Clinical trial NCT03924986
Conditions: Recurrent or Metastatic Nasopharyngeal Cancer
Sponsor: BeiGene
Start date: 2019-03-27; Completion date: 2023-12-08
Enrollment: 263 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to compare the efficacy and safety of tislelizumab (BGB-A317) combined with gemcitabine plus cisplatin versus placebo combined with gemcitabine plus cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal cancer.

Detailed description:

Arms: arm 1: Participants received tislelizumab 200 mg intravenously (IV) once every 3 weeks (Q3W), gemcitabine 1 g/m\^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m\^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have continued to receive tislelizumab monotherapy. arm 2: Participants received placebo IV once every 3 weeks, gemcitabine 1 g/m\^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m\^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have crossed over to receive tislelizumab 200 mg IV Q3W monotherapy.
Interventions: intervention 1: Tislelizumab intervention 2: Placebo intervention 3: Gemcitabine intervention 4: Cisplatin
Intervention descriptions: intervention 1: 200 mg intravenously (IV) once every 3 weeks (Q3W) intervention 2: Placebo to match tislelizumab (administered intravenously Q3W) intervention 3: 1 gram per square meter of body surface area (g/m\^2) on Day 1 and day 8 of each cycle, administered as an IV infusion within 30 minutes, for 4 to 6 cycles intervention 4: 80 milligrams per square meter of body surface area (mg/m\^2) on Day 1 of each cycle, administered as an IV infusion for over 4 hours if possible or with proper infusion time based on local clinical guidelines or clinical practice and according to the treating physician's clinical judgment, for 4 to 6 cycles.

Protocol documents:
Prot_000.pdf: 
BGB-A317-309 
BeiGene 
Protocol Amendment 1.0 
26 March 2021 
 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-
controlled Study to Compare the Efficacy and Safety of 
Tislelizumab (BGB-A317) Combined With Gemcitabine Plus 
Cisplatin Versus Placebo Combined With Gemcitabine Plus 
Cisplatin as First-Line Treatment for Recurrent or Metastatic 
Nasopharyngeal Cancer  
Protocol Identifier: 
BGB-A317-309 
Phase: 
3 
Investigational Product: 
Tislelizumab (BGB-A317) 
Indication: 
Recurrent or Metastatic Nasopharyngeal Cancer 
Sponsors: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc.  
2955 Campus Drive, Suite 200  
San Mateo, CA 94403  
USA 
 
BeiGene (Shanghai) Co., Ltd. 
4th Floor, Building D 
780 Cailun Road 
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China 201203 
 
Sponsor Medical 
Monitor: 
 
Telephone: 
 
Email: 
 
 
 
 
  
 
Original Protocol: 
28 November 2018  
Amendment 1.0: 
26 March 2021 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries.  This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s).  This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries.  Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without the prior written authorization 
from BeiGene, Ltd., or one of its subsidiaries. 




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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-controlled Study  
to Compare the Efficacy and Safety of Tislelizumab (BGB-A317)  
Combined With Gemcitabine Plus Cisplatin Versus Placebo Combined With 
Gemcitabine Plus Cisplatin as First-Line Treatment for Recurrent or  
Metastatic Nasopharyngeal Cancer  
 
Protocol Identifier: BGB-A317-309 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries.  I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
Instructions for Investigator: Please SIGN and DATE this signature page 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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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
SYNOPSIS ....................................................................................................................................11 
LIST OF ABBREVIATIONS AND TERMS ................................................................................20 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background Information on Nasopharyngeal Cancer ................................................22 
1.2. 
Current Treatment of NPC With Recurrence or Metastasis .......................................23 
1.2.1. 
Chemotherapy .............................................................................................................23 
1.2.2. 
Checkpoint Inhibitor ...................................................................................................24 
1.3. 
Background Information on Tislelizumab ..................................................................25 
1.3.1. 
Pharmacology .............................................................................................................25 
1.3.2. 
Toxicology ..................................................................................................................25 
1.3.3. 
Clinical Pharmacology ................................................................................................26 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................26 
1.3.4.1. 
BGB-A317_Study_001 (Data cutoff 28 August 2017) ..............................................26 
1.3.4.2. 
Study BGB-A317-102 (Data cutoff 28 August 2017) ................................................27 
1.3.4.3. 
Immune-Mediated Reactions ......................................................................................28 
1.4. 
Study Rationales .........................................................................................................29 
1.4.1. 
Rationale for Gemcitabine Plus Cisplatin as the Comparator ....................................29 
1.4.2. 
Rationale for Tislelizumab in the Treatment of NPC With Recurrence or 
Metastasis ...................................................................................................................29 
1.4.3. 
Rationale for Selection of Tislelizumab Dose in Combination With 
Chemotherapy .............................................................................................................29 
1.4.4. 
Rationale for Matched Placebo in Combination With Chemotherapy as the 
Comparator .................................................................................................................30 
1.4.5. 
Rationale for Primary Endpoint of Progression-free Survival as Assessed by 
the Independent Review Committee ...........................................................................30 
1.4.6. 
Rationale for Plasma EBV DNA Measurement .........................................................31 
1.4.7. 
Rationale for Allowing Patients to Continue Tislelizumab Until Loss of 
Clinical Benefit ...........................................................................................................31 


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1.4.8. 
Rationale for Selection of the Patient-Reported Outcome for Assessments of 
Health-Related Quality of Life ...................................................................................32 
1.5. 
Benefit-Risk Assessment ............................................................................................32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................34 
2.1. 
Study Objectives .........................................................................................................34 
2.1.1. 
Primary Objective .......................................................................................................34 
2.1.2. 
Secondary Objectives .................................................................................................34 
2.1.3. 
Exploratory Objectives ...............................................................................................34 
2.2. 
Study Endpoints ..........................................................................................................35 
2.2.1. 
Primary Endpoint ........................................................................................................35 
2.2.2. 
Secondary Endpoints ..................................................................................................35 
2.2.3. 
Exploratory Endpoints ................................................................................................36 
3. 
STUDY DESIGN .......................................................................................................37 
3.1. 
Summary of Study Design ..........................................................................................37 
3.2. 
Screening Period .........................................................................................................39 
3.3. 
Treatment Period ........................................................................................................39 
3.4. 
Safety Follow-up ........................................................................................................41 
3.5. 
Survival Follow-up .....................................................................................................41 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................42 
3.6.1. 
Discontinuation From Study Treatment .....................................................................42 
3.6.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) ...........42 
3.7. 
End of Study ...............................................................................................................42 
4. 
STUDY POPULATION .............................................................................................44 
4.1. 
Inclusion Criteria ........................................................................................................44 
4.2. 
Exclusion Criteria .......................................................................................................45 
5. 
STUDY TREATMENT ..............................................................................................48 
5.1. 
Formulation, Packaging, and Handling ......................................................................48 
5.1.1. 
Tislelizumab ...............................................................................................................48 
5.1.2. 
Matched Placebo .........................................................................................................48 
5.1.3. 
Chemotherapy Agents ................................................................................................48 
5.2. 
Dosage, Administration, and Compliance ..................................................................48 
5.2.1. 
Tislelizumab ...............................................................................................................49 
5.2.2. 
Matched Placebo .........................................................................................................49 


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5.2.3. 
Chemotherapy .............................................................................................................50 
5.3. 
Overdose .....................................................................................................................50 
5.4. 
Investigational Medicinal Product Accountability .....................................................50 
5.5. 
Dose Delay, Interruption and Modification ................................................................50 
5.5.1. 
General Guidance Regarding Dose Modifications .....................................................51 
5.5.2. 
Dose Interruption or Delay for Tislelizumab ..............................................................52 
5.5.3. 
Dose Modifications of Chemotherapy Treatment ......................................................52 
5.6. 
Criteria for Discontinuing Chemotherapy Regimens .................................................54 
5.7. 
Blinding ......................................................................................................................55 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................56 
6.1. 
Prior Therapy ..............................................................................................................56 
6.2. 
Concomitant Therapy .................................................................................................56 
6.2.1. 
Permitted Concomitant Medications ..........................................................................56 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................56 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................57 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................57 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
7.1. 
Screening ....................................................................................................................58 
7.1.1. 
Demographic Data and Medical History ....................................................................58 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................59 
7.1.3. 
Informed Consent and Screening Log ........................................................................59 
7.1.4. 
Patient Numbering ......................................................................................................59 
7.1.5. 
Pulmonary Function Tests ..........................................................................................59 
7.2. 
Enrollment ..................................................................................................................59 
7.2.1. 
Confirmation of Eligibility .........................................................................................59 
7.2.2. 
Randomization ............................................................................................................60 
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensation ............................................60 
7.4. 
Crossover ....................................................................................................................60 
7.4.1. 
Crossover for Patients in Chemotherapy in Arm B With Documented and 
IRC Confirmed Disease Progression ..........................................................................60 
7.4.2. 
Crossover Assessments and Procedures .....................................................................60 
7.5. 
Safety Assessments .....................................................................................................61 


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7.5.1. 
Vital Signs ..................................................................................................................61 
7.5.2. 
Physical Examinations ................................................................................................61 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status ........................................62 
7.5.4. 
Laboratory Safety Tests ..............................................................................................62 
7.5.5. 
Electrocardiograms .....................................................................................................62 
7.5.6. 
Adverse Events ...........................................................................................................62 
7.5.7. 
Hepatitis B and C Testing ...........................................................................................63 
7.6. 
Tumor and Response Evaluations ..............................................................................63 
7.7. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................64 
7.8. 
Biomarkers ..................................................................................................................65 
7.9. 
Patient-Reported Outcomes ........................................................................................66 
7.10. 
Visit Windows ............................................................................................................66 
7.11. 
Unscheduled Visits .....................................................................................................66 
8. 
SAFETY MONITORING AND REPORTING .........................................................67 
8.1. 
Risks Associated With Study Drugs ...........................................................................67 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................67 
8.1.2. 
Risks Associated With Cisplatin in Combination With Gemcitabine ........................67 
8.2. 
General Plan to Manage Safety Concerns ..................................................................68 
8.2.1. 
Eligibility Criteria .......................................................................................................68 
8.2.2. 
Safety Monitoring Plan ...............................................................................................68 
8.3. 
Adverse Events ...........................................................................................................69 
8.3.1. 
Definitions and Reporting ...........................................................................................69 
8.3.2. 
Assessment of Severity ...............................................................................................69 
8.3.3. 
Assessment of Causality .............................................................................................70 
8.3.4. 
Following Adverse Events ..........................................................................................70 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................71 
8.4. 
Definition of a Serious Adverse Event .......................................................................72 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................72 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................73 
8.6.1. 
Adverse Event Reporting Period ................................................................................73 
8.6.2. 
Reporting Serious Adverse Events .............................................................................73 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................73 


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8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................73 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................74 
8.6.3. 
Eliciting Adverse Events ............................................................................................74 
8.6.4. 
Disease Progression ....................................................................................................74 
8.6.5. 
Deaths .........................................................................................................................74 
8.6.6. 
Recording Pregnancies ...............................................................................................74 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................75 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................75 
8.7. 
Management of Adverse Events of Special Interest ...................................................75 
8.7.1. 
Infusion-Related Reactions .........................................................................................76 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................77 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................77 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................79 
9.1. 
Statistical Analysis ......................................................................................................79 
9.1.1. 
Randomization Methods .............................................................................................79 
9.1.2. 
Analysis Sets ...............................................................................................................79 
9.1.3. 
Patient Disposition ......................................................................................................79 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................79 
9.1.5. 
Prior and Concomitant Medications ...........................................................................80 
9.2. 
Efficacy Analyses .......................................................................................................80 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................80 
9.2.2. 
Secondary Efficacy Analyses .....................................................................................81 
9.2.3. 
Exploratory Efficacy Analyses ...................................................................................82 
9.3. 
Safety Analyses ..........................................................................................................83 
9.3.1. 
Extent of Exposure .....................................................................................................83 
9.3.2. 
Adverse Events ...........................................................................................................83 
9.3.3. 
Laboratory Analyses ...................................................................................................84 
9.3.4. 
Vital Signs ..................................................................................................................84 
9.4. 
Pharmacokinetic Analysis ..........................................................................................84 
9.5. 
Immunogenicity Analysis ...........................................................................................84 
9.6. 
Sample Size Consideration .........................................................................................85 
9.7. 
Interim Analyses .........................................................................................................85 


