs 
IVa 
• ECOG: 0 vs 1 
Safety assessment* 
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Archival tumor tissue will be collected for the purpose of biomarker analysis. If no archival 
samples are available, a fresh tumor biopsy at baseline is strongly recommended if feasible. 
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 or placebo in combination with cCRT up to approximately 6 weeks 
followed by tislelizumab or placebo for a total of up to 24 months (refer to Section 3.6.1 for 
details on treatment duration). Randomization will be stratified according to Eastern Cooperative 
Oncology Group (ECOG) performance status (0 versus 1) and clinical staging (II/III versus IVa). 
Crossover between treatment arms will not be allowed. 
Patients will receive blinded treatment with one of the following: 
• Arm A: Tislelizumab 200 mg intravenously once every 3 weeks in combination with 
cCRT up to approximately 6 weeks followed by tislelizumab for a total of up to 
24 months (about 35 cycles), or until disease progression per RECIST v1.1, 
unacceptable toxicity, withdrawal of consent, or another treatment discontinuation 
criterion is met, whichever occurs first 
• Arm B: Placebo 200 mg intravenously once every 3 weeks in combination with cCRT 
up to approximately 6 weeks followed by placebo for a total of up to 24 months (about 
35 cycles), or until disease progression per RECIST v1.1, unacceptable toxicity, 
withdrawal of consent, or another treatment discontinuation criterion is met, whichever 
occurs first 
Administration of tislelizumab or placebo will continue for a total of up to 24 months, or until 
progressive disease as assessed by the investigator per RECIST v1.1, unacceptable toxicity, or 
death, or until another discontinuation criterion is met. Once disease progression is assessed by 
the investigator, the BIRC is required to complete central image review and convey the results to 
the investigator as soon as possible. If the investigator-assessed disease progression is not 
confirmed by the BIRC, the medical monitor will discuss the findings with the investigator and 
the study treatment is recommended to continue as long as it is considered to be in the best 
interest of the patient. In the situation where the investigator believes the patient must urgently 
begin subsequent systemic therapy without waiting for confirmation of disease progression based 
on central imaging review, the investigator must contact the medical monitor to inform them of 
the plan to urgently discontinue study treatment. 
In both arms, treatment beyond the initial BIRC-assessed, RECIST v1.1-defined disease 
progression is permitted provided that the patient: a) has investigator-assessed clinical benefit 
(clinically stable, no progression requiring urgent intervention and willing to sign informed 
consent) and b) is tolerating study drug. Specific requirements for postprogression continuation 
of patients treated with tislelizumab/placebo and chemoradiotherapy are described in Section 7.5. 
Radiological evaluation of tumor status should be performed every 9 weeks (± 7 days) for the 
first 54 weeks, every 12 weeks (± 7 days) during Years 2 and 3, every 24 weeks (± 7 days) 
during Years 4 and 5, and then according to local standards with a minimum of 1 tumor response 
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assessment annually thereafter, regardless of treatment delays. Tumor response will be assessed 
by the 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 NCI-CTCAE v5.0), and laboratory results. The safety of tislelizumab/placebo in combination 
with cCRT will be assessed by IDMC in the first 20 patients (approximately 10 patients per each 
arm) after they have had at least 6 weeks of follow-up after the last dose of radiotherapy and will 
provide recommendations on the continuation of the study based on the safety and tolerability. 
During these assessments, the enrollment may continue. Vital signs, physical examinations, 
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). 
3.4. 
Safety Follow-up  
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
Safety Follow-up Visit (to occur within 30 days [± 7 days] after the last study treatment of 
tislelizumab/placebo or chemoradiotherapy [whichever occurs later], before the initiation of a 
new anticancer treatment, or before administration of the first dose in a long-term extension 
study or posttrial continued access program, whichever occurs first). In addition, telephone 
contacts with patients should be conducted to assess all AEs and concomitant medications (if 
appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 days, and 90 days 
(±14 days) after the last dose of study treatment, regardless of whether or not 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. 
The End of Treatment (EOT) visit at which a response assessment showed progressive disease, 
resulting in patient discontinuation, may be used as the Safety Follow-up Visit, if it occurred 
30 days (± 7 days) after the last study treatment. Patients who discontinue study treatment prior 
to disease progression will have their tumors assessed as outlined in Section 7.5. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
3.5. 
Survival Follow-up  
Patients who discontinue study treatment for reasons other than 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 begins a subsequent anticancer treatment, 
experiences disease progression (confirmed by the investigator or BIRC, whichever is later), 
withdraws consent, lost to follow-up, death, or until the study terminates, 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 approximately every 3 months (± 14 days) after the Safety Follow-up Visit or as directed 
by the sponsor until death, loss to follow-up, withdrawal of consent, or study termination by the 
sponsor. If applicable, the survival follow-up schedule may be adjusted within the allowed time 
window to perform the planned survival follow-up between 2 scheduled tumor response 
assessments for patients who enter the survival follow-up period but still need to continue tumor 
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response assessment per protocol requirement, especially after the completion of the 3-year 
tumor response assessment (eg, a survival follow-up may be arranged approximately 3 months 
after the last tumor response assessment, when a 6-month interval is required between 2 tumor 
assessments). In these survival follow-ups, potential symptoms or signs indicating disease 
progression should be followed actively. If any suspected symptoms or signs are reported, the 
investigator should arrange an unscheduled, on-site visit for further assessment. Tumor 
assessments will be at the discretion of the investigator, per local standards of care, at the time of 
symptoms or signs of disease progression. 
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 disease progression should be followed 
for assessments of antitumor activity (Section 7.5), safety (Section 7.4.1), 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 may discontinue study treatment for 
reasons which include, but are not limited to, the following:  
• Radiographic disease progression per RECIST v1.1 
• Patient withdrawal of consent 
• 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 other concurrent antineoplastic therapy (eg, chemotherapy, hormonal 
therapy, immunotherapy, or investigational agents)  
• Patient noncompliance 
When a patient reaches 24-month treatment duration of tislelizumab or placebo, patients may 
continue study therapy beyond 24-month treatment 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 24-month treatment must be explicitly approved by the 
sponsor medical monitor. The study assessment and procedure schedule may remain the same.  
Patients with durable response (CR or PR) or durable SD may stop treatment after 24-month 
treatment, the decision should be based on the investigator’s evaluation, with the patient’s 
clinical benefit and risk taken into consideration. Prior to stopping the treatment, the investigator 
should notify the sponsor with the decision of discontinuation from treatment. In these cases, the 
tumor assessments will remain the same. 
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:  
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• Patient withdrawal of consent 
• Death 
• Loss to follow-up 
• Patients have completed all study assessments 
3.6.3. 
End of Study  
The end of study is defined as the timepoint when the final data for a clinical study were 
collected, which is after the last study 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  
• Long-term extension study or posttrial continued access program 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 
Visit and Safety Follow-up Visit. 
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 long-
term extension study or posttrial continued access 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, applicable laws and regulations  
• Study activity is completed (ie, all patients have completed study and all obligations 
have been fulfilled) 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all of the following criteria: 
1. Able to provide written informed consent by the patient or by the patient’s legally 
acceptable representative and can understand and agree to comply with the requirements 
of the study 
2. 18 to 75 years on the day of signing the informed consent form 
3. Histologically confirmed diagnosis of localized ESCC and is suitable for cCRT, 
including:  
• Patients with Stage II-IVa (AJCC version 8 [Rice et al 2017]) inoperable ESCC 
(medically unsuitable for surgery or refuses surgical intervention) are eligible. 
Patients who received prior chemotherapy without radiotherapy can be enrolled. 
Note: treatment-naive patients are preferred, and prior chemotherapy should be 
≤ 3 cycles 
4. Measurable and/or nonmeasurable disease defined per RECIST v1.1  
5. ECOG Performance Status ≤ 1 assessed by the investigator within 7 days before 
randomization 
6. Adequate organ function as indicated by the following laboratory values (obtained within 
14 days prior to randomization): 
a. Patients must not have required a blood transfusion ,growth factor support or 
other supportive drugs with definite effects on neutrophil count, platelets or 
hemoglobin ≤ 14 days before sample collection at screening for the following 
i. Absolute neutrophil count ≥ 1.5 x 109/L 
ii. Platelets ≥ 100 x 109/L 
iii. Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration Equation (Appendix 9) 
c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be ≤ 3 x ULN for patients 
with Gilberts syndrome).  
d. Aspartate transaminase and ALT < 3 x ULN 
7. Patients with inactive/asymptomatic carrier, chronic or active HBV must have HBV 
deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at screening. 
Note: Patients with detectable hepatitis B surface antigen or detectable HBV DNA should be 
managed per treatment guidelines. Patients receiving antivirals at screening should have been 
treated for > 2 weeks prior to enrollment. 
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8. Females of childbearing potential 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 or 
placebo, ≥ 180 days after the last dose of chemotherapy and radiotherapy, and have a 
negative urine or serum pregnancy test ≤ 7 days of randomization 
9. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of tislelizumab or placebo and 
≥ 180 days after the last dose of chemotherapy and radiotherapy 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria must be excluded from this study: 
1. History of fistula due to primary tumor invasion 
2. Patients with high risk of fistula or sign of perforation 
3. Evidence of distant metastases (M1 disease AJCC version 8 [Rice et al 2017]) 
4. History of surgery for esophageal cancer 
5. Indicators of severe malnutrition 
6. Clinically uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage or medical intervention within 2 weeks prior to randomization 
7. Known to be intolerable or resistant to treatment with the protocol-specified 
chemotherapy 
8. Except ≤ 3 cycles of chemotherapy, received any other prior antineoplastic therapy(ies) 
for ESCC (eg, therapies targeting PD-1, PD-L1, PD-L2 or other immune-oncology 
therapies, radiotherapy, targeted therapies, ablation, or other systemic or local 
antineoplastic treatment)  
9. Active autoimmune diseases or history of autoimmune diseases that may relapse 
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 recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast) 
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 
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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 inhalational 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 uncontrolled diabetes or > Grade 1 laboratory test abnormality in potassium, or 
sodium despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days 
before randomization  
13. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled 
systemic diseases, including pulmonary fibrosis, acute lung diseases, etc. 
14. With severe chronic or active 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 HBV or hepatitis C virus 
infection. 
15. A known history of HIV infection 
16. Any major surgical procedure ≤ 28 days before randomization 
Note: Minimally invasive procedure (eg, introduction of peripherally inserted central catheter 
[PICC]) is not a major surgical procedure. 
17. Prior allogeneic stem cell transplantation or organ transplantation 
18. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization  
b. Symptomatic 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 7) ≤ 6 months before randomization  
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization  
f. Any history of cerebrovascular accident ≤ 6 months before randomization  
g. Uncontrolled hypertension: 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 
19. History of severe hypersensitivity reactions to other monoclonal antibodies or cisplatin or 
paclitaxel 
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20. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, 
etc) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) 
of the first study drug administration 
21. Has received any herbal medicine used to control cancer within 14 days of the first study 
drug administration 
22. 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, 
neuropathy and specific laboratory abnormalities) 
23. Was administered a live vaccine ≤ 28 days before randomization  
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
24. 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 result in insufficient or might impair 
compliance with study conduct. 