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10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................86 
10.1. 
Blinded Independent Central Review .........................................................................86 
10.2. 
Independent Data Monitoring Committee ..................................................................86 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................87 
11.1. 
Access to Information for Monitoring ........................................................................87 
11.2. 
Access to Information for Auditing or Inspections ....................................................87 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................88 
12.1. 
Regulatory Authority Approval ..................................................................................88 
12.2. 
Quality Assurance .......................................................................................................88 
12.3. 
Study Site Inspections.................................................................................................88 
12.4. 
Drug Accountability ...................................................................................................88 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................90 
13.1. 
Ethical Standard ..........................................................................................................90 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................90 
13.2.1. 
Protocol Amendments ................................................................................................90 
13.3. 
Informed Consent .......................................................................................................90 
13.4. 
Patient and Data Confidentiality .................................................................................91 
13.5. 
Financial Disclosure ...................................................................................................92 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................93 
14.1. 
Data Collection and Management Responsibilities ....................................................93 
14.1.1. 
Data Collection ...........................................................................................................93 
14.2. 
Data Management/Coding ..........................................................................................93 
14.3. 
Data Integrity and In-house Blinding .........................................................................93 
14.4. 
Study Records Retention ............................................................................................94 
14.5. 
Protocol Deviations ....................................................................................................94 
14.6. 
Publication and Data-Sharing Policy ..........................................................................95 
14.7. 
Study and Study Center Closure .................................................................................95 
14.8. 
Information Disclosure and Inventions ......................................................................96 
15. 
REFERENCES ...........................................................................................................97 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................103 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................108 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................109 


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APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................110 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................119 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................120 
APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................121 
APPENDIX 8. COCKCROFT-GAULT FORMULA AND CALVERT FORMULA .............131 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................132 
APPENDIX 10. DOSE MODIFICATION GUIDELINES FOR CHEMOTHERAPY ............134 
 
LIST OF TABLES 
Table 1. 
Chemotherapy for the Treatment of Advanced or Metastatic Nasopharyngeal 
Cancer .........................................................................................................................24 
Table 2. 
Selection and Timing of Dose for Each Patient ..........................................................49 
Table 3. 
Commonly and Specifically Reported Toxicity of the Chemotherapeutic 
Agents .........................................................................................................................67 
Table 4. 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................73 
Table 5. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................76 
Table 6. 
Immune-Mediated Adverse Events ............................................................................78 
Table 7. 
Analysis Timing and Stopping Boundaries for PFS in Each of the Primary 
Tests at a 1-sided α = 0.025 ......................................................................................85 
Table 8. 
Chemotherapy Dose Modification for Hematological Toxicity for 
Gemcitabine and Cisplatin ........................................................................................134 
Table 9. 
Chemotherapy Dose Modifications for Non-Hematological Toxicity for 
Gemcitabine and Cisplatin ........................................................................................135 
 
LIST OF FIGURES 
Figure 1. 
Study Schema .............................................................................................................38 
 


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SYNOPSIS 
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-controlled Study to 
Compare the Efficacy and Safety of Tislelizumab (BGB-A317) Combined With Gemcitabine Plus 
Cisplatin Versus Placebo Combined With Gemcitabine Plus Cisplatin as First-Line Treatment for 
Recurrent or Metastatic Nasopharyngeal Cancer 
Protocol Identifier: BGB-A317-309 
Phase of Development: 3 
Number of Patients: Approximately 256 
Study Centers: Approximately 42 sites 
Study Objectives: 
Primary: 
• 
To compare the progression-free survival as assessed by the Independent Review Committee per 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in an Intent-to-Treat analysis set 
between tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + 
cisplatin in patients with recurrent or metastatic nasopharyngeal cancer.   
Secondary: 
• 
To compare objective response rate as assessed by the Independent Review Committee per 
RECIST v1.1 between tislelizumab combined with gemcitabine + cisplatin and placebo + 
gemcitabine + cisplatin. 
• 
To compare duration of response as assessed by the Independent Review Committee per RECIST 
v1.1 between tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + 
cisplatin. 
• 
To compare overall survival between tislelizumab combined with gemcitabine + cisplatin and 
placebo + gemcitabine + cisplatin in an Intent-to-Treat analysis set. 
• 
To compare progression-free survival as assessed by the investigator per RECIST v1.1 between 
tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + cisplatin in an 
Intent-to-Treat analysis set. 
• 
To evaluate progression-free survival after next line of treatment as assessed by the investigator 
per RECIST v1.1 between patients who cross over to subsequent tislelizumab monotherapy after 
initial progression of disease and patients who do not cross over to subsequent tislelizumab 
monotherapy or other anti-programmed cell death protein-1 (PD1)/programmed cell death protein 
ligand-1 (PD-L1) agents for patients who are randomized to the placebo + gemcitabine + cisplatin 
arm. 
• 
To compare health-related quality of life between tislelizumab combined with gemcitabine + 
cisplatin and placebo + gemcitabine + cisplatin.  
• 
To evaluate the safety and tolerability of tislelizumab combined with gemcitabine + cisplatin 
compared with placebo + gemcitabine + cisplatin. 


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Exploratory: 
• 
To compare objective response rate as assessed by the investigator per RECIST v1.1 between 
tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + cisplatin. 
• 
To compare duration of response as assessed by the investigator per RECIST v1.1 between 
tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + cisplatin. 
• 
To compare tumor assessment outcomes (eg, disease control rate, time to response) between 
tislelizumab combined with gemcitabine + cisplatin and placebo + gemcitabine + cisplatin as 
assessed by the investigator per RECIST v1.1. 
• 
To evaluate the correlation between PD-L1 expression levels by immunohistochemistry and 
antitumor activity of tislelizumab combined with gemcitabine + cisplatin compared with placebo 
+ gemcitabine + cisplatin. 
• 
To assess tumor and blood-based biomarkers of tislelizumab response, resistance and patient 
prognosis. To explore potential predictive biomarkers including any association with response to 
study treatment and mechanism(s) of resistance. 
• 
To characterize the pharmacokinetics of tislelizumab when given in combination with 
gemcitabine + cisplatin.  
• 
To assess host immunogenicity to tislelizumab.  
Study Endpoints: 
Primary: 
• 
PFS as assessed by the IRC: the time from randomization to the first objectively documented 
disease progression, or death from any cause, whichever occurs first, as assessed by the IRC per 
RECIST v1.1 in an ITT analysis set. 
Secondary: 
• 
ORR as assessed by the IRC: the proportion of patients who had complete response (CR) or 
partial response (PR) as assessed by the IRC per RECIST v1.1 in all randomized patients with 
measurable disease at baseline. 
• 
DOR as assessed by the IRC: the time from the first occurrence of a documented objective 
response to the time of relapse, or death from any cause, whichever comes first, as assessed by the 
IRC per RECIST v1.1 in all randomized patients with documented objective responses. 
• 
OS: the time from the date of randomization to the date of death due to any cause in an ITT 
analysis set. 
• 
PFS as assessed by the investigator: the time from randomization to the first objectively 
documented disease progression, or death from any cause, whichever occurs first, as assessed by 
the investigator per RECIST v1.1 in an ITT analysis set. 
• 
PFS2 as assessed by the investigator: the time from randomization to second/subsequent disease 
progression after initiation of new anticancer therapy, or death from any cause, whichever occurs 
first.  
 
 


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• 
HRQoL is measured via patient reported outcomes (PRO) questionnaires using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) and its Head and Neck-35 module (EORTC QLQ-H&N35).   
• 
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.  
Exploratory: 
• 
ORR as assessed by the investigator: the proportion of patients who had CR or PR as assessed by 
the investigator per RECIST v1.1 in all randomized patients with measurable disease at baseline. 
• 
DOR as assessed by the investigator: the time from the first occurrence of a documented objective 
response to the time of relapse, or death from any cause, whichever comes first, as assessed by the 
investigator per RECIST v1.1 in all randomized patients with documented objective responses. 
• 
DCR: the proportion of patients who had CR, PR, or stable disease (SD) as assessed by the 
investigator per RECIST v1.1. 
• 
Time to response: the time from randomization to the first occurrence of a documented objective 
response as assessed by the investigator per RECIST v1.1. 
• 
Evaluate biomarkers from patient derived tumor tissue(s) and/or blood (or blood derivatives) 
samples obtained before, during and/or after treatment. Candidate biomarkers may include, but are 
not limited to, PD-L1 expression, cytokines and soluble proteins in peripheral blood, immune cell 
subpopulation analysis in peripheral blood and tumor tissues, tumor mutation analysis and gene 
expression profiling. 
• 
Levels of circulating Epstein-Barr virus (EBV) DNA as a potential surrogate biomarker for 
antitumor efficacy prediction in patients with EBV-positive disease. 
• 
Summary of serum concentrations of tislelizumab. 
• 
Assessment of immunogenicity of tislelizumab by determining the incidence of antidrug 
antibodies (ADAs). 
Study Design: 
This is a double-blind, placebo-controlled, randomized, multicenter Phase 3 study designed to compare the 
efficacy and safety of tislelizumab combined with gemcitabine + cisplatin (Arm A) versus placebo + 
gemcitabine + cisplatin (Arm B) as first-line treatment in approximately 256 patients who have NPC with 
recurrence or metastasis.  
The study schema is presented as below: 


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Abbreviations: D, Day; DOR, duration of response; h, hour; IV, intravenously; min, minutes; N, number of patients; NPC, 
nasopharyngeal cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, progression-
free survival after next line of treatment; QOL, quality of life; R, randomization ratio. 
 
The primary endpoint of the study is measured by PFS as assessed by the IRC in an ITT analysis set. 
Patients who have histologically or cytologically confirmed NPC with recurrence or metastasis are 
eligible.  
Eligible patients will be stratified by gender and metastatic status (with or without liver metastases), and 
randomized by 1:1 to receive one of the following treatment regimens: 
• 
Arm A: tislelizumab + gemcitabine + cisplatin 
• 
Arm B: placebo + gemcitabine + cisplatin  
Both Arm A and Arm B will be double blinded.  
Administration of 4 to 6 cycles will be at the investigator’s discretion. Chemotherapy will be administered 
on a 3-week cycle, until one of the following occurs (whichever occurs first): 1) completion of 
administration of 4 to 6 cycles; 2) unacceptable toxicity; or 3) documented disease progression per 
RECIST v1.1.  
For all patients in Arm A and Arm B, if progression of disease is unconfirmed by the IRC and the patient 
is clinically stable, it is at the discretion of the investigator to continue treating the patient with the 
assigned treatment per protocol until progression of disease is confirmed at least 28 days (or at the next 
scheduled tumor assessment) from the date of the scan suggesting progression of disease. If a patient has 
confirmed progression of disease by RECIST v1.1 as assessed by the IRC, the patient should not receive 
further chemotherapy treatment on study, and unblinding will be performed. The following guidance 
should be followed. 
For Arm A (Experimental arm):  
Patients whose tumors show progressive disease per RECIST v1.1 during the chemotherapy combination 
phase or thereafter while receiving tislelizumab monotherapy will be permitted to continue tislelizumab 
monotherapy provided that they meet all the following additional criteria, and upon discussion and 
agreement with the medical monitor: 
1. 
Evidence of clinical benefit as assessed by the investigator 
2. 
Absence of symptoms and signs (including clinically significant worsening of laboratory values [eg, 
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3. 
No decline in Eastern Cooperative Oncology Group (ECOG) performance status that can be 
attributed to disease progression 
4. 
Absence of tumor progression at critical anatomical sites (eg, central nervous system [CNS] disease) 
that cannot be managed by protocol-allowed medical interventions 
5. 
Patients must provide written consent to acknowledge deferring other treatment options in favor of 
continuing study treatment at the time of initial progression 
The decision to continue tislelizumab beyond investigator-assessed progression must be documented in 
the study records. 
Patients may continue tislelizumab until loss of clinical benefit as assessed by the investigator, withdrawal 
of consent, study termination by the sponsor, start of a new anticancer therapy, or death, whichever occurs 
first. 
For Arm B (Control arm): 
Patients who develop radiographic disease progression per RECIST v1.1 at an initial or, if continued 
treatment, at the time of repeat computed tomography (CT) scan, will be given the option to cross over to 
receive tislelizumab monotherapy (Section 7.4), provided that disease progression has been confirmed by 
the IRC and as long as the following criteria are met: 
1. 
ECOG performance status ≤ 1 
2. 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (eg, CNS 
disease) that cannot be managed by protocol-allowed medical interventions 
3. 
Patient provided written consent to acknowledge that tislelizumab is an experimental treatment used 
after failure of prior first-line platinum-containing regimen 
Crossover is optional and is at the discretion of the investigator and with the sponsor’s agreement. 
For Both Arms: 
Once patients are receiving tislelizumab monotherapy, the investigator may consider continuing 
tislelizumab monotherapy beyond investigator-assessed progression, provided that patients meet the above 
outlined criteria, and upon discussion and agreement with the medical monitor. 
The decision to continue tislelizumab beyond investigator-assessed progression must be documented in 
the study records. 
Patients may continue tislelizumab until loss of clinical benefit as assessed by the investigator, withdrawal 
of consent, study termination by the sponsor, start of a new anticancer therapy, or death, whichever occurs 
first. 
A Steering Committee consisting of qualified investigators will be implemented to support the study and 
structure the scientific input. 
Safety monitoring and interim efficacy data review will be performed by an Independent Data Monitoring 
Committee (IDMC). The first safety monitoring and review will occur after the first 30 patients recruited 
have been on treatment for ≥ 1 month or completed at least 1 cycle of study treatment. Thereafter, the 
IDMC will review data approximately every 6 months, or more frequently if indicated or requested by the 
medical monitor based on ongoing safety monitoring of patients on study. The IDMC may recommend 
study modification including early termination of the study due to safety concerns, or for evidence of 
compelling efficacy at a preplanned interim analysis. A formal interim analysis for PFS in an ITT analysis 
set is planned after approximately 70% of the targeted events in the ITT analysis set have been observed. 
The early stopping rule for the interim analysis will be set for superiority. The function and membership of 
the IDMC will be described in the IDMC charter.  