25. Concurrent participation in another therapeutic clinical trial 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia type I), containing a total of 100 mg of antibody in 10 
mL of isotonic solution. Tislelizumab has been aseptically filled in single-use vials with a 
Flurotec-coated butyl rubber stopper and an aluminum cap. Each vial is packaged into a single 
carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
Refer to the pharmacy manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the Investigator’s Brochure for other details regarding 
tislelizumab. 
5.1.2. 
Placebo  
Placebo is a sterile, preservative-free solution for infusion formulated in the same buffer as 
tislelizumab. All excipients used for the manufacture of placebo are of pharmacopeial grade. No 
animal-derived components are used in the manufacture of placebo. Each vial is packaged into a 
single carton box. 
As with tislelizumab, the contents of the label on placebo 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.  
Refer to the pharmacy manual for details regarding intravenous administration, accountability, 
and disposal.  
5.1.3. 
Chemotherapy Agents  
Management (ie, labeling, handling, storage, administration, and disposal) of these products will 
be in accordance with the relevant local guidelines and/or prescribing information. 
For further details, see the manufacturer’s prescribing information for the respective 
chemotherapy agents. 
5.2. 
Dosage, Administration, and Compliance  
Dosing schedules for both arms, broken out by individual arm, are provided in Table 2. The first 
dose of study drug is to be administered within 3 days of randomization. All patients will be 
monitored continuously for AEs. Treatment modifications (eg, dose delay, reduction, 
interruption or discontinuation) will be based on specific laboratory and AE criteria, as described 
in Section 5.5. 
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For each cycle, tislelizumab or placebo will be administered before chemotherapy drugs. The 
order of chemotherapy drug administration and radiotherapy will be conducted in accordance 
with the relevant local guidance and/or clinical practice. 
Patients should receive antiemetics and intravenous hydration for chemotherapy according to the 
standard of care and manufacturer’s instruction. Due to their immunomodulatory effects, 
premedication with steroids should be limited when clinically feasible. In addition, in the event 
of chemotherapeutic agent-related skin rash, topical steroid use is recommended as treatment 
whenever it is clinically feasible.  
In special situations (eg, when the administration is delayed due to management of AEs or in the 
case of an infusion-related reaction), administration of the subsequent study drugs might be 
delayed to the second day of each cycle.  
Table 2:  Selection and Timing of Dose for Each Patient 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment 
Tislelizumab 
or placebo 
200 mg 
Day 1 of every 3 
weeks 
Intravenous  
Up to 24 months, until disease progression, 
unacceptable toxicity, or voluntary 
withdrawal of consent per patient decision 
Paclitaxel 
135 mg/m2 
Day 1 of every 3 
weeks 
Intravenous 
Treatment will be administered until one of 
the following occurs (whichever occurs 
first): completed administration of 2 cycles; 
unacceptable toxicity; or documented disease 
progression. 
Cisplatin 
25 mg/m2 
Day 1 to 3 of 
every 3 weeks 
Intravenous 
5.2.1. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks) 
for up to 24 months (about 35 cycles).  
Tislelizumab will be administered by intravenous infusion through an intravenous 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 8.  
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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.  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.3. 
Chemotherapy  
Patients in both arms will receive treatment with paclitaxel and cisplatin. 
Paclitaxel 135 mg/m2 will be administered as an intravenous infusion over 3 hours on Day 1 of 
every 21-day cycle (every 3 weeks) for 2 cycles. In addition, all patients should receive the 
appropriate premedications as per the local approved label. 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 intravenously before paclitaxel), an 
antihistamine (H1 antagonist [such as diphenhydramine hydrochloride 50 mg intravenously or 
equivalent] or H2 antagonist [such as cimetidine 300 mg intravenously or equivalent]), and an 
antiemetic (such as ondansetron 8 mg/kg intravenously or equivalent administered 30 to 120 
minutes before paclitaxel).  
Cisplatin 25 mg/m2 will be administered as an intravenous infusion over 60 minutes on Day 1 to 
3 of every 21-day cycle (every 3 weeks) for 2 cycles. Additional premedications should be 
administered as per standard practice. 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 prior to and after dosing. The use of diuretics for fluid 
maintenance is allowable.  
All medications will be documented on the CRF. 
There is a 3-day window for all treatments in the second cycle. If dosing is delayed due to 
administrative or other reasons (holidays, intercurrent illnesses, etc), the subsequent visit should 
be scheduled as clinically appropriate.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately of any AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of chemotherapy. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.5. 
The chemotherapy should generally be delivered prior to the radiation therapy on the day of 
treatment. Chemotherapy doses that are missed during a 3-week schedule concurrent with 
radiotherapy are not to be administered to make up for missed individual doses, but these should 
be documented.  
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5.2.4. 
Radiotherapy  
Prior to inclusion of any patient on this study, the radiation oncologist will evaluate the thoracic 
computed tomography (CT) scan or magnetic resonance imaging (MRI) to ensure that the 
treatment volumes are unlikely to significantly exceed the specified normal tissue constraints and 
it is feasible to administer the radiotherapy dose at 50.4 Gy for the patients. 
All patients will receive radiotherapy using either a standardized intensity modulated 
radiotherapy (IMRT), or volumetric modulated arc therapy (VMAT) on a linear accelerator 
delivering a beam energy of ≥ 6 MV. The total dose of radiotherapy will be 50.4 Gy, 
administered in 28 once-daily fractions of 1.8 Gy and 5 fractions per week.  
Every effort should be made to continue the radiotherapy during the concurrent phase in an 
uninterrupted manner. Should a patient develop severe esophagitis necessitating interruption of 
chemotherapy, the radiotherapy may continue, provided that the investigator believes supportive 
care will enable the patient to complete this part of the therapy without excess risk. 
Strictly refer to the radiotherapy manual for detailed instructions. 
5.2.5. 
Supportive Care  
Patients should receive full supportive care, including epoetin and other hematopoietic growth 
factors (eg, colony-stimulating factors), transfusions of blood and blood products, antibiotics, 
antiemetics, other applicable medications, as needed according to local standard of care 
guidelines or practices. 
All patients are strongly suggested to accept nutrition support if there is any indication including 
(not limited to): Medium-severe dysphagia; Weight loss > 5% in 1 month; BMI < 18.5 kg/m2; 
Scored patient-generated subjective global assessment ≥ 4 score; Food intake is < 60% required 
for > 3 days. 
5.3. 
Overdose  
Any overdose (defined as ≥ 600 mg of tislelizumab or placebo in a 24-hour period) or incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF. 
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 8.7. 
Supportive care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study 
(tislelizumab and 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 IMPs 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. 
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5.5. 
Dose Delay and Modification  
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. 
5.5.1. 
General Guidance Regarding Dose Modifications  
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 severity of AEs will be 
graded according to the NCI-CTCAE v5.0 grading system. 
The chemotherapy-related toxicities should be managed according to the prescribing information 
for the approved product or institutional standard practices. The details in this section are for 
reference of this study: 
• 
Baseline body weight is used to calculate the required chemotherapy doses. Dose 
modifications are required if the patient’s body weight changes by ≥ 10% from 
baseline (or the newly referred body weight). Chemotherapy doses should not be 
modified for any body weight change of <10%, unless there is an ongoing toxicity 
requiring dose modification. When several toxicities with different grades of severity 
occur at the same time, the dose modifications should be made according to the 
highest grade observed. 
• 
In case of chemotherapy-related toxicity, chemotherapy should be delayed until it is 
resolved to baseline or ≤ Grade 1 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 and radiotherapy should continue as scheduled. If the 
AE is resolved to baseline or ≤ Grade 1 within 21 days from Cycle 1 Day 1 (C1D1), 
chemotherapy will be administrated on Cycle 2 Day 1 (C2D1) as scheduled. If the AE 
is not resolved within 21 days from C1D1, chemotherapy will be delayed until the AE 
is resolved. If the AE is not resolved within 21 days from planned C2D1, 
chemotherapy should be discontinued. 
• 
In case of tislelizumab or placebo related toxicity, tislelizumab or placebo will be 
delayed until the toxicity resolves to baseline or ≤ Grade 1 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 and radiotherapy should continue as 
scheduled. If the AE is resolved to baseline or ≤ Grade 1 within 10 days from the 
scheduled date of dose administration, tislelizumab or placebo will be administrated. 
If the AE is not resolved within 10 days from the scheduled date of dose 
administration, tislelizumab or placebo will be held until the next cycle. If AE is 
resolved to baseline or ≤ Grade 1 within 21 days from the scheduled date of dose 
administration, tislelizumab or placebo will be administered on Day 1 of the next 
planned cycle.  
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• 
The tumor assessment schedule will not be altered if chemotherapy and/or 
tislelizumab or placebo are delayed or discontinued.  
• 
Every effort should be made to continue treatments in combination when patient’s 
condition allows, also taking into consideration patient’s convenience for the 
treatment schedule. 
• 
Following either completion of or discontinuation from chemotherapy and 
radiotherapy, tislelizumab or placebo should be continued as scheduled, if clinically 
appropriate.  
• 
If 1 component of chemotherapy is discontinued permanently during the initial 
6 weeks of treatment for reasons other than progressive disease, the other component 
of chemotherapy could be continued per the study protocol or local practice. The 
patient may continue the radiotherapy and tislelizumab or placebo per the study 
protocol. 
• 
If tislelizumab or placebo is discontinued permanently during the initial 6 weeks of 
treatment for reasons other than progressive disease, the patient may continue the 
chemotherapy and radiotherapy per the study protocol.  
• 
If radiotherapy is discontinued permanently during the initial 6 weeks of treatment for 
reasons other than progressive disease, the patient may continue the chemotherapy 
and tislelizumab or placebo per the study protocol.  
Dose modification guidelines for chemotherapy are described in Section 5.5.3 depending on the 
severity of toxicity and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care. 
5.5.2. 
Dose Delay or Modification for Tislelizumab or placebo  
There will be no dose reduction for tislelizumab or placebo in this study.  
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. The patients should resume 
tislelizumab or placebo if AE recovers within 10 days of AE onset. If AE is ongoing more than 
10 days, the patients should hold tislelizumab or placebo until the next cycle. The patients should 
resume tislelizumab or placebo treatment as soon as possible after AEs recover to baseline or 
Grade 1 (whichever is more severe) and within 12 weeks after last dose of tislelizumab or 
placebo. If the patient is unable to resume tislelizumab or placebo within 12 weeks after the last 
dose of tislelizumab or placebo, then the patient should be discontinued from treatment. 
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 modifications related to imAEs and infusion-related reactions are described in Appendix 8 
and Section 8.7.1, respectively.  
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5.5.3. 
Dose Delay or Modifications for Chemotherapy  
Chemotherapy related toxicities must be resolved to baseline or Grade 0-1 prior to administering 
the next dose, with the exception of alopecia or Grade 2 fatigue, or other AEs which, in the 
opinion of the investigator, would not affect the safety evaluation of the study drugs. A 
maximum dose reduction of 2 levels is permitted for cisplatin and paclitaxel. Dose reduction of 
one chemotherapeutic agent does not require the same dose reduction of the other 
chemotherapeutic agent within the combination, unless the toxicities can reasonably be attributed 
to both agents. There will be no dose escalations in this study. If any chemotherapy agent is held 
for more than 3 weeks from the anticipated treatment date, or the dose is not tolerated, 
chemotherapy should be permanently discontinued. The possibility of immune-mediated toxicity 
should also be considered when managing patients (see Appendix 8). 
Dose modification guidelines for chemotherapy are described as below depending on the severity 
of toxicity and an assessment of the risk versus benefit for the patient, and dose modifications are 
permitted per local standards or at investigator’s discretion. 
5.5.3.1. 
Dose Reduction Level and Dose Modification for Hematologic Toxicity  
Dose adjustments are based on nadir blood counts since the first dose chemotherapy 
administration. Dose reduction levels for cisplatin and paclitaxel are provided in Table 3. 
Recommended dose modifications in next cycle for hematologic toxicity are provided in Table 4.  
Table 3:  Dose Reduction Level of Cisplatin and Paclitaxel 
Drug Dose  
Standard Level 
(Every 3 weeks as a cycle) 
1st Level 
2nd Level 
Cisplatin 
25 mg/m2 (Day 1-3) 
20 mg/m2 (Day 1-3) 
15 mg/m2 (Day 1-3) 
Paclitaxel 
135 mg/m2 (Day 1) 
100 mg/m2(Day 1) 
50 mg/m2(Day 1) 
Table 4:  Dose Modification based on Hematologic Nadir Values Prior to the Next Dose 
ANC x 109/L 
 