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The study is a double-blind, placebo-controlled, randomized, and multicenter study. 
Study Assessments: 
Patients will undergo tumor assessments at baseline and every 6 weeks (± 7 days) for the first 6 months, 
every 9 weeks (± 7 days) for the remainder of Year 1, and every 12 weeks (± 7 days) from Year 2 onwards 
based on RECIST v1.1, regardless of dose delays to manage toxicities. After completion of the Week 52 
tumor assessment, tumor assessment will continue every 12 weeks. Patients will undergo tumor 
assessments until radiographic disease progression per RECIST v1.1, or loss of clinical benefit (for 
tislelizumab-only patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), or the second radiographic disease progression per RECIST v1.1 (for patients randomized 
to Arm B who cross over to receive tislelizumab after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by sponsor, start of a new anticancer therapy, or 
death, whichever occurs first.  
Patients who discontinue treatment for reasons other than radiographic disease progression (eg, toxicity) 
will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, loss to follow-up, study termination by sponsor, start of a new anticancer therapy, 
or death, whichever occurs first. 
To determine the pharmacokinetic (PK) properties of tislelizumab and host immunogenic response to 
tislelizumab, blood samples will be collected at various timepoints as outlined in Appendix 1. 
Patients will be evaluated for adverse events (AEs) and immune-mediated adverse events (imAEs) (all 
grades according to NCI-CTCAE v5.0). Serious adverse events (SAEs) and any AE that lead to treatment 
discontinuation will be followed and documented until the event resolves, the investigators assess the 
event as stable, or the patient is lost to follow-up, whichever occurs first. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to the study drug, will be 
reported until either 30 days after last dose of study treatment (including chemotherapy) or initiation of 
new anticancer therapy, whichever occurs first. All imAEs (serious or nonserious) should be reported up 
to 90 days after the last dose of tislelizumab (or placebo), regardless of whether 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 should be reported regardless of time since the last dose of treatment. 
Duration of Patient Participation: 
The duration of the study from first enrolled patient to final analysis for PFS is estimated to be 
approximately 21.5 months. 
Study Population:  
The study will enroll approximately 256 patients who meet the following inclusion/exclusion criteria, with 
approximately 128 patients each in Arm A (tislelizumab combined with gemcitabine + cisplatin) and Arm 
B (placebo + gemcitabine + cisplatin) at a 1:1 randomization ratio. 
Key Eligibility Criteria: 
The population under study are adult patients (18 to 75 years old on the day the patient voluntarily agrees 
to participate in the study) with histologically or cytologically confirmed NPC with recurrence or 
metastasis. Patients must be able to provide fresh or archival tumor tissues (formalin-fixed paraffin-
embedded [FFPE] blocks or approximately 10 [≥ 5] freshly cut unstained FFPE slides) with an associated 
pathological report. In the absence of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion at 
baseline is mandatory. Patients must have an ECOG performance status of ≤ 1. Patients must have ≥ 1 
measurable lesions as defined per RECIST v1.1 and must be treatment-naive for NPC with recurrence or 
metastasis. Patients who have received prior neoadjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for nonmetastatic disease must have experienced a treatment-free 


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interval of ≥ 6 months from the last dose of chemotherapy and/or radiotherapy prior to randomization. 
Patients who have received prior neoadjuvant chemotherapy regimen for ≥ 4 cycles are excluded. Patients 
who have received prior treatment with therapies targeting PD-1 or PD-L1 are excluded. Patients must 
have a life expectancy of ≥ 12 weeks. Patients must have adequate organ function as indicated by the 
screening laboratory values (obtained within 7 days prior to randomization) described in Section 4.1. 
Test Product, Dose, and Mode of Administration:  
Tislelizumab will be administered at a dose of 200 mg intravenously (IV) once every 3 weeks (Q3W). 
Reference Therapy, Dose, and Mode of Administration:  
Cisplatin: 80 mg/m2, Day 1 of each cycle, administered as an IV infusion for over 4 hours if possible or 
with proper infusion time based on local clinical guidelines or clinical practice according to the treating 
physician’s clinical judgment for 4 to 6 cycles. 
Gemcitabine: 1 g/m2, Day 1, Day 8 of each cycle, administered as an IV infusion within 30 minutes, for 
4 to 6 cycles. 
Statistical Methods: 
Analysis Sets: 
The ITT analysis set includes all randomized patients. Patients will be analyzed according to their 
randomized treatment arms. This will be the primary analysis set for all efficacy analysis, including 
analyses of PFS and OS endpoints.   
The Safety analysis set includes all randomized patients who received any dose of any component of study 
drug; it will be the analysis set for the safety analyses. Patients will be analyzed according to the actual 
treatment regimen received. 
The PK analysis set includes all patients who receive any dose of tislelizumab per the protocol, for whom 
any postdose PK data are available. 
The Immunogenicity analysis set includes all patients who receive any dose of tislelizumab for whom both 
baseline ADA and ≥ 1 postbaseline ADA results are available. 
Primary Efficacy Endpoint Analysis: 
PFS as assessed by the IRC: 
PFS per the IRC is defined as the time from randomization to the first documented disease progression as 
assessed by the IRC with the use of RECIST v1.1, or death from any cause, whichever occurs first. PFS 
will be analyzed in the ITT analysis set. Actual tumor assessment visit date will be used to calculate PFS.  
PFS per the IRC will be compared between tislelizumab + gemcitabine + cisplatin (Arm A) and placebo + 
gemcitabine + cisplatin (Arm B) at a 1-sided α of 2.5% using stratified log-rank test methodology. The 
hypothesis test is formed as follows:  
The null hypothesis to be tested is: 
H0: PFS in Arm A ≤ PFS in Arm B 
Against the alternative hypothesis: 
Ha: PFS in Arm A > PFS in Arm B 
The p-values from a stratified log-rank test will be presented using stratification factors with actual values 
as recorded in the electronic data capture (EDC) system at randomization. The hazard ratio (HR) for PFS 
will be estimated using a stratified Cox regression model, respectively. The 95% confidence interval [CI] 
for the HR will be provided. Unstratified analysis will also be presented. Kaplan-Meier methodology will 


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be used to estimate median PFS for each treatment arm, and a Kaplan-Meier curve will be constructed to 
provide a visual description of the difference among arms.  
Secondary Efficacy Endpoint Analyses: 
Objective response rate per the IRC  
ORR (confirmation not required according to RECIST v1.1) is the proportion of patients who had CR or 
PR per RECIST v1.1 in all randomized patients with measurable disease at baseline. The difference in 
ORR between arms in the ITT analysis set will be evaluated using the Cochran-Mantel-Haenszel chi-
square test with the actual stratification factors as strata. The two-sided 95% CIs for the odds ratio and the 
difference in ORR will be calculated, as well as Clopper-Pearson 95% CIs for the ORR within each arm. 
Duration of response per the IRC 
DOR is defined as the time from the first documented objective response to documented disease 
progression using RECIST v1.1, or death from any cause, whichever occurs first. DOR will be estimated 
using Kaplan-Meier methodology. Comparison between Arm A and Arm B will be made using the 
stratified and unstratified log-rank test for descriptive purposes only.  
Overall survival  
OS is defined as the time from randomization to death from any cause. OS will be analyzed in the ITT 
analysis set.  
Similar methodology used to evaluate PFS per the IRC will be applied to OS analysis. 
Progression-free survival per the investigator 
PFS per the investigator is defined as the time from randomization to the first objectively documented 
disease progression, or death from any cause, whichever occurs first, as determined per RECIST v1.1 in 
an ITT analysis set.  
Similar methodology used to evaluate PFS per the IRC will be applied to analysis of PFS per the 
investigator. 
Second progression-free survival per the investigator 
Analysis of progression-free survival after next line of treatment (PFS2), defined as the time from 
randomization to second/subsequent disease progression after initiation of new anticancer therapy, or 
death from any cause, whichever occurs first, will be carried out. Patients alive and for whom a second 
objective disease progression has not been observed will be censored at the last time known to be alive 
and without second objective disease progression. Descriptive analysis of PFS2 will be performed as 
needed. 
Health-related quality of life  
HRQoL is measured via PRO questionnaires using the EORTC QLQ-C30 and EORTC QLQ-H&N35. 
Descriptive statistics analysis of time to deterioration (TTD) will be performed and the results will be used 
for comparisons between Arm A and Arm B on the PRO endpoints. 
Safety Analyses: 
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v5.0. Laboratory 
values (eg, hematology, clinical chemistry, urinalysis), vital signs, electrocardiograms (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. 
Sample Size Considerations: 
The sample size calculation is based on the number of events required to demonstrate the PFS superiority 


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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 with regard to PFS are based on the following 
assumptions: 
1. 
Median PFS of 7 months in Arm B. 
2. 
At a 1-sided α of 0.025, 82% power to detect a HR of 0.65, corresponding to an improvement in 
median PFS from 7 months to 10.8 months, in the PFS of A versus B comparison. 
3. 
Randomization ratio: 1:1. 
4. 
PFS evaluation dropout rate of 5% per 12 months. 
5. 
A steady-state enrollment rate of 20 patients per month and enrollment ramp up duration of three 
months, ie, enrollment rate of 5 patients per month from study month 0 to month 1, 10 patients per 
month from month 1 to 2, 15 patients per month from month 2 to month 3, and 20 patients per month 
afterwards. 
6. 
One interim analysis is planned when approximately 70% of total PFS events occurred, with 
Lan-DeMets O'Brien-Fleming approximation spending function. 
With these assumptions, a total of 181 PFS events are required for final analysis of PFS. 
Assuming 256 patients are to be enrolled over a 14.3-month period, the final analysis will occur at 
approximately 21.5 months after the first patient is randomized. 
Sample size is calculated by EAST (version 6.0). 
Interim Analyses: 
There will be one interim efficacy analysis of PFS performed in the ITT analysis set. The interim efficacy 
analysis will be performed when approximately 127 PFS events (70% of the target number of 181 PFS 
events) are observed. It is estimated that it will take approximately 15.6 months to reach time of interim 
analysis. The interim boundary for each comparison is based on Lan-DeMets O'Brien-Fleming 
approximation spending function. The interim and final analysis timing, and stopping boundaries are 
summarized in Section 9.7, Table 7. 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BICR 
Blinded Independent Central Review 
CI 
confidence interval 
CL 
clearance 
CNS 
central nervous system 
CR 
complete response 
CSR 
Clinical Study Report 
CT 
computed tomography 
CPI 
checkpoint inhibitor 
CYP 
cytochrome P-450 
DCR 
disease control rate 
DOR 
duration of response 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
EORTC QLQ-H&N35 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Head and Neck-35 modules 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G (eg, IgG1, IgG2, IgG3, IgG4); other types of immunoglobulins 
include IgD and IgM  
imAE 
immune-mediated adverse event 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPC 
nasopharyngeal cancer 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PS 
performance status 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
t1/2 
half-life  
TEAE 
treatment-emergent adverse event 
TTR 
time to response 
ULN 
upper limit of normal 