PLT x 109/L 
Dose for Cisplatin or paclitaxel 
≥ 1 
and 
≥ 75 
Full dose 
0.5-1 
or 
50-75 
1st dose level 
< 0.5  
or 
< 50 
2nd dose level 
Abbreviations: ANC, absolute neutrophil count; PLT, platelets. 
Prior to treatment, the absolute neutrophil count must be ≥ 1.5 x 109/L and platelets must be ≥ 
100 x 109/L. For any grade toxicity, if the hematologic toxicity does not recover to Grade 1 or 
baseline despite the G-CSF support in 3 weeks, chemotherapy must be discontinued. 
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5.5.3.2. 
Dose Modifications for Renal and Hepatic Impairment  
Dose adjustments are based on renal or hepatic function since the first dose chemotherapy 
administration. Recommended dose modifications in next cycle for renal or hepatic toxicity are 
provided in Table 5 and Table 6. 
Dose Modifications for Renal Impairment 
Table 5:  Dose Modifications of Cisplatin for Renal Impairment 
eGFR mL/min  
Dose for Cisplatin 
> 50 mL/min 
Full dose 
41-50 mL/min 
1st dose level 
≤ 41 mL/min 
Discontinue Cisplatin  
Dose Modification for Hepatic Impairment 
Table 6:  Treatment Modification of Paclitaxel for Hepatic Impairment 
Degree of Hepatic Impairment 
Treatment 
Transaminase levels 
 
Bilirubin Levels 
< 10 x ULN 
And 
≤ 1.25 x ULN 
Full dose 
< 10 x ULN 
And 
1.26 - 2.0 x ULN 
1st dose level 
< 10 x ULN 
And 
2.01 - 5.0 x ULN 
2nd dose level 
≥ 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 to Grade1 in 3 weeks, paclitaxel must be 
discontinued.  
Does Modification for Allergic Reaction/Hypersensitivity 
For moderate symptoms, paclitaxel infusion must be stopped; and diphenhydramine 25 to 50 mg, 
dexamethasone 10 mg, or other appropriate therapy as per institutional guidelines must be 
administered. Paclitaxel infusion may be gradually resumed after recovery of symptoms. 
Paclitaxel may be dosed over 3 hours. If symptoms recur with reinstitution of the paclitaxel 
infusion, the infusion must be stopped. 
Patients who experience severe or life-threatening symptoms of hypersensitivity despite standard 
pretreatment medications must discontinue paclitaxel permanently. 
5.5.3.3. 
Chemotherapy Delay or Dose Modification for Other Toxicities  
For other non-hematologic toxicities such as Grade 3 nausea, vomiting, diarrhea or stomatitis 
that occur despite supportive care, chemotherapy will be held at the first occurrence and resume 
at the first dose level once the toxicity has recovered to Grade 0-1 in severity within 3 weeks. In 
the event of skin reactions, paronychia, alopecia, fatigue, nausea/vomiting or other AEs which, in 
the opinion of the investigator, would not affect the safety evaluation of the study drugs, 
chemotherapy can resume when the toxicity has recovered to ≤ Grade 2. 
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Some radiotherapy related AE may require delay or discontinuation of chemotherapy and/or 
tislelizumab/placebo. Refer to the radiotherapy manual for detailed instructions. 
If considered in the best interest of the patient and consistent with local practice, investigators 
may decide to use supportive measures or treatment and/or secondary prophylaxis for the next 
dose. 
5.5.4. 
Dose Delay or Modifications for Radiotherapy  
Strictly refer to the radiotherapy manual for detailed instructions. 
5.5.5. 
Blinding  
This is a randomized, double-blind, Phase 3 study. Patients will be randomized to receive either 
tislelizumab or matching placebo in a double-blind fashion that neither the investigator, nor the 
patient, nor medical or ancillary medical staff, nor the blinded sponsor or its designees, will 
know which drug is being administered in addition to cCRT.  
• 
Emergency unblinding  
Emergency unblinding for AEs may be performed through the Interactive Response 
Technology (IRT). 
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 contact the sponsor medical monitor prior to 
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. 
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 this 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) disease progression confirmed by BIRC 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. 
• 
Inadvertent unblinding  
Every effort should 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 
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will not be a sufficient cause (in and of itself) for that patient to be discontinued from the 
study therapy or excluded from any safety or efficacy analyses. 
• 
Unblinding after PFS final analysis 
Investigators, site personnel, and patients will be unblinded to the treatment arms after the PFS 
final analysis. Placebo administration will be discontinued after the unblinding for patients in 
Arm B who are still on study treatment. Crossover between the treatment arms will not be 
allowed. 
Bioanalysis laboratory 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. 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
The exclusion criteria (Section 4.2) specify that patients must have not received any prior 
therapies targeting PD-1, PD-L1 or PD-L2 or other immune-oncology therapies. Prior 
radiotherapy is not allowed. All prior cancer treatments, treatments for underlying active medical 
conditions, 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 must be recorded on the appropriate CRF. 
6.2. 
Concomitant Therapy  
6.2.1. 
Permitted Concomitant Medications  
Most concomitant medications and therapies deemed necessary and in keeping with the local 
standards of medical care at the discretion of the investigator for the supportive care (eg, 
antiemetics, antidiarrheals, pain medications, and nutritional support) and in a patient’s 
well-being are allowed. All concomitant medications will be recorded on the eCRF including all 
prescriptions, over-the-counter drugs, herbal supplements, and intravenous medications and 
fluids. If changes (dose, stop, or start) in concomitant medication occur during the study, 
documentation of drug dosage, frequency, route, date, and reason for use will be recorded on the 
eCRF. 
All concomitant medications received within 30 days before the first dose of study drug and 
30 days after the last infusion or dose of study treatment should be recorded. 
Nutritional support for patients with a history of weight loss is strongly recommended as a 
routine standard-of-care therapy, and such support should be recorded as a concomitant 
medication. 
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 8) and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab or placebo administration. The short-term use of steroids as 
prophylactic treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) 
is permitted. Patients may continue to receive hormone replacement or supportive care if 
initiated prior to enrollment. Premedication with steroids for chemotherapy is acceptable.  
Bisphosphonates are permitted during the study for a non-malignant indication. 
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL at screening, must initiate 
antiviral treatment 2 weeks prior to randomization and continue until 6 months after the last 
dose. Patients should continue effective antiviral treatment during the study to decrease potential 
viral reactivation 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 2016). The investigator might use other antiviral agents, if appropriate, 
following local guidelines. However, interferon-based therapy for hepatitis B is not permitted on 
study.  
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Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, as aligned with 
local guidance. Such medications must be documented in the patient’s chart and recorded in the 
eCRF.  Patients receiving antivirals at screening should be treated for > 2 weeks before 
enrollment and continue treatment during the study and for 6 months after study drug treatment 
discontinuation.  
Patients with detectable hepatitis C virus RNA and who are receiving treatment at screening 
should remain on continuous, effective antiviral therapy during the study. The investigator 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 hepatitis C virus is not permitted on study. Patients who are given antiviral 
therapy must initiate treatment > 2 weeks prior to randomization.  
6.2.2. 
Prohibited Concomitant Medications  
The following medications are prohibited during the study: 
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
Country) herbal medicine] for the treatment of cancer) is not allowed. 
• Live vaccines within 28 days before randomization 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.  
6.2.3. 
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 completely and should avoid other addictive drugs during 
the study.  
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be 
carefully monitored.  
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. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
The potential for drug-drug interaction between the study drugs (tislelizumab) and small-
molecule drug products is very low, given that tislelizumab is a therapeutic monoclonal 
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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. 
During cisplatin use, concurrent therapy with drugs having a potential ototoxic or nephrotoxic 
effect (eg, aminoglycosides, cefalotin, furosemide, amphotericin B) should be avoided or 
adequately monitored since this may lead to increased or exacerbated toxicity due to platin-
induced changes in renal clearance of these substances. 
The metabolism of paclitaxel is catalyzed, in part, by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4. Therefore, in the absence of a PK drug-drug interaction study, caution should be 
exercised when administering paclitaxel concomitantly with medicines known to inhibit either 
CYP2C8 or CYP3A4 (eg, ketoconazole and other imidazole antifungals, erythromycin, 
fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir), 
because the toxicity of paclitaxel may be increased due to higher paclitaxel exposure. 
Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or 
CYP3A4 (eg, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended 
because efficacy may be compromised because of lower paclitaxel exposures. 
Refer to the approved product labeling for chemotherapy complete information regarding drug-
drug interactions. 
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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. All patients will 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. 
Procedures conducted during the Screening Visit 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 7.7) sections. The PK sampling schedule is shown in Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with sponsor, 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 year of birth (or age), 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). 
Cancer history will include pathologic diagnosis, stage at screening, tumor location and an 
assessment of prior drug therapy, including start and stop dates, best response and reason for 
discontinuation. Radiographic studies performed prior to study entry may be collected for review 
by the investigator. 
7.1.2. 
Females of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 10 for contraception guidelines and definitions of “women of childbearing 
potential” and “no childbearing potential.” 
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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  
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed for all patients during the screening period to assist in determining the suitability 
for the study.  Respective test results must be submitted to the sponsor. 
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
(FEV1) < 60% or diffusing capacity of the lungs for carbon monoxide (DLCO) (if performed) 
< 60% of age and sex adjusted predicted performance levels (Pellegrino et al 2005), the medical 
monitor must be consulted to confirm eligibility. 
Tests may be repeated as clinically indicated while on 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 a treatment authorization form and send it to 
the medical monitor or designee to approve 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 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 3 days after randomization.  
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7.3. 
Tislelizumab or Placebo Drug Dispensation  
Tislelizumab or placebo 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, heart rate, respiratory 
rate, weight, 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 the screening visit, 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 v5.0 and 
recorded on the eCRF with appropriate disease/condition terms.  
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. 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. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 4) will be assessed during the study.  
7.4.4. 
Laboratory Safety Tests  
Local laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Appendix 3.  
If laboratory tests at screening are not performed within 7 days 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 C reactive protein) as specified in 
Appendix 3 should be performed weekly and reviewed 72 hours before study drug(s) 
administration for the cCRT duration and at the beginning of subsequent tislelizumab/placebo 
cycles. After Cycle 1 of tislelizumab/placebo, results are to be reviewed within 72 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. 
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. 
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Patients should rest in semi-recumbent supine position for at least 10 minutes prior to ECG 
collection.  
7.4.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6. 
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. During the study, tumor imaging will be performed approximately every 9 weeks 
(± 7 days) for the first 54 weeks, every 12 weeks (± 7 days) during Years 2 and 3, every 
24 weeks (± 7 days) during Years 4 and 5, and then according to local standards with a minimum 
of 1 tumor response assessment annually thereafter, regardless of treatment delays. All tumor 
responses will be assessed by the BIRC and investigators using RECIST v1.1 criteria.   
Screening assessments must include CT scans (with oral/intravenous contrast, unless 
contraindicated) or MRI of the neck, chest, and abdomen, ultrasound of cervical and 
supraclavicular lymph nodes, and esophagography. If feasible, esophagoscopy, including 
esophagoendoscopic ultrasonography should be included as well. Other known or suspected sites 
of disease must be included in the imaging assessments (bone, brain, etc). 
Tumor assessments must include CT scans (with oral/intravenous contrast, unless 
contraindicated) or MRI, with preference for CT, of the neck, chest, and abdomen, and 
esophagography. Esophagoscopy and biopsy (if disease progression is suspected) could be 
included. 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. 
• 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 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. 
Response will be assessed by BIRC and the investigator using RECIST v1.1 (see Appendix 5). 
The same evaluator should perform assessments, if possible, to ensure internal consistency 
across visits. 
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later after the first response or at the next scheduled assessment time point. 
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For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic disease progression per RECIST v1.1 
assessed by the BIRC is suspected by the investigator to reflect pseudoprogression, patients may 
continue treatment with tislelizumab or placebo until progressive disease is confirmed by 
repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from the date of initial 
documentation of progressive disease). The following criteria must be met in order to treat 
patients with suspected pseudoprogression: 
• 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 BIRC-assessed progression must be agreed 
with the sponsor medical monitor and documented in the study records. 
Tumor assessment will continue until disease progression has been confirmed by the 
investigators or BIRC (whichever is later). Patients who discontinue study treatment early for 
reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments 
following the original plan until the patient begins a subsequent anticancer treatment, 
experiences disease progression (confirmed by the investigator or BIRC, whichever is later), 
withdraws consent, lost to follow-up, death, 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. 
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.  
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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 
• 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. 
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 and Schedule of Assessments (Appendix 1 and 
Appendix 2).  
Archival tumor tissues (formalin-fixed paraffin-embedded block or approximately 15 [≥ 6] 
unstained slides), if feasible, are required for PD-L1 assessment and exploratory biomarker 
analysis at a central laboratory or sponsor designed laboratory. In addition to PD-L1 expression, 
other exploratory predictive biomarkers, such as TMB/gene mutation/MSI, GEP, and TILs that 
are related to response or clinical benefit of tislelizumab may also be evaluated. If no archival 
samples are available, a fresh tumor biopsy at baseline is strongly recommended if feasible. The 
baseline tissue sample can be collected at any stage of study after local regulation approval. 
Optional biopsies will also be taken from patients who have disease progression during the study 
from accessible tumor sites to explore resistance mechanism. 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. 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. Fine-
needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  
Blood for ctDNA (10 mL each timepoint) will be requested at baseline (predose at Day 1 of 
Cycle 1), and optional at C3D1 (predose at Day 1 of Cycle 3), and from patients who have 
disease progression. Blood for flow cytometry (9 mL each timepoint; panel: A173, A167, A163, 
and A378) and PBMC isolation for immune cell profiling (10 mL each timepoint) will be 
collected at baseline (predose at Day 1 of Cycle 1), C3D1 (predose at Day 1 of Cycle 3), and 
from patients who had disease progression to explore the potential resistance mechanism. Blood 
collection and testing for flow cytometry will be terminated after 50 paired samples (C1D1 and 
C3D1) are collected. Written patient consent is required for blood sample collections. 
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7.8. 
Patient-Reported Outcomes  
Patients will be asked to complete the EORTC QLQ-C30 and EORTC QLQ-OES18 
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. 
7.9. 
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 other 
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 every 3 weeks 
from Cycle 1 Day 1. 
7.10. 
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; 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 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  
8.1. 
Risks Associated With Study Treatment  
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 workup procedures for suspected imAEs are provided in 
Appendix 8. 
8.1.2. 
Risks Associated With Concurrent Chemotherapy  
Cisplatin 
Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside 
antibiotics. The serum creatinine, blood urea nitrogen, creatinine clearance, magnesium, sodium, 
potassium, and calcium levels should be measured prior to initiating therapy, and prior to each 
subsequent course. 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.  
Toxicity 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 
cisplatin-induced ototoxicity is reversible. Careful monitoring by audiometry should be 
performed prior to initiation of therapy and prior to subsequent doses of cisplatin.  
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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 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. 
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 
re-challenged 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 < 1.5 x 109/L or before 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. 
8.1.3. 
Risks Associated With Radiotherapy  
Adverse effects related to radiation therapy include nausea/vomiting, diarrhea, weight loss, 
fatigue, myelosuppression, skin erythema, subcutaneous fibrosis, esophagitis, esophageal 
stricture, esophageal fistula, carditis, myelitis, acute radiation pneumonitis, and late pulmonary 
fibrosis. 