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1. 
INTRODUCTION 
1.1. 
Background Information on Nasopharyngeal Cancer  
Nasopharyngeal cancer (NPC), while uncommon worldwide with a crude incidence of less than 
1 per 100,000 persons year in western countries, is endemic in Southern China, Southeast Asia, 
and the Middle East/North Africa with an incidence approaching 30 cases per 100 000 people. 
NPC remains an important cause of death from cancer with a global incidence of mortality of 
approximately 50,000 cases per year (Chang and Adami 2006; World Health Organization: 
GLOBOCAN 2012; Tang et al 2016).  
Depending on the degree of differentiation NPC is categorized into three pathological subtypes 
on the basis of WHO criteria. Differentiated tumors with surface keratin are defined as type I, 
whereas types II and III refer to non-keratinizing differentiated and undifferentiated tumors, 
respectively. In 1991, types II and III were combined into a single category of non-keratinizing 
carcinoma. In regions where NPC is endemic, nonkeratinizing subtypes constitute most cases 
(> 95%) and are invariably associated with Epstein-Barr virus (EBV) infection, whereas type I 
disease is more common in other parts of the world (Wang et al 2013; Wei and Sham 2005; 
Nicholls 1997). EBV infection is the most extensively studied etiological factor for NPC. On the 
basis of in situ hybridization techniques for EBV-encoded RNAs, the virus is detected 
exclusively in all tumor cells but not in normal nasopharyngeal epithelium, suggesting that EBV 
activation is necessary in the pathogenesis of NPC (Pathmanathan et al 1995; Chan et al 2000). 
The incidence and mortality rate of NPC have decreased in several endemic areas, possibly as a 
result of lifestyle changes, and advances in management, including improvement of radiotherapy 
technology, broader application of chemotherapy, and more accurate disease staging (Lau et al 
2013; Hsu et al 2006). Current therapeutic decisions are based mainly on disease stage (NCCN 
guidelines 2018; Chan et al 2012): Stage I disease are treated with radiotherapy alone; Stage II 
disease are treated with radiotherapy with or without concurrent chemotherapy; Stage III to IVb 
disease are treated with radiotherapy and concurrent chemotherapy. Local and regional control of 
nearly 90% at 3 years after treatment for stage III-IVb NPC can be achieved (Kam et al 2007; 
Lee et al 2009; Ng et al 2014; Tham et al 2009; Peng et al 2012; Zhong et al 2017). However, 
between 17-54% of patients with NPC fail treatment due to distant metastases and approximately 
one third of patients presented with disseminated disease at Stage IVc primary diagnosis (Liu et 
al 2003; Lee et al 1992; Chiesa and De Paoli 2001; Ng et al 2014; Sun et al 2014; Lee et al 
2015). Most recurrent cases are not amenable to salvage therapy with surgery and/or 
radiotherapy with or without concurrent chemotherapy. Treatment options for the majority of 
patients with NPC with recurrence or metastasis are largely limited to palliative systemic 
therapies (Lee et al 2015). For patients with stage IVc and recurrent disease, the reported 
progression-free survival (PFS) was 7 months, and overall survival (OS) was 20-29 months, 
respectively (Boussen et al 1991; Au and Ang 1994; Yeo et al 1998; Taamma et al 1999; Ngan 
et al 2002; Chua et al 2005; Li et al 2008; Ma et al 2009; Chan 2010). 
High plasma EBV DNA levels are a poor prognostic factor (Lin et al 2004) and the dynamic 
change of plasma EBV DNA after chemotherapy or chemoradiotherapy correlates with treatment 
efficacy (An et al 2011). In addition, EBV DNA levels are also useful for assessing treatment-
response and detecting disease relapse after radiotherapy (Lo et al 1999a; Lo et al 1999b; Lo et al 


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2000; Chan et al 2002). Novel prognostic markers using genetic signatures and microRNA have 
also shown promising results (Liu et al 2012; Wang et al 2011). 
1.2. 
Current Treatment of NPC With Recurrence or Metastasis 
1.2.1. 
Chemotherapy 
The unique geographic distribution and low overall incidence of this disease has presented 
challenging obstacles for the development of new agents and treatment options assessment for 
patients with recurrent or metastatic NPC in Phase 3 randomized clinical trials. Cisplatin and 
fluorouracil have been the conventional choices achieving response rates of 70-80% while 
cisplatin-based doublets that include combination with 5-FU, paclitaxel, docetaxel, gemcitabine 
have been demonstrated as effective regimens (reported response rate range between 60-74%) 
which are well tolerated as first-line chemotherapy for patients with recurrent or metastatic NPC 
(Jin et al 2012).  
A randomized Phase 3 clinical trial comparing two platinum-based combination chemotherapy 
regimens in the first-line setting for NPC with recurrence or metastasis reported improved 
median OS for gemcitabine plus cisplatin (GP) compared to fluorouracil plus cisplatin (FP): 29.1 
months versus 20.9 months (hazard ratio [HR]= 0.62 [95% CI: 0.45-0.84]; p = 0.0025]. The 
reported PFS for GP versus FP is 7 months versus 5.6 months (HR = 0.55 [95% CI: 0.44-0.68]; 
p < 0.001). Overall, both treatment regimens were well tolerated with predictable toxic profiles 
and low rates of discontinuation (Zhang et al 2016). 
The standard treatment for this patient population is platinum-based doublet chemotherapy 
(NCCN Guidelines 2018). However, very poor outcomes have been observed, with a median OS 
of about 20 months (Wei and Sham 2005). Therefore, improvements in clinical outcomes are 
needed for metastatic patients and for patients unsuitable for radiotherapy (Lee et al 2016; Zhang 
et al 2016). 


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Table 1. 
Chemotherapy for the Treatment of Advanced or Metastatic 
Nasopharyngeal Cancer 
Study 
Zhang et al 2016 
Chua et al 
2005 
Leong et al 
2008 
Patient number 
N = 362 
N = 19 
N = 28 
Treatment 
Gemcitabine + 
cisplatin 
(n = 181) 
Fluorouracil + 
cisplatin 
(n = 181) 
Docetaxel + 
cisplatin 
(n = 19) 
Gemcitabine + paclitaxel + 
carboplatin 
(n = 28) 
OS (months) 
29.1  
20.9 
12.4 
22 
HR (95% CI) 
0.62 (0.45-0.84); p = 0.0025 
NA 
NA 
mPFS (months) 
7.0 
 (4.4-10.9) 
5.6 
 (3.0-7.0) 
5.6 
8 
HR (95% CI) 
0.55 (0.44-0.68); p < 0·0001 
NA 
NA 
ORR (%) 
64 
42 
62.5 
86 
p-value 
p < 0.001 
NA 
NA 
TEAE ≥ Grade 3 (%) 
43 
36 
NA 
NA 
Abbreviations: HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; 
TEAE, treatment-emergent adverse event.  
1.2.2. 
Checkpoint Inhibitor 
The availability of checkpoint inhibitors (CPIs) bringing promising and effective treatment for 
melanoma (Wolchok et al 2013), renal cell carcinoma (Motzer et al 2015), lung cancer (Reck 
et al 2016) has expanded the development of new treatment strategy for NPC. Programmed cell 
death protein ligand-1 (PD-L1) expression is reported to occur in 89% to 95% of NPC tumors, 
with greater than 50% of tumor cells staining positive for PD-L1 in the majority of these tumors 
and a positive correlation of PD-L1 expression with clinical outcomes in NPC patients had been 
observed (Fang et al 2014; Zhang et al 2015; Chen et al 2013). In a Phase 1b trial that enrolled 
27 patients with recurrent NPC harboring tumors with ≥ 1% PD-L1 expression tumors, the 
patients received pembrolizumab monotherapy. Of the 27 patients, 70.4% had received 3 or more 
prior therapies. Partial response (PR) and stable disease (SD) were observed in 7 and 14 patients, 
respectively, for an objective response rate (ORR) of 25.9% (95% CI, 11.1 to 46.3) over a 
median follow-up of 20 months (Hsu et al 2017); nivolumab also demonstrated ORR of 20.5% 
with 1-year OS rate of 59% (95% CI, 44.3% to 78.5%) and 1-year PFS rate was 19.3% (95% CI, 
10.1% to 37.2%) (Ma et al 2018). Preliminary antitumor activity of camrelizumab (SHR-1210, a 
programmed cell death-1 [PD-1] inhibitor) in Chinese patients with recurrent or metastatic NPC 
had been reported in two Phase 1 studies. The first trial tested camrelizumab monotherapy in 93 
patients who received at least one previous line of treatment for NPC with recurrence or 
metastasis, where an ORR of 34% (95% CI, 24% to 44%) was observed and 2 patients had a 
complete response (CR). The second trial tested camrelizumab in combination with gemcitabine 
and cisplatin as a first-line treatment in 23 treatment-naive patients, where an ORR of 91% (95% 
CI, 77% to 97%) was reported and 1 patient had a CR. Both trials showed good safety profiles 


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with no treatment-related deaths observed. These are the most promising results reported so far 
for PD-1 inhibitors tested in NPC (Fang et al 2018). Collectively, these preliminary results 
arising from both tumor antigen-specific and agnostic immunotherapeutic strategies favor the 
notion of EBV-positive NPC as a highly immune-enriched tumor, and therefore supports 
extending the consideration of immunotherapy in combination with chemotherapy in treatment-
naïve metastatic NPC.  
1.3. 
Background Information on Tislelizumab 
1.3.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD] = 0.15 nM). It competitively blocks binding 
efforts by both PD-L1 and programmed cell death protein ligand-2, 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 
preactivated, primary peripheral blood mononuclear cells. In addition, tislelizumab has 
demonstrated antitumor activity in several allogeneic xenograft models, in which peripheral 
blood mononuclear cells were coinjected with human cancer cells (A431 [epidermoid 
carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into immunocompromised mice.  
The IgG4 variant antibody has very low binding affinity to gamma fragment crystallizable region 
(Fc) receptor IIIA (FcγRIIIA) and complement 1q, a subunit of complement 1, by in vitro assays, 
suggesting either low or no antibody-dependent cellular cytotoxicity (ADCC) or complement-
dependent cytotoxicity (CDC) effects in humans (Labrijn et al 2009). 
Please refer to the tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.3.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and monkeys and in a 13-week repeat dose toxicology study in cynomolgus 
monkeys. The tissue cross-reactivity was evaluated in the normal frozen tissues from both 
humans and monkeys. The cytokine release assays were also evaluated using fresh human whole 
blood cells. The pivotal toxicology studies were conducted following Good Laboratory Practice 
(GLP) regulations. The single dosing regimens spanned from the intended human doses to 10-
fold higher than the maximum of the intended human doses, and the repeat dosing regimens 
spanned to 3-fold higher than the maximum of the intended human doses. The 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 monkey toxicity studies. No tissue cross-
reactivity was found in either human or monkey tissues, nor was any effect on cytokine release 
observed in human whole-blood assay. The toxicokinetics profile was well characterized with 


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dose proportional increases in systemic exposure without apparent accumulation or sex 
difference. Immunogenicity was observed without apparent immunotoxicity or effect on the 
systemic exposure. The No-Observed-Adverse-Effect-Level of tislelizumab in the 13-week 
monkey toxicity study was considered to be 30 mg/kg. The safety profile of tislelizumab is 
considered adequate to support the current study BGB-A317-309. 
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.3.3. 
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 by noncompartmental methods, 
using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, 10 mg/kg once 
every 2 weeks (Q2W) and 2.0 mg/kg, 5.0 mg/kg, 200 mg once every 3 weeks (Q3W) (Phase 1a 
Parts 1, 2, and 3, and Phase 1b in BGB-A317_Study_001) and patients who received doses of 
200 mg Q3W in Phase 1 of Study BGB-A317-102 (n = 19). The maximum observed plasma 
concentration (Cmax) and the area under the plasma or serum concentration-time curve increased 
in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both after single-dose 
administration at steady state. Preliminary PK data from 27 patients who were administered 1 
dose of 200 mg Q3W (Phase 1a, Part 3 and Study BGB-A317-102) showed tislelizumab 
concentrations between the range of concentrations observed for patients who were administered 
2 mg/kg and 5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first order elimination 
shows a systemic plasm clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution in 
the central and peripheral compartments of 2.89 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 CL 
of tislelizumab, which supports fixed-dosing across different ethnic groups. 
1.3.4. 
Prior Clinical Experience of Tislelizumab 
As of 20 May 2020, there are currently 28 ongoing studies with tislelizumab with over 
1917 patients treated. Of these, 15 studies have preliminary data available in the Investigator’s 
Brochure (IB) version 8, dated 10 September 2020: 7 monotherapy studies, 2 chemotherapy 
combination therapy studies, and 6 targeted therapy combination studies. Of the ongoing 
monotherapy studies in solid tumors, available data from BGB-A317_Study_001 and BGB-
A317-102 are summarized in Section 1.3.4.1 and Section 1.3.4.2 (with a clinical cutoff date of 
28 August 2017).  
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on efficacy 
and safety of tislelizumab. 
1.3.4.1. 
BGB-A317_Study_001 (Data cutoff 28 August 2017) 
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts: to establish the maximum tolerated dose, if any; a 
recommended Phase 2 dose (RP2D) for the Phase 1b; and a flat dose (fixed dose); followed by a 


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Phase 1b component to investigate efficacy in select tumor types in indication expansion arms 
and to further evaluate safety and tolerability of tislelizumab.  
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens 
including 0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg Q2W; 2 mg/kg or 5 mg/kg Q3W; and 
200 mg Q3W. In Phase 1b, 323 patients had received tislelizumab in Phase 1b across 
9 indication-expansion cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the 
population was male, and 65.6% of patients were white. The median number of prior anticancer 
therapy regimens was 2 (range: 0 to 12). The median treatment exposure duration was 2.50 
months (range: 0 to 23.0) and the median study follow-up duration was 5.56 months (range: 0.0 
to 26.9).  As of 28 August 2017, there were 210 patients (47.8%) remaining on study in Study 
BGB-A317_Study_001.   
Preliminary Safety 
Of the 439 total patients in the Safety Population for BGB-A317_Study_001, 240 (54.7%) 
experienced at least 1 treatment-emergent adverse event (TEAE) assessed as related to 
tislelizumab by the Investigator and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE. 
The most commonly occurring related TEAEs for patients treated with the tislelizumab 
monotherapy in BGB-A317_Study_001 were fatigue (12.8%), rash (7.7%), nausea (6.8%), 
diarrhea (6.6%), and hypothyroidism (4.8%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 
patients were pneumonitis (6 patients, 1.4%); colitis and alanine aminotransferase (ALT) 
increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate 
aminotransferase (AST) increased (3 patients each, 0.7%); and diarrhea, 
gamma-glutamyltransferase (GGT) increased, and diabetic ketoacidosis (2 patients each, 0.5%). 
All other events occurred in single patients.  Lastly, 18 patients (4.1%) experienced an infusion-
related reaction; all were mild/moderate in severity.  
Preliminary Efficacy 
For patients in Phase 1a (n = 116, evaluable), there were 20 patients with a confirmed response 
and 42 patients with a best overall response (BOR) of SD.  
For patients in Phase 1b (n = 286 evaluable), a total of 26 patients had a confirmed response. 
Additionally, there were 101 patients with a BOR of SD.  
1.3.4.2. 
Study BGB-A317-102 (Data cutoff 28 August 2017) 
This Phase 1/2 study was a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.  
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of 
the population was male, and 100% of patients were Asian (Chinese). The median number of 
prior anticancer therapy regimens was 2 (range: 0 to 9). The median treatment exposure duration 
was 1.78 months (range: 0 to 8.0) and the median study follow-up duration was also 1.78 months 
(range: 0.0 to 8.0). As of 28 August 2017, there were 113 patients (91.9%) remaining on study in 
Study BGB-A317-102. 