Refer to the radiotherapy manual for details. 
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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 trial. 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 at risk for study-emergent active autoimmune diseases, or with a history of autoimmune 
diseases that may relapse, and patients who have received a live viral vaccine within 28 days 
before randomization are excluded from the study. Patients with contraindications for cisplatin or 
paclitaxel or radiation 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 v5.0. 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.  
In this study, 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.  
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 
treatment, whether considered related to study treatment 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) 
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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 for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
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 8.6.2.3. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study treatment 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 assess the 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 in 
light of follow-up information, amending the SAE report accordingly.  
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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 treatment (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 criteria 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 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
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8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
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. 
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. 
• 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) 
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The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the 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 treatments (including chemoradiotherapy) 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 or placebo, 
regardless of whether or not the patient starts a new anticancer therapy. All SAEs considered 
related to the study drug(s) that are brought to the attention of the investigator must 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 7. 
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Table 7:  Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-
up Report 
Documentation 
Method 
Reporting  
Method 
All SAEs  
Within 24 hours of 
first knowledge of 
the AE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Email or fax 
SAE form or 
Pregnancy 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE Report 
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 is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality at the time of the initial report 
as described in Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a 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 SUSARs (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. 
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8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask 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. 
Recording Disease Progression  
Disease progression (including fatal disease progression) is expected in this study population and 
measured as an efficacy endpoint and therefore; 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 as an 
AE term. However, if there is any uncertainty as to whether a nonserious AE is due to disease 
progression, it should be recorded as an 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 event, eg, death, death 
of unknown cause, or death unexplained. 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab or placebo, or within 
180 days after the last dose of chemotherapy or radiotherapy, 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 6 to 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. 
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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 prescribing information 
• Paclitaxel prescribing information 
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. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 8. 
An extensive list of potential imAEs appears in Table 9. All conditions similar to 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 8. 
8.7. 
Management of AE of Special Interest  
As a routine precaution, after infusion of tislelizumab/placebo on Day 1 of Cycle 1 and Cycle 2, 
patients must be monitored for at least 1 hour afterward 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. 
Infusion-Related Reactions  
The symptoms of infusion-related reactions include 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, and cardiogenic shock. 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, intravenous 
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 8.  
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Table 8:  Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab/Placebo 
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, intravenous 
fluids); prophylactic medications indicated for ≤ 24 h 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions have 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described 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/placebo 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/placebo 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 intravenous 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.  
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 intravenous 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. 
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 adverse events 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 9. All conditions similar to those listed should 
be evaluated in patients receiving tislelizumab or placebo to determine whether they are 
immune-mediated.  
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology and American Society of Clinical Oncology (ASCO) guidelines 
(Haanen et al 2017, Brahmer et al 2018) and common immune-mediated toxicities are detailed in 
Appendix 8. For any AEs not included in Appendix 8, please refer to the ASCO Clinical Practice 
Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation and management of 
immune-mediated toxicities. 
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Table 9:  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 8. 
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.  
9.1. 
 Statistical Analysis   
9.1.1. 
Randomization Methods  
As stated in Section 7.2.3, patients will be randomized using the IRT system for this study. 
Permuted block stratified randomization with stratification factors of ECOG performance status 
(0 versus 1) and clinical stage (II/III versus IVa as per AJCC version 8 [Rice et al 2017]) will be 
used. 
9.1.2. 
Analysis Sets  
The ITT Analysis Set includes all randomized patients. It will be the primary analysis set 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 set for safety analysis. 
The PK Analysis Set includes all patients who are randomized to the tislelizumab arm, and for 
whom postdose PK data are available. 
The ADA Analysis Set includes all patients who are randomized to the tislelizumab arm and 
have a baseline and at least 1 postbaseline ADA result. 
9.1.3. 
Patient Disposition  
The number of patients randomized, treated, and discontinued from study treatment and/or study 
and those with major protocol deviations will be counted. The primary reason for study treatment 
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. Major protocol deviations will be summarized 
and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized in the ITT Analysis Set 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis; categorical variables include gender, ECOG, race, smoking status, and 
alcohol use, clinical staging (AJCC version 8 [Rice et al 2017]), prior chemotherapy. 
9.1.5. 
Prior and Concomitant Medications  
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 
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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 treatment. Concomitant medications will be defined as medications that 
1) started before the first dose of study treatment and were continuing at the time of the first dose 
of study treatment, or 2) started on or after the date of the first dose of study treatment 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 treatments regardless of whether the patient starts a new anticancer therapy. 
9.2. 
Efficacy Analyses  
PFS is the primary endpoint of the study with the one-sided alpha (α) type I error rate controlled 
under 0.025. The initial α allocated to PFS will be transferred to secondary endpoints once the 
primary endpoint is statistically significant. The secondary endpoints will be tested sequentially, 
ie, starting with the key secondary endpoint (OS), and followed by HRQoL. Testing for the 
secondary endpoints will continue until the first failure of rejection occurs. 
9.2.1. 
Primary Efficacy Analysis  
9.2.1.1. 
PFS Assessed by BIRC  
PFS assessed by BIRC is defined as the time from randomization to the first documented disease 
progression as determined by the BIRC according to RECIST v1.1, or death by any cause, 
whichever occurs first. The actual tumor assessment visit date will be used to calculate PFS. The 
PFS censoring rule will follow the United States (US) Food and Drug Administration (FDA) 
Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer drugs and Biologics 
(US FDA Center for Drug Evaluation Research and Center for Biologics Evaluation and 
Research, 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 
anticancer therapy will be censored at the last tumor assessment date prior to the introduction of 
new therapy. 
The null hypothesis to be tested is: 
H0: PFS in Arm A ≤ PFS in Arm B 
against the alternative: 
H1: PFS in Arm A > PFS in Arm B 
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This will be the primary analysis once the targeted PFS event number assessed by BIRC is 
reached. The p-value from the stratified log-rank test will be presented using the stratification 
factor at randomization (ECOG performance status: 0 versus 1 and stage: II/III versus IVa).  
The median PFS 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. The treatment effect 
in the form of HR and its 95% CI will be estimated using a Cox regression model incorporating 
the treatment arm as the independent variable and the prespecified stratification factors as the 
strata. These analyses will be performed in the ITT Analysis Set as the primary analysis.  
Detailed plan of sensitivity/supportive analyses and subgroup analyses of PFS will be provided 
in the statistical analysis plan.  
9.2.2. 
Secondary Efficacy Analyses  
9.2.2.1. 
Key Secondary Endpoint - Overall Survival  
The OS is defined as the time from the date of randomization to the date of death due to any 
cause.  
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 distribution of OS will be compared between the 2 treatment arms using a stratified log-rank 
test at one-sided 2.5% level of significance, the p-value from the stratified log-rank test will be 
presented using the stratification factors at randomization (ECOG: 0 versus 1 and stage: II/III 
versus IVa). The median OS 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. The 
treatment effect in the form of HR and its 95% CI will be estimated using a Cox regression 
model incorporating the treatment arm as the independent variable and the prespecified 
stratification factors as the strata. These analyses will be performed in the ITT Analysis Set. 
9.2.2.2. 
HRQoL  
HRQoL is an assessment of a patient’s overall health status using the EORTC QLQ-C30 and 
EORTC QLQ-OES18. The postbaseline scores will be compared between the 2 treatment arms, 
and the changes from the baseline scores will be summarized descriptively.  
9.2.2.3. 
Objective Response Rate by the BIRC  
The ORR is the proportion of patients who had a CR or PR as determined by BIRC per RECIST 
v1.1 in the ITT Analysis Set. Patients without any postbaseline assessment will be considered 
nonresponders. The 2-sided 95% CIs for the odds ratio in the ORR will be calculated, as well as 
Clopper-Pearson 95% CIs of ORR for each treatment arm. 
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9.2.2.4. 
Duration of Response  
The DOR assessed by BIRC per RECIST v1.1 will be analyzed only in responders. The 
statistical methods applied to DOR is similar to the analysis described in Section 9.2.1.1. 
9.2.3. 
Exploratory Efficacy Analyses  
9.2.3.1. 
1-Year PFS rate  
The 1-year PFS rate is defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 1 year after randomization. The 1-year PFS rate and the 2-sided CIs for the 
2 arms will be estimated using the Kaplan-Meier estimator. 
9.2.3.2. 
2-Year PFS rate  
The 2-year PFS rate is defined as the Kaplan-Meier estimator of proportion of patients alive and 
progression free at 2 years after randomization. The 2-year PFS rate and the 2-sided CIs for the 
2 arms will be estimated using the Kaplan-Meier estimator. 
Distribution of PD-L1 expression in tumor tissue will be examined in the ITT Analysis Set. The 
association between PD-L1 expression and tislelizumab treatment effect over the control (PFS, 
OS, ORR, DOR and DCR) will be explored.  
Status of PD-L1 expression in tumor tissue will be examined in the ITT Analysis Set. The 
association between PD-L1 expression and study treatment will be explored. 
Other immune, ESCC-related, and exploratory biomarkers including but not limited to gene 
expression profiling and tumor mutational profile and their association with disease status and/or 
response to study treatment will also be explored. 
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry), vital signs, ECGs, and physical 
examinations will also be used in determining safety. 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 treatment will be summarized descriptively as the number of 
cycles received (number and percentage of patients), duration of exposure (days), cumulative 
total dose received per patient (milligrams), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and 
treatment discontinuation due to AEs will be summarized for each study treatment. 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. 
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9.3.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA. The AEs will be coded to MedDRA (Version 20.1 or higher) lower level term, 
preferred term and primary system organ class. 
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 treatment and up to 30 days following study 
treatment discontinuation or initiation of new anticancer 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. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE v5.0 within a system organ class and preferred term, even if the 
patient experienced more than 1 TEAE within a specific system organ class and preferred term. 
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study treatment. 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, imAEs, treatment-related TEAEs and TEAEs that lead to 
treatment discontinuation, dose interruption, dose reduction, or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry) 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 v5.0 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, 
heart rate, respiratory rate, temperature, and weight) and changes from baseline will be presented 
by visit for all visits. Vital signs will be listed by patient and visit. 
9.4. 
Pharmacokinetic Analysis  
Tislelizumab postdose and trough serum concentration (Ctrough) data will be tabulated and 
summarized by visit/cycle at which these concentrations are collected. Descriptive statistics will 
include means, medians, ranges, and standard deviations, as appropriate. 
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Additional PK analyses, including population PK analyses and exposure-response (efficacy, 
safety endpoints) analyses may be conducted as appropriate and the results of such analysis may 
be reported separately from the CSR.  
9.5. 
Immunogenicity Analyses  
Samples to assess anti-tislelizumab antibodies will be collected in all randomized patients and at 
sites that are able to adequately perform the sampling, handling, and processing procedures 
outlined in the laboratory manual, but will be tested only for patients randomized to receive 
tislelizumab. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 
9.6. 
Sample Size Consideration  
The sample size calculation is based on the number of events required to demonstrate the PFS 
superiority of Arm A over Arm B in the ITT Analysis Set. Exponential distribution is assumed 
for PFS. The estimates of the number of events required to demonstrate efficacy of PFS in the 
primary comparisons are based on the following assumptions: 
• Median PFS of 14 months in Arm B. 
• 1.5-month delayed treatment effect (ie, assuming HR = 1 in the first 1.5 months; and 
HR = 0.65 thereafter, corresponding to an improvement in median PFS from 14 
months to 21.5 months). 
• One-sided α of 0.025. 
• 1-year drop-out rate of 5% for both treatment arms.  
• Randomization ratio of 1:1. 
With these assumptions, approximately 200 PFS events are required to occur in the ITT Analysis 
Set for the PFS final analysis to obtain approximately 80% power.  Approximately 366 patients 
will be enrolled, with enrollment duration of 24.0 months. The interim PFS analysis will be 
performed at 25.5 months after the first patient was randomized, when 115 PFS events occurred, 
with error spent from a Lan-DeMets O'Brien-Fleming approximation spending function. The 
boundaries for PFS interim and final analysis could be found in Table 10.  
To demonstrate the OS superiority of Arm A over Arm B in the ITT Analysis Set, the following 
assumptions are made: (1) median OS of 35 months in Arm B; (2) HR of 0.65, corresponding to 
an improvement in median OS from 35 months to 53.8 months. Approximately 191 death events 
will provide approximately 85% power using a 1-sided α of 0.025, with interim analysis for OS 
at the time of the interim PFS analysis.  
The final analysis of PFS and OS will be performed concurrently when approximately 200 PFS 
events or approximately 191 OS events have been observed, whichever occurs first. 
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9.7. 
Interim Analyses  
PFS 
One PFS interim analysis was planned when 115 PFS events were reported.  
The efficacy boundary is estimated based on the Lan-DeMets O'Brien-Fleming approximation 
spending function. The stopping boundaries (p-values) of the stratified log-rank test for PFS at 
the interim and final analysis are shown in Table 10. The boundaries will be updated according 
to the actual number of events during analysis, to ensure overall type I error controlled. 
OS 
The key secondary endpoint of OS will be tested only after the primary endpoint is statistically 
significant. If the test of PFS is significant, the total α = 0.025 will be allocated to OS interim and 
final analyses to test for significance.  
The interim analysis of OS was planned at the time of the PFS interim analysis, with a fixed  
1-sided α level of 0.0001 allocated; the remaining fixed 1-sided α = 0.0249 will be allocated for 
final analysis of OS. 
Table 10:  The Analysis Timing and Efficacy Boundary for PFS in the Interim Analysis 
and Final Analysis 
 