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Preliminary Safety 
Of the 123 total patients in the Safety Population for Study BGB-A317-102, 69 (56.1%) 
experienced at least 1 TEAE assessed as related to tislelizumab by the investigator and 10 (8.1%) 
were ≥ Grade 3 in severity. The most commonly occurring related TEAEs were aspartate 
aminotransferase (AST) increased (20 patients, 16.3%), alanine aminotransferase (ALT) 
increased (17 patients, 13.8%), and blood bilirubin increased and anaemia (13 patients each, 
10.6%).  The ≥ Grade 3 related TEAEs occurring in ≥ 2 patients were AST increased (3 patients, 
2.4%) and ALT increased (2 patients, 1.6%). All other events occurred in single patients 
including a case of retinal detachment (Grade 4). 
Preliminary Efficacy in NPC Patients 
As of 12 October 2018, 20 patients (including 17 males) were enrolled to the NPC cohort, with 
median age of 49 years (range: 7-61 years). The median number of prior systemic anticancer 
therapy regimens was 2.6 (range: 0 to 10). There were 10 patients (50%) remaining on study. 
Median duration of treatment is 25.5 weeks (range: 9-63). All patients were evaluable for 
response, 6 with a confirmed response, 2 with an unconfirmed response, and 10 patients with a 
BOR of SD. All patients had tumors with PD-L1 expression (data on file). 
1.3.4.3. 
Immune-Mediated Reactions 
In patients treated with tislelizumab monotherapy, the following immune-mediated adverse 
events (imAEs) were observed: 
• Acute hepatitis and abnormal liver function have been reported, including 1 patient with 
fatal hepatitis. Additionally, 3.2% of patients experienced treatment-related abnormal 
liver function tests, and 1.4% of patients experienced immune-mediated hepatitis or 
hyperbilirubinaemia. 
• Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal 
pneumonitis.  
• Colitis has been reported in 2% of patients treated. Diarrhea has been reported in 6.6% of 
patients.  
• Endocrinopathies have been reported including diabetes mellitus (hyperglycemia and 
ketoacidosis). In addition, thyroiditis, including thyrotoxicosis and hypothyroidism has 
been reported. Furthermore, hypophysitis has been reported in < 1% of patients treated.  
• Other immune-mediated events (<1% of patients with tislelizumab monotherapy except 
where noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); 
haemolytic anaemia, nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, 
pancreatitis, stomatitis, uveitis, and dry eye (1.4%). 


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Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in 
combination with paclitaxel and cisplatin (see tislelizumab Investigator’s Brochure). The 
patient’s initial symptoms were dyspnea and tea-colored urine 2 weeks after starting treatment. 
Elevated urine and serum cardiac and skeletal muscle enzymes were reported. The patient died 
of multi-organ failure 6 days later. 
1.4. 
Study Rationales  
1.4.1. 
Rationale for Gemcitabine Plus Cisplatin as the Comparator 
In 2016, Zhang et al (Zhang et al 2016) reported a phase 3 randomized clinical trial comparing 
the efficacy and toxicity of GP versus FP as first-line chemotherapy in NPC with recurrence or 
metastasis, which was the first head-to-head randomized study in this disease in recent era. It is 
reported that ORR was higher in the GP group (64% versus 42%, relative risk = 1.5 (95% CI, 
1.2-1.9), P < 0.0001) while DCR was similar for both groups (90% versus 86%). GP prolonged 
PFS (7.0 versus 5.6 months; hazard ratio = 0.55 (95% CI, 0.44-0.68), P < 0.0001). Meta-analysis 
showed ORR and DCR of GP and FP regimens are similar, while 1-year OS rate of GP regimen 
is a little lower than taxanes plus platinum regimen but higher than FP regimen. GP regimen 
prolongs PFS in patients with NPC with recurrence or metastasis (Ma et al 2018). The results 
establish GP as the standard ﬁrst-line treatment option for this population. 
1.4.2. 
Rationale for Tislelizumab in the Treatment of NPC With Recurrence or 
Metastasis  
The immune CPI programmed cell death protein-1 (PD-1) and its major ligand PD-L1 are 
overexpressed in NPC, contributing to immune evasion (Hsu et al 2010; Zhang et al 2015; Lee et 
al 2016; Zhou et al 2017). Tislelizumab disrupts PD-1-mediated signaling, restoring T-cell 
antitumor function. Immunotherapy is emerging as a new treatment modality with promising 
initial data and a robust breadth of ongoing trials. Efficacy with anti-PD-1 observed is yet limited 
with monotherapy pembrolizumab, nivolumab and JS001 showed efficacy in later line setting 
(Chiun et al 2017; Ma et al 2017; Wang et al 2017). Preliminary data of tislelizumab in NPC arm 
of study BGB-A317-102 is encouraging (refer to Section 1.3.4.2 for details). 
1.4.3. 
Rationale for Selection of Tislelizumab Dose in Combination With 
Chemotherapy 
The PK, safety, and efficacy data obtained from the first-in-human study BGB-
A317_Study_001, as well as other clinical study data, were analyzed in aggregate to determine 
the recommended dose for pivotal studies of tislelizumab. The flat dose of 200 mg IV Q3W was 
selected for further evaluation. 
Rates of treatment-related AEs and serious adverse events (SAEs) observed in patients receiving 
2 mg/kg and 5 mg/kg Q2W and Q3W were comparable, suggesting no clear dose-dependence 
across these regimens. Similarly, confirmed ORRs in patients treated with tislelizumab 2 mg/kg 
and 5 mg/kg Q2W ranged between 10% and 15%, compared to a range of 15% to 38% for 
patients treated at 2 mg/kg and 5 mg/kg Q3W. 


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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 SD, 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 Q3W. This also allows for a convenient integration with common 
chemotherapeutic regimens. 
The doses of all chemotherapy drugs are based on product labelling, literature, and local 
guidelines. Several Phase 1 and Phase 2 studies showed that the safety profile of anti PD-1 
antibodies in combination with carboplatin-based doublet chemotherapy was consistent with that 
expected in individual agents. There were no known overlapping, significant toxicities or drug–
drug interactions between anti-PD-1 antibodies and carboplatin or paclitaxel observed in these 
studies.  
Further, preliminary data from the ongoing Phase 2 BGB-A317-206 study which evaluates the 
combination of tislelizumab at the fixed dose of 200 mg Q3W with various chemotherapies at 
the dose of standard of care as treatment for first-line NSCLC (see tislelizumab Investigator’s 
Brochure) supports the dose and schedule. 
In conclusion, tislelizumab 200 mg Q3W is the recommended dose for combination with 
chemotherapy in this Phase 3 global safety study. 
1.4.4. 
Rationale for Matched Placebo in Combination With Chemotherapy as the 
Comparator 
The comparator arm (Arm B) will consist of a chemotherapy doublet in combination with the 
matched placebo and compared to the same chemotherapy in combination with the study drug 
tislelizumab. The “matched” placebo will contain the same composition as the solution for the 
active drug (tislelizumab), except that no active drug will be present in the formulation. The 
placebo will be used to preserve the scientific integrity of the study and reduce any potential 
observational or assessment bias. Patients in the placebo arm (Arm B) will still receive the 
recommended chemotherapy doublet for this patient population, minimizing the risk generally 
associated with placebo-alone arms in controlled studies.  
1.4.5. 
Rationale for Primary Endpoint of Progression-free Survival as Assessed by the 
Independent Review Committee 
PFS as an endpoint can reflect tumor growth and can be assessed before the determination of a 
survival benefit; in addition, its determination is generally not confounded by subsequent 
therapies. 
Whether an improvement in PFS represents a direct clinical benefit or a surrogate for clinical 
benefit depends on the magnitude of the effect and the benefit-risk of the new treatment 
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New treatment modalities, such as targeted therapies and immunotherapy as monotherapy in 
patients with highly expressing PD-L1 tumors or in combination with chemotherapy (Langer et 
al 2016), are emerging as highly effective regimens that are providing improvements in patient 
outcomes far beyond what has been achieved before (Ellis et al 2014). In particular, 
immunotherapy has been correlated or associated with durable responses, significant 
prolongation of PFS, and improvement of quality of life (Langer et al 2016).  
The subjectivity in the measurement of PFS assessments is acknowledged with the fact that the 
assessment depends on frequency, accuracy, reproducibility, and completeness, and may affect 
the observed magnitude of effect and carry the risk of bias. Therefore, tumor assessment by the 
IRC per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, scheduled every 6 weeks 
for the first 6 months, every 9 weeks for the remainder of Year 1, and every 12 weeks from Year 
2 onwards, regardless of treatment delay until disease progression, is to be implemented in this 
study to ensure lack of bias when comparing Arm A versus Arm B. 
1.4.6. 
Rationale for Plasma EBV DNA Measurement 
The quantitative real-time polymerase chain reaction method has already been developed to 
measure the plasma EBV DNA level (Lo et al 2000). A direct relationship between tumor load 
and plasma EBV DNA concentration is established in NPC patients, therefore it is reasonable to 
deduce that the change of plasma EBV DNA level would be useful to predict clinical benefit of 
NPC patients after different therapy (Ma et al 2006). Furthermore, pretreatment plasma EBV 
DNA was discovered as prognostic biomarker for overall disease-free survival in a previous 
study (Leung et al 2006). In this study, we will explore the plasma EBV level as a surrogate 
biomarker for antitumor efficacy prediction, and whether plasma EBV DNA could become a 
predictive biomarker for PD-1/PD-L1 treatment. 
1.4.7. 
Rationale for Allowing Patients to Continue Tislelizumab Until Loss of Clinical 
Benefit 
Conventional response criteria may not adequately assess the activity of immunotherapeutic 
agents because progressive disease (determined by initial radiographic evaluation) does not 
necessarily reflect therapeutic failure. A recent retrospective analysis of the Phase 3 OAK study 
evaluated 332 NSCLC patients who experienced disease progression per RECIST v1.1 while 
being treated with atezolizumab (Gandara et al 2017). The results showed that 51% (n = 168) 
continued treatment with atezolizumab beyond progression. Of those 7% (12/168) achieved 
subsequent response in target lesions (≥ 30% reduction from new baseline at disease 
progression) and 49% (83/168) had stable target lesions (best change between +20% and -30%). 
Median OS was 12.7 months (95% CI: 9.3, 14.9) post progressive disease for patients on 
atezolizumab treatment beyond progression, with a tolerable safety profile. That is in contrast to 
median OS of 8.8 months (95% CI: 6.0, 12.1) and 2.2 months (95% CI: 1.9, 3.4) for patients who 
either received other (n = 94, 28%) or no anticancer treatment (n = 70, 21%), respectively, at the 
time of progression. These data suggest considerable benefit from continued immunotherapy 
treatment past disease progression, which may include patients with recurrent or metastatic NPC. 
Recent results from Phase 1-2 trials reported manageable safety profiles and favorable antitumor 
activities (ORR ranged from 20.5% to 43%) of anti-PD-1 drugs, such as pembrolizumab, 
nivolumab, camrelizumab, toripalimab, and tislelizumab, in patients who have NPC with 


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recurrence or metastasis and have failure on ≥ 1 line of platinum-based chemotherapies (Hsu et 
al 2017; Ma et al 2018; Fang et al 2018; Wang et al 2020; Wang et al 2019). These preliminary 
results arising from both tumor antigen-specific and agnostic immunotherapeutic strategies favor 
the notion of EBV-positive NPC as a highly immune enriched tumor, which supports extending 
the consideration of immunotherapy in previously treated patients who have NPC with 
recurrence or metastasis. 
This study will allow patients randomized to the tislelizumab in combination with chemotherapy 
treatment arm to remain on tislelizumab-containing treatment after apparent radiographic 
progression, provided the benefit-risk ratio is judged to be favorable. Patients should be 
discontinued for unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as assessed by the investigator after an integrated assessment of radiographic data 
and clinical status (Section 3.3). 
This study will allow patients randomized to the placebo in combination with chemotherapy 
treatment arm to have the opportunity to cross over to receive tislelizumab if they experience 
radiographic disease progression on chemotherapy; that is, if disease progression per RECIST 
v1.1 has been confirmed by the IRC and provided the benefit-risk ratio is judged to be favorable 
and approved by the medical monitor (Section 7.4). Patients should be discontinued for 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as assessed 
by the investigator after an integrated assessment of radiographic data and clinical status (Section 
3.3). 
1.4.8. 
Rationale for Selection of the Patient-Reported Outcome for Assessments of 
Health-Related Quality of Life 
Patient-reported outcomes (PROs) assessments have been shown to provide the most robust 
descriptions of the treatment experience, with the incorporation of multiple modes of endpoint 
measurements in clinical studies, and would supplement the data derived from clinically reported 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Dajczman et al 2008). With 
growing recognition of the importance of patient-centered care, PROs have also been reported to 
have positive effects on the well-being of patients with cancer (Basch et al 2016). Evidence of 
benefits of incorporating PROs in the chemotherapeutic setting, specifically in patients with lung 
cancer, would further characterize clinical benefit beyond radiographic measures.  
Two validated and frequently used PRO instruments have been selected: the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(QLQ-C30) to measure general cancer signs and symptoms, and its head and neck cancer 
module QLQ-H&N35 to measure nasopharyngeal-specific symptoms. 
1.5. 
Benefit-Risk Assessment 
Available data from clinical studies of other anti-PD-1 antibodies, such as nivolumab and 
pembrolizumab, have demonstrated favorable benefit/risk profiles in patients with advanced 
NPC (Chiun et al 2017; Ma et al 2017). Preliminary data of tislelizumab in an expansion cohort 
of patients with NPC in Study BGB-A317-102 is encouraging (refer to Section 1.3.4.2 for 
details). Preliminary data from the ongoing Phase 2 BGB-A317-206 study, which evaluates the 
combination of tislelizumab at the fixed dose of 200 mg Q3W with various chemotherapies at 


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the dose of standard of care as treatment for first-line lung cancer, supports the dose and 
schedule (Zhao et al 2018). 
As of 28 August 2017, 439 patients have been treated with tislelizumab monotherapy at 
clinically relevant doses (≥ 2 mg/kg) and in combination. Clinical activity with a manageable 
and tolerable safety profile is expected to be maintained in patients receiving tislelizumab 
200 mg Q3W. The safety profile is largely consistent with that of other anti-PD-1 antibodies and 
included mostly mild/moderate AEs. Very few Grade 3/4 imAEs have been observed and have 
been generally reversible and manageable with study drug interruption and/or steroid treatment. 
(For further information on the safety profile of tislelizumab, please refer to the Investigator’s 
Brochure.) Preliminary data from the ongoing Phase 2 BGB-A317-206 study, which evaluates 
the combination of tislelizumab at the fixed dose of 200 mg Q3W with various chemotherapies 
at the dose of standard of care as treatment for first-line lung cancer, including tislelizumab in 
combination with pemetrexed + platinum (n = 16), paclitaxel + platinum (n = 15), gemcitabine + 
platinum (n = 6), and etoposide + platinum (n = 17), supports the dose and schedule. As of 5 
June 2018, the median duration of treatment was 20 weeks; all 54 patients with lung cancer 
enrolled in the study were evaluated for response, with a total of 35 patients remaining on 
treatment. Among 54 evaluable NSCLC and small cell lung cancer patients, there were 29 
patients with a confirmed response and 17 patients with a BOR of SD. The safety profile of 
tislelizumab in combination with chemotherapy has been largely consistent with the known 
tolerability profile of PD-1 inhibitors in combination with chemotherapy (Zhao et al 2018). 
Therefore, the clinical development of tislelizumab, an anti-PD-1 antibody, in combination with 
chemotherapy, may improve upon outcomes for Chinese patients with advanced solid tumors, 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
• To compare the progression-free survival as assessed by the Independent Review 
Committee per RECIST v1.1 in an Intent-to-Treat analysis set between tislelizumab 
combined with gemcitabine + cisplatin and placebo + gemcitabine + cisplatin in 
patients with recurrent or metastatic nasopharyngeal cancer. 
2.1.2. 
Secondary Objectives  
• To compare objective response rate as assessed by the Independent Review 
Committee per RECIST v1.1 between tislelizumab combined with gemcitabine + 
cisplatin and placebo + gemcitabine + cisplatin. 
• To compare duration of response as assessed by the Independent Review Committee 
per RECIST v1.1 between tislelizumab combined with gemcitabine + cisplatin and 
placebo + gemcitabine + cisplatin. 
• To compare overall survival between tislelizumab combined with gemcitabine + 
cisplatin and placebo + gemcitabine + cisplatin in an Intent-to-Treat analysis set. 
• To compare progression-free survival as assessed by the investigator per RECIST 
v1.1 between tislelizumab combined with gemcitabine + cisplatin and placebo + 
gemcitabine + cisplatin in an Intent-to-Treat analysis set. 
• To evaluate the progression-free survival after next line of treatment as assessed by 
the investigator per RECIST v1.1 between patients who cross over to subsequent 
tislelizumab monotherapy after initial progression of disease and patients who do not 
cross over to subsequent tislelizumab monotherapy or other anti- PD-1/PD-L1 agents 
for patients who are randomized to placebo + gemcitabine + cisplatin arm. 
• To compare health-related quality of life between tislelizumab combined with 
gemcitabine + cisplatin and placebo + gemcitabine + cisplatin.  
• To evaluate the safety and tolerability of tislelizumab combined with gemcitabine + 
cisplatin compared with placebo + gemcitabine + cisplatin. 
2.1.3. 
Exploratory Objectives  
• To compare objective response rate as assessed by the investigator per RECIST v1.1 
between tislelizumab combined with gemcitabine + cisplatin and placebo + 
gemcitabine + cisplatin. 
• To compare duration of response as assessed by the investigator per RECIST v1.1 
between tislelizumab combined with gemcitabine + cisplatin and placebo + 
gemcitabine + cisplatin. 
• To compare tumor assessment outcomes (eg, disease control rate, time to response) 
between tislelizumab combined with gemcitabine + cisplatin and placebo + 
gemcitabine + cisplatin assessed by the investigator per RECIST v1.1. 


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• To evaluate the correlation between PD-L1 expression levels by 
immunohistochemistry and antitumor activity of tislelizumab combined with 
gemcitabine + cisplatin compared with placebo + gemcitabine + cisplatin. 
• To assess tumor and blood-based biomarkers of tislelizumab response, resistance and 
patient prognosis. To explore potential predictive biomarkers including any 
association with response to study treatment and mechanism(s) of resistance. 
• To characterize the pharmacokinetics of tislelizumab when given in combination with 
gemcitabine + cisplatin.  
• To assess host immunogenicity to tislelizumab. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
• PFS as assessed by the IRC: the time from randomization to the first objectively 
documented disease progression, or death from any cause, whichever occurs first, as 
assessed by the IRC per RECIST v1.1 in an ITT analysis set. 
2.2.2. 
Secondary Endpoints  
• ORR as assessed by the IRC: the proportion of patients who had CR or PR as 
assessed by the IRC per RECIST v1.1 in all randomized patients with measurable 
disease at baseline. 
• DOR as assessed by the IRC: the time from the first occurrence of a documented 
objective response to the time of relapse, or death from any cause, whichever comes 
first, as assessed by the IRC per RECIST v1.1 in all randomized patients with 
documented objective responses. 
• OS: the time from the date of randomization to the date of death due to any cause in 
an ITT analysis set. 
• PFS as assessed by the investigator: the time from randomization to the first 
objectively documented disease progression, or death from any cause, whichever 
occurs first, as assessed by the investigator per RECIST v1.1 in an ITT analysis set. 
• PFS2 as assessed by the investigator: the time from randomization to 
second/subsequent disease progression after initiation of new anticancer therapy, or 
death from any cause, whichever occurs first.  
• HRQoL is measured via PRO questionnaires using the EORTC QLQ-C30 and 
EORTC QLQ-H&N35. 
• Incidence and severity of TEAEs graded according to NCI-CTCAE v5.0. 


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2.2.3. 
Exploratory Endpoints 
• ORR as assessed by the investigator: the proportion of patients who had CR or PR as 
assessed by the investigator per RECIST v1.1 in all randomized patients with 
measurable disease at baseline. 
• DOR as assessed by the investigator: the time from the first occurrence of a 
documented objective response to the time of relapse, or death from any cause, 
whichever comes first, as assessed by the investigator per RECIST v1.1 in all 
randomized patients with documented objective responses. 
• DCR: the proportion of patients who had CR, PR, or SD as assessed by the 
investigator per RECIST v1.1. 
• Time to response: the time from randomization to the first occurrence of a 
documented objective response as assessed by the investigator per RECIST v1.1. 
• Evaluate biomarkers from patient derived tumor tissue(s) and/or blood (or blood 
derivatives) samples obtained before, during and/or after treatment. Candidate 
biomarkers may include, but are not limited to, PD-L1 expression, cytokines and 
soluble proteins in peripheral blood, immune cells subpopulation analysis in 
peripheral blood and tumor tissues, tumor mutation analysis and gene expression 
profiling. 
• Levels of circulating EBV DNA as potential surrogate biomarker for antitumor 
efficacy prediction with EBV-positive disease. 
• Summary of serum concentrations of tislelizumab. 
• Assessments of immunogenicity of tislelizumab by determining the incidence of 
antidrug antibodies. 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a double-blind, placebo-controlled, randomized, multicenter Phase 3 study designed to 
compare the efficacy and safety of tislelizumab combined with gemcitabine + cisplatin (Arm A) 
versus placebo + gemcitabine + cisplatin (Arm B) as first-line treatment in approximately 
256 patients who have NPC with recurrence or metastasis.  
The primary endpoint of the study is measured by PFS as assessed by the IRC in the ITT analysis 
set. 
Patients who have histologically or cytologically confirmed NPC with recurrence or metastasis 
are eligible.  
Eligible patients will be stratified by gender and metastatic status (with or without liver 
metastases), and randomized by a 1:1 ratio to receive one of the following treatment regimens: 
• Arm A: tislelizumab + gemcitabine + cisplatin 
• Arm B: placebo + gemcitabine + cisplatin  
Both Arm A and Arm B will be double blinded. 
The study schema is presented in Figure 1.  
 


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Figure 1. 
Study Schema 
 
Abbreviations: D, Day; DOR, duration of response; h, hour; IV, intravenously; min, minutes; N, number of patients; NPC, nasopharyngeal cancer; ORR, 
objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, progression-free survival after next line of treatment; QOL, quality of life; R, 
randomization ratio. 
Cisplatin: 80 mg/m2, Day 1, administered as an IV infusion for over 4 hours if possible or with proper infusion time based on local 
clinical guidelines or clinical practice according to the treating physician’s clinical judgment.  
Gemcitabine: 1 g/m2, Day 1 and Day 8, administered as an IV infusion within 30 minutes. 
For all study procedures see Appendix 1. 