Estimated 
Timing (Months) 
Estimated # of 
Events 
Observed 
p-value a for 
Efficacy 
Approximate 
HR Threshold 
Interim Analysis 
25.5 
115 
< 0.0062 
< 0.627 
Final Analysis b  
45.1 
200 
< 0.0224  
< 0.753 
Abbreviations: HR, hazard ratio; PFS, progression-free survival. 
a One-sided. 
b If target number of PFS events have not been observed when there have been approximately 191 OS events, the 
PFS final analysis will be performed at that time, regardless of the number of PFS events observed. 
An IDMC will be responsible for making the recommendation regarding stopping the study early 
for compelling efficacy results. More details will be given in the IDMC charter.  
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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 
the patient should be enrolled or 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  
Regular safety monitoring (at least every 6 months), and efficacy monitoring will be performed 
by an IDMC. The first IDMC safety review will occur when the first 20 patients (ie, 
approximately 10 patients per treatment arm) have had at least 6 weeks of follow-up after the last 
dose of radiotherapy in order to determine if the proposed regimen of tislelizumab/placebo 
concurrent with cCRT is safe to continue. The IDMC will also be responsible for reviewing the 
results from pre-defined analyses, including interim analysis of PFS and making the 
recommendations for stopping the study for compelling efficacy results. 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 the IDMC review and discussion, the sponsor will make all final decisions regarding 
any changes in study conduct. Please see the details in the IDMC charter. 
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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 Council for Harmonisation (ICH) good clinical practice 
guidelines, the study monitor must have direct access to the investigator’s source documentation 
in order 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 with the investigational drug from the 
China regulatory agency in accordance with applicable regulatory requirements in China before 
the study is initiated at a study center. 
12.2. 
Quality Assurance  
To ensure compliance with good clinical practice 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. 
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 including 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. 
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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 ICH 
E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting). 
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 
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. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality  
Patient Confidentiality and Data Protection 
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 deidentified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients is NOT shared: 
• Names or initials (full or partial); 
• Full dates of birth; 
• Contact information (such as phone numbers or home or email addresses);  
• 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  
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• Information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Upon enrollment, patients will be required to provide their names, phone and contact 
information, and similar information on secondary contacts.  This information will be stored 
separately from the study clinical database.  Documents generated by the site that will be shared 
with the sponsor, such as patient enrollment logs, need to have this information redacted before 
being shared.  This information will only be used to obtain patients vital status and disposition if 
the patients becomes lost to follow-up or in other specific circumstances specified in the ICF 
provided to the patient at the time of the collection of informed consent for participation in the 
study (eg, for purposes of expense reimbursement or mailing the latest version of the ICF to the 
patients when he or she cannot travel to the site). 
Patients’ personal and medical information obtained during this study is confidential and may 
only be disclosed to third parties as permitted by the signed ICF (or a separate authorization for 
the use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law.  
Patient tissue samples (blocks or slides) that are collected before and during the study will be 
assigned a unique identification number by the hospital where the biopsy procedure was done.  
This identification number is sometimes called a “block ID.” This identification number is 
necessary for the laboratory to keep track of the patient’s sample during testing, and therefore 
this identification number will be collected together with the patient’s tissue sample.  This 
identification number will not contain any of the patient’s personal information or identity, but it 
can be traced back to records held by their study doctor. 
In certain circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain uncoded personal information to the sponsor and/or its 
representatives.  Such personal information may not be provided as part of the study protocol 
(eg, as part of the eCRF, on samples or reports submitted to the central laboratory, on safety 
reporting forms, or on product dispensing logs provided to the sponsor, etc.). 
Investigator and site must use only the specific forms and clinical study systems (eg, the EDC 
system and any secure file transfer platforms) designated by the sponsor for sharing and transfer 
of personal and medical information.  Should a site use its own form, it must be reviewed and 
redacted in accordance with this section before being shared with the sponsor. 
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all risk containment and remediation 
steps and reporting obligations under applicable laws.  If the sponsor identifies personal or 
medical information that was not properly de-identified, it may be required to report the 
disclosure under local applicable laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes where allowed by local 
law or the patient’s signed ICF.  
Data generated during this study must be available for inspection upon request by representatives 
of the China National Medical Product Association; and all other national and local health 
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authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. Every effort will be made to keep the patient’s personal data 
confidential. 
In any presentations or in publications of the results of the study, the participants’/patients’ 
identities will remain anonymous and confidential. 
BeiGene Confidential Information 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational new drug, and any other 
study information, are confidential and 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. 
In cases of discrepancies between the confidentiality or data privacy provisions contained in a 
written contract for the conduct of the study and this Section 13.4 of the protocol, that contract’s 
provisions shall apply to the extent that they provide for a higher level of protection of patients’ 
rights to confidentiality and data privacy or of BeiGene’s confidential information. 
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 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 20.1 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 20.1 or higher. 
14.2. 
Data Integrity and In-house Blinding  
In this double-blind, placebo-controlled study, all patients and personnel involved in the conduct 
and interpretation of the study, including the investigators, BeiGene study team, and site 
personnel, will be blinded to the treatment assignment. Randomization data will be kept strictly 
confidential; filed securely by the appropriate groups for BeiGene, the IRT and the IDMC; and 
will be accessible only to authorized persons per SOPs until the time of unblinding.  
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Depending on the recommendation from IDMC based on interim analysis, the Sponsor may 
prepare a regulatory submission; limited sponsor personnel may be unblinded to the treatment 
assignment, if required, in order to act on the recommendations of the IDMC and facilitate 
regulatory filling. The extent to which individuals are unblinded with respect to results of interim 
analysis will be documented. Key aspects of the interim analyses are described in Section 9.7. 
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 of 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 CSR 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 
regulatory guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the study. The data generated in this clinical study are the exclusive 
property of the sponsor and are confidential. For multicenter studies, 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 2016). 
After conclusion of the study and without prior written approval from BeiGene, investigators in 
this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of BeiGene in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 2 years. 
• No such communication, presentation, or publication will include BeiGene’s 
confidential information.  
• Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsor prior to submission. This allows the sponsors to 
protect proprietary information, provide comments based on information from other 
studies that may not yet be available to the investigator, and ensure scientific and 
clinical accuracy. 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. 
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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  
• 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.  
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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 
• Information is necessary to disclose to provide appropriate medical care to a 
patient Study results which 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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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screeni
ng1 
Treatment 
Safety 
Follow-
up3 
Survival 
Follow-
up4 
Treatment Period of During cCRT (Cycle1, 2) 
(every week) 
 
 
Treatment Period After cCRT 
(Cycle3) up to 24 months 
(every 21 days) 
EOT 
Visit2 
Days (Window) 
-28 to 
~ -1 
C1D1 
D1 
C1D8 
D8 
(± 3) 
C1D15 
D15 
(± 3) 
C2D1 
D22 
(± 3) 
C2D8 
D29 
(± 3) 
C2D15 
D36 
(± 3) 
Day 1 of each 21-day cycle 
from Cycle 3 (± 3) 
0 to 7 
Days 
30± 7 
Days 
After 
Last Dose 
Every 3 
Months 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria evaluation 
x 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x5 
 
 
 
 
 
 
 
 
 
Demographics/med
ical history/prior 
medications6 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs/ 
height7 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Physical 
examination8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG 
Performance Status 
x 
x 
 
 
x 
 
 
x 
x 
x 
 
12-lead ECG9 
x 
As clinically indicated 
x 
 
Adverse events10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Hematology11 
x1 
x 
x 
x 
x 
x 
x 
x 
x2 
x 
 
Serum chemistry11 
x1 
x 
x 
x 
x 
x 
x 
x 
x2 
x 
 
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Assessment 
Screeni
ng1 
Treatment 
Safety 
Follow-
up3 
Survival 
Follow-
up4 
Treatment Period of During cCRT (Cycle1, 2) 
(every week) 
 
 
Treatment Period After cCRT 
(Cycle3) up to 24 months 
(every 21 days) 
EOT 
Visit2 
Days (Window) 
-28 to 
~ -1 
C1D1 
D1 
C1D8 
D8 
(± 3) 
C1D15 
D15 
(± 3) 
C2D1 
D22 
(± 3) 
C2D8 
D29 
(± 3) 
C2D15 
D36 
(± 3) 
Day 1 of each 21-day cycle 
from Cycle 3 (± 3) 
0 to 7 
Days 
30± 7 
Days 
After 
Last Dose 
Every 3 
Months 
Coagulation 
parameters11,12 
x 
x 
 
 
x 
 
 
x 
x2 
x 
 
Urinalysis11 
x 
As clinically indicated 
 
Pregnancy test13 
x 
x 
 
 
x 
 
 
x 
 
 
 
Thyroid function14 
x1 
 
 
 
 
 
 
x 
 
x 
 
HBV/HCV tests15 
x 
As clinically indicated 
 
Pulmonary 
function tests16 
x 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics17 
 
x 
 
 
x 
 
 
x 
 
x 
 
Anti-tislelizumab 
antibodies18 
 
x 
 
 
x 
 
 
x 
 
x 
 
Tumor 
assessment19 
x 
 
 
 
 
 
 
x 
x2 
 
x 
Archival tumor 
tissue (if feasible)20 
x 
 
 
 
Fresh tumor tissue 
(optional)21 
x 
 
 
 
 
 
 
x 
 
 
Blood collection22 
refer to Appendix 2 
 
 
Tislelizumab/ 
placebo 
administration23 
 
x 
 
 
x 
 
 
x 
 
 
 
Chemotherapy24 
 
x 
 
 
x 
 
 
 
 
 
 
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Assessment 
Screeni
ng1 
Treatment 
Safety 
Follow-
up3 
Survival 
Follow-
up4 
Treatment Period of During cCRT (Cycle1, 2) 
(every week) 
 
 
Treatment Period After cCRT 
(Cycle3) up to 24 months 
(every 21 days) 
EOT 
Visit2 
Days (Window) 
-28 to 
~ -1 
C1D1 
D1 
C1D8 
D8 
(± 3) 
C1D15 
D15 
(± 3) 
C2D1 
D22 
(± 3) 
C2D8 
D29 
(± 3) 
C2D15 
D36 
(± 3) 
Day 1 of each 21-day cycle 
from Cycle 3 (± 3) 
0 to 7 
Days 
30± 7 
Days 
After 
Last Dose 
Every 3 
Months 
EORTC QLQ-
C3025 
x 
x 
 
 
x 
 
 
x 
x 
 
 
EORTC QLQ-
OES1825 
x 
x 
 
 
x 
 
 
x 
x 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: AE, adverse event; cCRT: concurrent chemoradiotherapy; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC 
QLQ-OES, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Oesophageal Cancer Module; EORTC QLQ-C30, 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT: end of treatment; FFPE, formalin-fixed paraffin-
embedded; FT3, free triiodothyronine; FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, 
hepatitis C virus; HBsAb, hepatitis B surface antibody; IEC, Independent Ethics Committee; imAE, immune-mediated adverse event; IRB, Institutional Review 
Board; IRT, interactive response technology; IV, intravenous; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Events; PET, positron emission tomography; PK, pharmacokinetic; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria in 
Solid Tumors; RNA, ribonucleic acid; SAE, serious adverse event; TSH, thyroid stimulating hormone. 
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. 
2. The End of Treatment Visit is conducted when the investigator determines that tislelizumab or placebo will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End of Treatment Visit, tests need not be repeated. Tumor assessment is not required 
at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last assessment. Patients who discontinue study treatment prior to 
disease progression (confirmed by the investigator or BIRC, whichever is later) will need to undergo tumor assessments as outlined in Section 7.5.  
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last study treatment of tislelizumab/placebo or chemoradiotherapy 
(whichever occurs later), before the initiation of a new anticancer treatment, or before administration of the first dose in a long-term extension study or 
posttrial continued access program, whichever occurs first. In addition, telephone contacts with patients should be conducted to assess all AEs and 
concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 days, and 90 days (±14 days) after the last dose of 
study treatment, regardless of whether or not the patient starts a new anticancer therapy. 
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. The schedule of survival follow-up may be adjusted 
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within the allowed time window to perform the planned survival follow-up between 2 scheduled tumor response assessments for patients who enter the 
survival follow-up period but still need to continue tumor response assessment per protocol requirement, especially after the completion of the 3-year tumor 
response assessment (eg, a survival follow-up is performed approximately 3 months after the last tumor response assessment when a 6-month interval is 
required between 2 tumor assessments). In these survival follow-ups, potential symptoms or signs indicating disease progression should be followed 
actively. If any suspected symptoms/signs are reported, the investigator should arrange an unscheduled on-site visit for further assessment. Tumor 
assessments will be at the discretion of the investigator, per local standards of care, at the time of symptoms or signs of disease progression.   
5. Patients will be randomized into either the tislelizumab or placebo arms via IRT. All patients are required to receive study treatment within 3 days of 
randomization. 
6. Includes history of treatment for the primary diagnosis, including prior medication, 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 temperature, pulse rate, heart rate, respiratory rate, weight, and blood pressure (systolic and diastolic) while the patient 
is in a seated position after resting for 10 minutes. The patient’s vital signs are required to be recorded within 60 minutes before; during; and 30 minutes after 
the first infusion of tislelizumab or placebo. 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. Please consider specifying that a complete physical examination is required at screening while subsequent visits entail limited, symptom-directed physical 
examinations (as detailed in Section 7.4.2).  
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 semi-recumbent supine position for at least 10 minutes prior to each ECG collection. 
10. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the informed consent form 
has been signed, but prior to the administration of study treatment, only SAEs should be reported. After initiation of study treatment, all AEs and SAEs, 
regardless of relationship to study treatment, will be reported until 30 days after last study treatment (including chemoradiotherapy), 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 or not the patient starts a new anticancer therapy. 
11. Local laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will be collected as 
specified in Appendix 3. If laboratory tests at screening are not performed within 7 days of Cycle 1 Day 1, these tests should be repeated and reviewed 
before Cycle 1 Day 1. Hematology and serum chemistry (including C reactive protein) will be performed weekly for the cCRT period and then at the 
beginning of subsequent cycles (data collected as specified in Appendix 3). After Cycle 1, results are to be reviewed within 72 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.  
12. Coagulation parameters include international normalized ratio, prothrombin time, and activated partial thromboplastin time. 
13. Urine pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
within 7 days prior to randomization. Urine pregnancy tests will be performed at each visit prior to dosing. A serum pregnancy test must be performed if the 
urine pregnancy test is positive or equivocal. 
14. Analysis of FT3, FT4, and TSH will be performed by the local study site laboratory. Thyroid function tests will be performed at Screening and every 3 
cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at the Safety Follow-up Visit. 
15. Testing will be performed by the local laboratory at Screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody), and may 
also include viral load assessment (HBV DNA and HCV RNA) as per relevant local guidance and/or clinical practice.  
16. All patients 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 in determining suitability for the study. 
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17. 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/placebo infusion) sample is required to be 
collected at Day 1 of Cycles 1 and 5. An additional PK sample is required to be collected at the Safety Follow-up. Should a patient present with any 
≥ Grade 3 imAE, an additional blood PK sample may be taken to determine the serum concentration of tislelizumab/placebo. These tests for patients 
randomized to receive tislelizumab are required when it is allowed by local regulations/IRBs/IECs. 
18. 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. These tests for patients 
randomized to receive tislelizumab are required when it is allowed by local regulations/IRBs/IECs. 
19. 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. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. 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 approximately every 
9 weeks (± 7 days) for the first 54 weeks, every 12 weeks (± 7 days) during Years 2 and 3, every 24 weeks (± 7 days) during Years 4 and 5, and then 
according to local standards with a minimum of 1 tumor response assessment annually thereafter based on RECIST v1.1, regardless of treatment delays, or 
until disease progression (confirmed by the investigator or BIRC, whichever is later). 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 disease 
progression (eg, toxicity) will continue to undergo tumor assessments following the original plan until the patient begins a subsequent anticancer treatment, 
experiences disease progression (confirmed by the investigator or BIRC, whichever is later), withdraws consent, lost to follow up, death, or until the study 
terminates, whichever occurs first. Patients who continue tislelizumab/placebo treatment beyond radiographic disease progression assessed by BIRC per 
RECIST v1.1 (Section 7.5) will be monitored with a follow-up scan no more than 6 to 8 weeks beyond the initial BIRC assessment of radiographic disease 
progression before discontinuation of tislelizumab/placebo treatment.  
Screening assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI of the neck, chest, and abdomen, ultrasound of 
cervical and supraclavicular lymph nodes, and esophagography. If feasible, esophagoscopy, including esophagoendoscopic ultrasonography should be 
included as well. Other known or suspected sites of disease must be included in the imaging assessments (bone, brain, etc). 
Tumor assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI, with preference for CT, of the neck, chest, and 
abdomen, and esophagography. The same radiographic procedure used to assess disease sites at screening is 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. The 
modality of tumor assessment at screening and subsequent assessment please refer to Section 7.5 for detailed instructions. 
20. Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 [≥ 6] unstained slides) for biomarker analysis if feasible. The 
baseline tissue sample can be collected at any stage of study after local regulation approval. 
21. Fresh biopsy: In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 28 days before randomization) is strongly 
recommended if feasible. For all randomized patients who have disease progression, a fresh biopsy will be optionally obtained (written informed consent is 
required prior to fresh tumor biopsies). See Section 7.7 for more information. 
22. Blood biomarker: Refer to Appendix 2. 
23. Tislelizumab/placebo will be given intravenously Q3W. The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes, and then can be 
administered over 30 minutes for subsequent infusions if well tolerated. Patients must be monitored for 60 minutes after infusion of tislelizumab/placebo on 
Day 1 of Cycle 1 and Cycle 2. From Cycle 3 onward, at least a 30-minute monitoring period is required. The first dose will be given on Cycle 1 Day 1 and 
subsequent dosing will continue on the scheduled 21-day intervals. 
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24. Chemotherapy will be given intravenously for all patients for 2 cycles. Cisplatin 25 mg/ m2 intravenously on Day 1 to 3 Q3W; paclitaxel 135 mg/m2, 
intravenously on Day 1 Q3W. Refer to Section 5.2.3 for detail dose and schedule. 
25. EORTC QLQ-C30, EORTC QLQ-OES18 will be completed at screening or baseline, prior to dosing of every treatment cycle for first 6 Cycles, then every 2 
cycles thereafter and at EOT. QoL will be completed prior to any clinical activities during on-study site visits. 
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APPENDIX 2. BLOOD BIOMARKER ANALYSIS  
Assessment 
Screening 
Treatment 
Days 
-28 to ~ -1 
Cycle 1 Day 1 
Cycle 3 Day 1  
EOT Visit 
ctDNA1 
 