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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. Patients who are suspected to have serious respiratory concurrent 
illness or exhibit significant respiratory symptoms unrelated to underlying cancer will also take a 
pulmonary function test (refer to Section 7.1.5 and Appendix 1 for details). Screening 
evaluations may be repeated as needed within the screening period; the investigator will assess 
preliminary patient eligibility according to the latest screening assessment results. 
3.3. 
Treatment Period 
Patients must be able to provide fresh or archival tumor tissues (formalin-fixed 
paraffin-embedded [FFPE] blocks or approximately 10 [≥ 5] freshly cut unstained FFPE slides) 
with an associated pathological report. In the absence of sufficient archival tumor tissues, a fresh 
biopsy of a tumor lesion at baseline is mandatory (Section 7.8). 
Treatment Period 
After completing all screening activities, patients confirmed to be eligible by the sponsor will be 
randomized.  
Administration of 4 to 6 cycles will be at the investigator’s discretion. Chemotherapy will be 
administered on a 3-week cycle until one of the following occurs (whichever occurs first): 
1) completion of administration of 4 to 6 cycles; 2) unacceptable toxicity; or 3) documented 
disease progression per RECIST v1.1. 
For all patients in Arm A and Arm B, if progression of disease is unconfirmed by the IRC and 
the patient is clinically stable, it is at the investigator’s discretion to continue treating the patient 
with the assigned treatment per protocol until progression of disease is confirmed at least 28 days 
(or at the next scheduled tumor assessment) from the date of the scan suggesting progression of 
disease. If a patient has confirmed progression of disease by RECIST v1.1, as assessed by the 
IRC, the patient should not receive further chemotherapy treatment on study, and unblinding will 
be performed. The following guidance should be followed. 
For Arm A (Experimental arm): 
Patients whose tumors show progressive disease per RECIST v1.1 during chemotherapy 
combination phase or thereafter while receiving tislelizumab monotherapy will be permitted to 
continue tislelizumab monotherapy provided that they meet all the following additional criteria, 
and upon discussion and agreement with the medical monitor: 
1. Evidence of clinical benefit as assessed by the investigator; 
2. Absence of symptoms and signs (including clinically significant worsening of laboratory 
values [eg, new, or worsening hypercalcemia]) indicating unequivocal progression of 
disease; 
3. No decline in ECOG performance status that can be attributed to disease progression; 
4. Absence of tumor progression at critical anatomical sites (eg, central nervous system [CNS] 
disease) that cannot be managed by protocol-allowed medical interventions; 


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5. Patients must provide written consent to acknowledge deferring other treatment options in 
favor of continuing study treatment at the time of initial progression. 
The decision to continue tislelizumab beyond investigator-assessed progression must be 
documented in the study records. 
Patients may continue tislelizumab until loss of clinical benefit as assessed by the investigator, 
withdrawal of consent, study termination by the sponsor, start of a new anticancer therapy, or 
death, whichever occurs first. 
For Arm B (Control arm): 
Patients who develop radiographic disease progression per RECIST v1.1 at an initial or, if 
continued treatment, at the time of repeat computed tomography (CT) scan, will be given the 
option to cross over to receive tislelizumab monotherapy (Section 7.4), provided that disease 
progression has been confirmed by the IRC and as long as the following criteria are met: 
1. ECOG performance status ≤ 1; 
2. Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, CNS disease) that cannot be managed by protocol-allowed medical interventions; 
3. Patient provided written consent to acknowledge that tislelizumab is an experimental 
treatment used after failure of prior first-line platinum-containing regimen. 
Crossover is optional and is at the discretion of the investigator and with the sponsor’s 
agreement. 
For Both Arms: 
Once patients are receiving tislelizumab monotherapy, the investigator may consider continuing 
tislelizumab monotherapy beyond investigator-assessed progression, provided that patients meet 
the above outlined criteria, and upon discussion and agreement with the medical monitor.  
The decision to continue tislelizumab beyond investigator-assessed progression must be 
documented in the study records. 
Patients may continue tislelizumab until loss of clinical benefit as assessed by the investigator, 
withdrawal of consent, study termination by the sponsor, start of a new anticancer therapy, or 
death, whichever occurs first. 
All patients will undergo tumor assessments at baseline and every 6 weeks (± 7 days) for the first 
6 months, every 9 weeks (± 7 days) for the remainder of Year 1, and every 12 weeks (± 7 days) 
from Year 2 onwards based on RECIST v1.1, regardless of dose delays to manage toxicities. 
After completion of the Week 52 tumor assessment, tumor assessment will continue every 12 
weeks. Patients will undergo tumor assessments until radiographic disease progression per 
RECIST v1.1, loss of clinical benefit (for tislelizumab-only patients who continue treatment after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, study 
termination by sponsor, start of a new anticancer therapy, or death, whichever occurs first.  
For patients randomized to Arm B (placebo + gemcitabine + cisplatin arm) who cross over to 
subsequent tislelizumab monotherapy after initial progression of disease, tumor assessments are 
to be continued until the subsequent radiographic disease progression as assessed by the 


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investigator per RECIST v1.1, loss of clinical benefit, withdrawal of consent, study termination 
by sponsor, start of a new anticancer therapy, or death, whichever occurs first.  
To determine the PK properties of tislelizumab and host immunogenic response to tislelizumab, 
blood samples will be collected at various timepoints as outlined in Appendix 1. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per NCI-CTCAE v5.0), and laboratory results. Vital signs, physical examinations, ECOG 
performance status change, electrocardiogram (ECG) results, and other examinations will also be 
used for safety assessment. Safety assessments are further detailed in Section 7.5 and the 
Schedule of Assessments (Appendix 1). 
The End of Treatment Visit is conducted when the investigator determines that tislelizumab or 
chemotherapy will no longer be used. If routine laboratory tests (eg, hematology, serum 
chemistry) are completed within 7 days before the End of Treatment Visit, these tests need not to 
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. 
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 dose of study drug 
(including chemotherapy-only) or before the initiation of a new anticancer treatment, whichever 
occurs first. In addition, telephone contacts with patients should be conducted to assess imAEs 
and concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer 
therapy) at 60 days, and 90 days (± 14 days) after the last dose of study treatment, regardless of 
whether the patient starts a new anticancer therapy. If patients report a suspected imAE at a 
telephone follow-up contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
All AE, 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 or more after the last study treatment. Patients who discontinue study treatment prior to 
disease progression will have their tumors assessed as outlined in Section 7.6. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
3.5. 
Survival Follow-up 
Patients who discontinue study drug for reasons other than disease progression (eg, toxicity) will 
continue to undergo tumor assessments according to Section 7.6 and the Schedule of 
Assessments (Appendix 1), until the patient experiences disease progression, withdraws consent, 
loss to follow-up, death, or until the study completes, whichever occurs first.  
Patients will be followed for survival and further anticancer therapy information after 
discontinuation of study treatment via telephone calls, patient medical records, and/or clinic 
visits 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 completion by the 
sponsor.  


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3.6. 
Discontinuation From the Study Treatment or From the Study 
3.6.1. 
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 7.6), safety (Section 7.5) 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 from the study 
treatment for reasons that 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 determines may jeopardize the patient’s 
safety, if he or she were to continue the study treatment 
• Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicines] for the treatment of cancer) (Section 6.2.2). 
• Patient noncompliance 
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:  
• Patient withdrawal of consent 
• Death 
• Lost to follow-up 
Note: If attempts to contact the patient by telephone are unsuccessful, additional 
attempts should be made to obtain protocol-required follow-up information. It may 
be possible to obtain the information from other contacts such as referring physicians 
or relatives. Attempts of contact should be documented in the patient’s source 
documents. If a patient cannot be contacted despite all attempts, the patient will be 
considered lost to follow-up, and death information should be obtained through a 
public record search if local agencies permit. 
• Patients have completed all study assessments 
3.7. 
End of Study 
The end of study is defined as the timepoint when the final data for a clinical study were 
collected, which is after the last study patient has made the final visit to the study location.  


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The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients  
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit and Safety Follow-up Visit. 
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 Board (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 communicated to the 
site in advance. Reasons for closing a site may include but are not limited to the following:  
• Excessively slow recruitment  
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• Noncompliance with Good Clinical Practice (GCP), applicable laws and regulations  
• Study activity is completed (ie, all patients have completed and all obligations have 
been fulfilled) 


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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments 
2. Aged between 18 to 75 years on the day of signing the informed consent form (or the 
legal age of consent in the jurisdiction in which the study is taking place) 
3. Histologically or cytologically confirmed NPC with recurrence or metastasis 
4. Patients must be able to provide fresh or archival tumor tissues (FFPE blocks or 
approximately 10 [≥ 5] freshly cut unstained FFPE slides) with an associated pathological 
report. In the absence of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion 
at baseline is mandatory  
5. ECOG performance status ≤ 1 
6. Patients must have ≥ 1 measurable lesions as defined per RECIST v1.1 
7. Must be treatment-naive for recurrent or metastatic NPC  
8. Patients who have received prior neoadjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for nonmetastatic disease must have experienced 
a treatment-free interval of ≥ 6 months from the last dose of chemotherapy and/or 
radiotherapy prior to randomization 
9. Patients who have received prior neoadjuvant chemotherapy regimen for < 4 cycles 
10. Life expectancy ≥ 12 weeks 
11. Adequate organ function as indicated by the following laboratory values (obtained within 
7 days prior to randomization): 
a. Patients must not have required a blood transfusion or growth factor support ≤ 14 
days before sample collection at screening for any of the following: 
i. 
Absolute neutrophil count ≥ 1.5 x 109/L  
ii. 
Platelets ≥ 100 x 109/L  
iii. 
Hemoglobin ≥ 90 g/L  
iv. 
International normalized ratio or prothrombin time ≤ 1.5 x upper limit of 
normal (ULN) 
v. 
Activated partial thromboplastin time or partial thromboplastin time ≤ 1.5 
x ULN 
b. Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (GFR) 
≥ 60 mL/min/1.73 m2 


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c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilbert’s syndrome) 
d. AST and ALT ≤ 2.5 x ULN or AST and ALT ≤ 5 x ULN for patients with liver 
metastases  
12. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and ≥120 days after the last dose of 
tislelizumab or placebo, and have a negative urine or serum pregnancy test ≤ 7 days 
before randomization 
13. Nonsterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥120 days after the last dose of tislelizumab or placebo 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria must be excluded from this study:  
1. Patients with locally recurrence suitable for curative surgery or radiotherapy 
2. Received any approved systemic anticancer therapy, including hormonal therapy, within 
28 days prior to initiation of study treatment. The following exception is allowed: 
- 
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed 
> 7 days prior to baseline imaging.  
3. Has received any immunotherapy (including but not limited to interferons, interleukin-2, 
tumor necrosis factor interleukin, and thymoxin) or any investigational therapies within 
14 days or 5 half-lives (whichever is longer) of randomization 
4. Received prior therapies targeting PD-1 or PD-L1  
5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis 
• Patients with a history of treated and, at the time of screening, asymptomatic CNS 
metastases are eligible, provided they meet all the following: 
- 
Brain imaging at screening shows no evidence of interim progression 
- 
Have measurable disease outside the CNS 
- 
No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsants at a stable dose allowed 
- 
No stereotactic radiation or whole-brain radiation within 14 days prior to 
randomization 
• Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases. 
- 
Following treatment, these patients may then be eligible, provided all other 
criteria, including those for patients with a history of brain metastases, are met. 
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Note: Patients with the following diseases are not excluded and may proceed to further 
screening:  
a. 
Controlled Type I diabetes 
b. 
Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. 
Controlled celiac disease 
d. 
Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. 
Any other disease that is not expected to recur in the absence of external triggering 
factors 
7. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast)  
8. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization  
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. 
Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)  
b. 
Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. 
Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for 
contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, 
delayed-type hypersensitivity reaction caused by contact allergen) 
9. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before randomization  
10. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled 
diseases including pulmonary fibrosis, acute lung diseases, hypertension, etc 
11. With severe chronic or active infections (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal or antiviral therapy within 14 days prior to 
randomization or first dose of study drugs 
12. A known history of HIV infection 
13. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers 
whose HBV DNA is ≥ 500 IU/mL or patients with active hepatitis C virus (HCV) should 
be excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and 
stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be 
enrolled.  
14. Any major surgical procedure requiring general anesthesia ≤ 28 days before 
randomization 
15. Prior allogeneic stem cell transplantation or organ transplantation 


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16. 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 6) ≤ 6 months before randomization  
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization or first dose of study drug  
f. Any history of cerebrovascular accident ≤ 6 months before randomization or first 
dose of study drug 
17. A history of severe hypersensitivity reactions to other monoclonal antibodies 
18. 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) 
19. History of allergic reactions to cisplatin, or other platinum-containing compounds 
20. ≥ Grade 2 peripheral neuropathy, as defined by NCI-CTCAE v5.0 criteria 
21. Was administered a live vaccine ≤ 4 weeks before randomization  
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines, and are not allowed 
22. 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 
23. Concurrent participation in another therapeutic clinical study 


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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial (20R 
glass, United States Pharmacopeia 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 IV administration, accountability, and 
disposal. Please also refer to the tislelizumab Investigator’s Brochure for other details regarding 
tislelizumab. 
5.1.2. 
Matched Placebo 
Matched placebo will be provided in a single-use vial (20R glass, United States Pharmacopeia 
type I), containing 10 mL of isotonic solution. These single-use vials contain a Flurotec-coated 
butyl rubber stopper and an aluminum cap. Each vial is packaged into a single carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The vials must be kept at the temperature condition as specified on the label.  
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal. 
5.1.3. 
Chemotherapy Agents 
Management (ie, labelling, 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 all study arms, broken out by individual arm, are provided in Table 2. The 
first dose of study drug is to be administered within 2 business 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. 
For each cycle, tislelizumab or placebo will be administered before chemotherapy drugs. The 
order of chemotherapy drug administration will be conducted in accordance with the relevant 
local guidance and/or clinical practice. 