X 
X 
X 
Flow cytometry2 
 
X 
X 
X 
PBMC2 
 
X 
X 
X 
Abbreviations: ctDNA: circulating tumor DNA; EOT, end of treatment; PBMC, peripheral blood mononuclear cells.  
1. 10 mL blood will be collected mandatorily at predose stage (Cycle 1 Day 1) for all randomized patients. An optional additional blood 
collection will be collected at C3D1 (predose of Cycle 3 Day 1) for those who have disease progression.  
2. 9 mL blood for flow cytometry test and 10 mL blood for PBMC isolation will be collected optionally at predose stage (Cycle 1 Day 1), C3D1 
(predose of Cycle 3 Day 1), and for those who have disease progression, respectively. 
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS  
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
CRP 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or 
urea 
Potassium 
Sodium 
Total calcium b  
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
CK c 
CK-MB c 
Hematocrit  
Hemoglobin  
Platelet counts 
WBC count  
Lymphocyte 
count 
Neutrophil 
count 
Prothrombin time 
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
INR  
 
 
Glucose 
Protein  
Blood  
24-hour protein a 
Random urine 
protein-to-
creatinine ratio 
 
Abbreviations: CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CRP, C reactive protein; INR, 
international normalized ratio; WBC, white blood cell. 
a. 
On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein or 
a random urine sample for total protein and creatinine to determine a protein-to-creatinine ratio. 
b. Total calcium values will be corrected for patients with hypoproteinemia. 
c. 
In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead.  
 
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APPENDIX 4. 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, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX 5. 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;45:228-47. 
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 (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  
Note: Lesions are either measurable or nonmeasurable 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 nonmeasurable. 
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Bone lesions: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above 
• 
Blastic bone lesions are 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. 
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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. 
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 
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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 where 
recurrence following complete response 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 complete response. 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 in order 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 non-target) 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 
one 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 
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• 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 complete response 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, in order to qualify for CR, each node must achieve a short axis 
<10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
• Target lesions that become “too small to measure”. While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the 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.” 
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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 non-target 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 one or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of one 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 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one 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 non-target 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. 
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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 partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate 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. 
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. 
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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 treatment, 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 inevaluable. 
 
Target Lesions 
Non-target 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”.  
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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 inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, ie, in 
randomized trials (phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of 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). 
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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 complete response 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 randomised 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 progression-free survival 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 5.1 ESOPHAGEAL PRIMARY LESION ASSESSMENT AND 
RESPONSE EVALUATION  
In this trial, the esophageal primary lesion will be considered nonmeasurable disease, thus should 
be identified  as non-target lesion. 
In order to ensure the accuracy of the assessment of esophageal primary lesion, esophagography 
is included into each tumor assessment and the objective criteria below are applied for response 
evaluation of esophageal primary lesion in the trial, with the reference of Chinese guideline of 
radiotherapy in esophageal cancer 2019 (Li et al 2019):  
• Disappearance: when images of both enhanced CT/enhanced MRI and 
esophagography are evaluable, all below criteria are met: 
o On enhanced CT/enhanced MRI: disappearance of esophageal primary lesion. 
Note: If the esophageal primary lesion is not completely disappeared, but it 
can be well supported on esophagography as not contributing to tumor, eg, 
fibrotic/scarring related lesions, the evaluation can be overridden to be 
“disappearance” when below criteria for esophagography is met. 
o On esophagography:  the tumor is completely disappeared, the lining of the 
esophagus is smooth, the barium meals pass smoothly, the wall of the 
esophagus can be slightly stiff, the lumen has little or no stenosis (the ratio of 
normal upper esophagus to the stenosis ≤ 3:2), and the mucosa is normal or 
slightly thickened. 
• Unequivocal progression: when either images of enhanced CT/enhanced MRI or 
esophagography are evaluable, any of below criteria is met: 
o On enhanced CT/enhanced MRI: unequivocal progression (as detailed in prior 
sections of Appendix 5) of esophageal primary lesion, or dynamic 
enlargement of esophageal primary lesion in at least 3 consecutive CT/MRI 
scans. 
o On esophagography:  significant worsening of mucosal destruction, filling 
defects, or stenosis in at least 3 consecutive esophagography, taking as 
reference the image of the best response on study (this includes the baseline 
images). 
• Present: when images of enhanced CT/enhanced MRI are evaluable, persistence 
of esophageal primary lesion without meeting the above criteria of 
“disappearance” or “unequivocal progression”. 
 
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APPENDIX 6. 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 7. 
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. 
If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. 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 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any 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 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 AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of  
Possible Immune-Mediated Adverse Events 
Immune-Mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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Recommended Diagnostic Tests in the Management of  
Possible Immune-Mediated Adverse Events 
Immune-Mediated 
Toxicity 
Diagnostic Evaluation Guideline 
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. 
Rheumatology 
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.  
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CNS, central nervous system; CRP, C-reactive protein; CT, computed tomography; DLCO, 
diffusing capacity for carbon monoxide; FBC, full blood count; HIV, human immunodeficiency virus; INR, 
international normalized ratio; LCI, liver cystolic 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. 
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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 
 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month. If there is no improvement 
in 48 hours, treat as Grade 3-4. Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. Initiate 
pulse intravenous 
methylprednisolone 1 mg/kg for 
patients with headache/visual 
disturbance due to pituitary 
inflammation. Convert to oral 
prednisolone and taper over at least 1 
month. Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen. 
Consider Pneumocystis infection 
prophylaxis. Taper corticosteroids 
over 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with intravenous 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 2 
months. Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day. Taper over at least 4 
weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or intravenous 
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. 
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 intravenous 
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. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
symptoms 
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. 
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: intravenous 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate intravenous 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
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 
intravenous (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 intravenous 
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 intravenous methylprednisolone 
• 
If on IV, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
Hold study treatment 
until the cause is 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
or > 3X-6X ULN 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate 
intravenous (methyl)prednisolone 
1-2 mg/kg. Taper corticosteroids 
over at least 4 weeks. 
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. 
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 
Initiate intravenous 
(methyl)prednisolone 2 mg/kg/day. 
Discontinue study 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Blindness (at least 
20/200) in the affected 
eyes 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
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 intravenous 
(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. 
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 intravenous 
(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 
Admit to hospital for emergency 
care. Consider intravenous 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
complications or 
dehydration 
corticosteroids if not contraindicated 
by infection. 
Myoditis/ 
Rhabodomyolysis 
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 intravenous 
(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 
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 intravenous 
(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, chronic heart failure; INR, international normalized ratio; IV, intravenous; LFT, liver 
function test; MMF, mycophenolate mofetil; NYHA, New York Heart Association; T4, thyroxine; TB, 
tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, 
upper limit of normal. 
 
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APPENDIX 9. 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 
 
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 10. 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) 
• 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.  
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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: 
≥ 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 concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If a follicle-stimulating hormone 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 11. EORTC-QLQ-C30 QUESTIONNAIRE  
 
 
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APPENDIX 12. EORTC QLQ-OES18 QUESTIONNAIRE  
 
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