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Patients should receive antiemetics and IV hydration for cisplatin-based doublet treatments 
according to the local standard of care and manufacturer’s instruction. Due to their 
immunomodulatory effects, premedication with steroids should be limited when clinically 
feasible. Dexamethasone is recommended to be administrated 7.5 mg once daily for 3 days as 
premedication. In addition, in the event of chemotherapeutic agent-related skin rash, topical 
steroid use is recommended as front-line treatment whenever it is clinically feasible.  
In special situations (eg, when the administration is delayed due to management of adverse 
events 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 each cycle 
Intravenous 
See Section 3.3 
Gemcitabine 
1 g/m2 
Day 1, Day 8 of each cycle 
Intravenous 
Cisplatin 
80 mg/m2 
Day 1 of each cycle 
Intravenous 
Chemotherapy will be administered on a 3-week cycle. 
The number of treatment cycles (4 to 6) will be at the discretion of the investigator. 
5.2.1. 
Tislelizumab 
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks).  
Tislelizumab will be administered by IV infusion through an IV line containing a sterile, 
non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter. Specific 
instructions for product preparation and administration are provided in the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents before chemotherapy. From Cycle 3 onward, a  30-minute monitoring period 
is required in an area with resuscitation equipment and emergency agents before chemotherapy. 
The initial infusion (Cycle 1, Day 1) will be delivered for over 60 minutes; if this is well 
tolerated, then the subsequent infusions may be administered for 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 for imAEs and infusion-related reactions are provided in details in Section 5.5, 
Section 8.7 and Appendix 7.  
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.2. 
Matched Placebo 
Patients will be randomized to receive tislelizumab or matched placebo in a double-blind fashion 
in Arm A and Arm B such that neither the investigator nor the patient, medical or ancillary 


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medical staff, or blinded sponsor staff and designees will know which drug is being administered 
in addition to chemotherapy. Administration of the 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 
Cisplatin will be administered after completion of gemcitabine. 
Gemcitabine l g/m2 will be administered as an IV infusion within 30 minutes on Day 1 and Day 
8 of each cycle, for 4 to 6 cycles. In addition, all patients should receive the appropriate 
premedications as per the local approved label. Additional premedications should be 
administered as per standard practice. 
Cisplatin 80 mg/m2 is suggested to be administered as an IV infusion for over 4 hours if possible 
or with proper infusion time based on local clinical guidelines or clinical practice according to 
the treating physician’s clinical judgment on Day 1 of each cycles for 4 to 6 cycles. All patients 
should receive adequate hydration (including pre-treatment hydration) and diuretics. Urinary 
output > 2000 mL must be maintained in the following 24 hours of the infusion.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of chemotherapy therapy. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.5. 
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 Section 8.6. 
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 or placebo, gemcitabine, and cisplatin) will be provided by the sponsor, as required 
by local or country-specific guidance. The investigational site will acknowledge receipt of IMPs. 
Any damaged shipments will be replaced.  
Accurate records of all IMP received, dispensed, returned, and disposed should be recorded on 
the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management. 
5.5. 
Dose Delay, Interruption and Modification  
Dose delay is defined as interruption of the treatment regimen (ie, the drug is withheld beyond 
visit window). Dose interruption is defined as an interruption of infusion.  


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Every effort should be made to administer tislelizumab or placebo and chemotherapies on the 
same day according to the planned dose and schedule (see Appendix 1), and as the patient’s 
condition allows. In the event of significant toxicities, dosing may be delayed and/or reduced 
based on the guidelines provided below. Reasons for dose modifications or delays, the 
supportive measures taken, and the outcome will be documented in the patient's chart and 
recorded in the eCRF. 
The tumor assessment schedule (see Appendix 1) will not be altered if chemotherapy or 
tislelizumab or placebo are delayed or discontinued. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Patients should continue study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the sponsor.  
5.5.1. 
General Guidance Regarding Dose Modifications 
The severity of adverse events will be graded according to the NCI-CTCAE v5.0 grading system. 
• Dose modifications for chemotherapy should be performed per prescribing 
information and per local practice according to the treating physician’s clinical 
judgment (please see Section 5.5.3).  
• Tislelizumab or placebo might be delayed as defined in Section 5.5.2. 
• For any adverse events already apparent at baseline, the dose modifications will apply 
according to the corresponding shift in toxicity grade, if the investigator feels it is 
appropriate. For example, if a patient has Grade 1 asthenia at baseline that increases 
to Grade 2 during treatment, this will be considered a shift of 1 grade and treated as 
Grade 1 toxicity for dose-modification purposes. 
• When several toxicities with different grades of severity occur at the same time, the 
dose modifications should be according to the highest grade observed. 
o 
If one component of the chemotherapy regimen is held due to AE, the other 
component will also be held until AE resolution permits continuation of both 
components of the chemotherapy regimen. Tislelizumab or placebo may 
continue as indicated. 
o 
If both components of the chemotherapy are withheld because of toxicity for 
more than 2 cycles, chemotherapy should be discontinued; tislelizumab or 
placebo may be continued if the toxicity resulting in chemotherapy 
discontinuation is not considered by the investigator to be related to 
tislelizumab. Exceptions based on clinical benefit require the prior approval of 
the medical monitor. 
o 
If tislelizumab or placebo is discontinued permanently during the 4 to 6 cycles 
of chemotherapy treatment, the patient may continue the chemotherapy. 
• Administration of chemotherapy should ideally remain synchronized with pre-defined 
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o 
If chemotherapy related toxicities warrant dose delays, chemotherapy 
administration should be restarted to ideally coincide with the next treatment 
cycle or may be given during an unscheduled visit and resynchronized at later 
cycle, if possible. For example, if chemotherapy related toxicity resolves on 
Day 7, chemotherapy may be administered that day and resynchronized as 
permissible at next or subsequent cycle; if chemotherapy related toxicity 
resolves on Day 14, chemotherapy may be administered on Day 1 of the next 
planned cycle. 
• Following either completion of, or discontinuation from chemotherapy, tislelizumab 
or placebo should be continued as scheduled, if clinically appropriate (Section 3.3).  
• Dose modification guidelines for chemotherapy, described below (Section 5.5.3), 
depend on the severity of toxicity and an assessment of the risk versus benefit for the 
patient, with the goal of maximizing the patient’s compliance and access to 
supportive care.  
5.5.2. 
Dose Interruption or Delay for Tislelizumab  
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 treatment as soon as possible after the 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 modification related to imAEs and infusion-related reactions are described in Appendix 7 
and Section 8.7.1, respectively. 
If a dose is delayed for tislelizumab or placebo for ≤ 10 days for a planned dosing cycle (eg, 
Cycle 3 Day 1), tislelizumab or placebo should be administered. If the delay is > 10 days, the 
patient should skip the tislelizumab or placebo dose, and tislelizumab or placebo will be 
administered on Day 1 of the next planned cycle (ie, Cycle 4 Day 1).  
5.5.3. 
Dose Modifications of Chemotherapy Treatment 
Dose modifications for chemotherapy should be performed per prescribing information and per 
local practice according to the treating physician’s clinical judgment.  
• 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 new reference body weight). Chemotherapy doses should not be 
modified for any body weight change of less than 10%.  


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• Study-drug-related toxicities are highly recommended to be resolved to baseline or 
Grade 0-1 prior to administering the next dose, except for alopecia or Grade 2 fatigue. 
A maximum of 2 dose reductions for each chemotherapeutic agent is allowed. Once 
the dose has been decreased, it should remain reduced for all subsequent 
administrations or further reduced if necessary. There will be no dose escalations in 
this study. If additional reductions are required, that chemotherapeutic agent must be 
discontinued. 
• Chemotherapy treatment may be delayed up to 21 days, if the reason for the delay is 
toxicity/AE. All subsequent chemotherapy doses must be rescheduled according to 
the last chemotherapy dose administration date. 
Dose modification of gemcitabine and cisplatin: restart at 75% of the initial or previous dose for 
patients who had Grade 3 or 4 hematological and non-hematological AE that resolved to 
NCI-CTCAE < Grade 2. For patients with neutropenia, Day 8 gemcitabine could be given at a 
reduced dose or postponed for up to 5 days to allow for recovery, otherwise it should be skipped. 
SELECTED PRECAUTIONS: 
• Neutropenia: Fever or other evidence of infection must be assessed promptly and 
treated aggressively following the local clinical practice and/or the guidelines. 
- 
Renal toxicity: nephrotoxicity is common with cisplatin. Encourage oral 
hydration. Avoid nephrotoxic drugs such as aminoglycoside antibiotics. 
- 
Hemolytic uremic syndrome can occur in patients treated with gemcitabine. 
Hemolytic uremic syndrome was reported in 0.25% of patients. Most fatal cases 
of renal failure were due to hemolytic uremic syndrome. 
• Ototoxicity and sensory neural damage should be assessed prior to each cycle. 
Cisplatin is contraindicated in patients with a pre-existing hearing deficit. 
• Prolongation of the infusion time of gemcitabine beyond 60 minutes resulted in an 
increased incidence of clinically significant hypotension, severe flu-like syndromes 
etc. It is recommended that gemcitabine infusion time is limited to 30 minutes.  
• Pulmonary toxicity has been reported in patients who were treated with gemcitabine. 
In some cases, these events can lead to fatal respiratory failure. 
• Capillary leak syndrome with severe consequences has been reported in patients 
treated with gemcitabine. 
• Posterior reversible encephalopathy syndrome has been reported in patients receiving 
gemcitabine. Posterior reversible encephalopathy syndrome can present with 
unspecific neurological symptoms. 
• For toxicities not listed above, dose modifications are permitted per local standards.  
• For cisplatin, dose modiﬁcation should be based on the prechemotherapy creatinine 
clearance rate (CCR) in every cycle, calculated with the Cockcroft-Gault formula.  
- 
If CCR is higher than or equal to 60 mL/min, cisplatin should be given at full 
dose.  


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- 
If CCR is between 41 mL/min and 59 mL/min, an equal dose to the CCR value 
(mg/m²) should be applied.  
- 
If CCR is less than 41 mL/min, cisplatin should be stopped in the current cycle 
and the dose of cisplatin should be evaluated in the next cycle.  
• Recommended premedication for cisplatin is dexamethasone 7.5 mg once daily for 
three days.  
Guidance regarding dose modifications for certain toxicities is presented in detail in 
Appendix 10. 
5.6. 
Criteria for Discontinuing Chemotherapy Regimens 
Except where specified above, both chemotherapy drugs in the cisplatin-based doublet regimen 
should be discontinued for any of the following: 
• Any Grade 3 peripheral neuropathy. 
• Persistent Grade 3 paraesthesia. 
• Grade 3 or 4 drug-related thrombocytopenia associated with clinically significant 
bleeding 
• Any drug-related liver function test abnormality value that meets any of the following 
criteria requires discontinuation: 
o 
AST or ALT > 5 to 10 x ULN for > 2 weeks  
o 
AST or ALT > 10 x ULN or 
o 
Total bilirubin > 5 x ULN or 
o 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any cisplatin-related decrease in creatinine clearance to <30 mL/min (using the 
Cockroft-Gault formula) requires discontinuation of cisplatin.  
• Any drug-related AE that recurs after 2 prior dose reductions for the same drug-
related AE requires discontinuation of the drug(s). 
• Any Grade 3 or 4 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) assessed to be causing the reaction. If the drug is 
assessed as not related to the hypersensitivity reaction or infusion reaction, it may be 
continued. 
• Any Grade 4 AE that the investigator considers related to study drug and 
inappropriate to be managed by dose reduction(s) requires discontinuation of drug(s). 
If the drug is not assessed to be related to the event it may be continued. 
• If any toxicity does not resolve within 21 days, that component will be discontinued.  
For toxicities not listed above, the investigator’s medical judgment would determine whether 
chemotherapy regimen should be discontinued, in accordance with patient’s well-being and local 
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Refer to Section 3.4 regarding safety follow-up procedures. 
5.7. 
Blinding 
This is a randomized, double-blind, placebo-controlled Phase 3 study.  
Patients will be randomized to receive tislelizumab or matched placebo in a double-blind fashion 
in Arm A and Arm B such that neither the investigator, nor the patient, nor medical or ancillary 
medical staff, nor the blinded sponsor staff or its designees, will know which drug is being 
administered in addition to chemotherapy. 
Emergency unblinding 
Emergency unblinding for AEs may be performed through an Interactive Web Response System. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the 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. 
Inadvertent unblinding 
Every effort will be made to blind both the patient and the investigator to the identity of 
tislelizumab or placebo, but the inadvertent unblinding of a patient may occur. If an investigator, 
site personnel performing assessments, or patient is unblinded, the unblinding will not be 
sufficient cause (in and of itself) for that patient to be discontinued from study therapy or 
excluded from any safety or efficacy analyses. 
Additionally, there may be ethical reasons to have the patient remain on the study treatment. For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from the Sponsor medical monitor for the patient to continue in the study. 


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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
The exclusion criteria (Section 4.2) specify that patients will not have received prior systemic 
therapies targeting PD-1 or PD-L1. 
6.2. 
Concomitant Therapy 
6.2.1. 
Permitted Concomitant Medications 
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care at the discretion of the investigator for the supportive care (eg, anti-
emetics, antidiarrheals) and in a patient’s interest are allowed. Patients should receive full 
supportive care, including epoetin and other hematopoietic growth factors, transfusions of blood 
and blood products, antibiotics, antiemetics, and/or other applicable medications, as needed. 
Systemic corticosteroids given for the control of imAEs must be tapered gradually (Appendix 7) 
and be at nonimmunosuppressive 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.  
Bisphosphonates and Receptor activator of nuclear factor kappa-Β ligand inhibitors are allowed 
for bone metastases if initiated prior to enrollment and at a stable dose. Bisphosphonates are 
permitted during the study for a nonmalignant indication. 
Whole-brain radiation therapy and stereotactic radiosurgery are permitted for patients with 
disease progression limited to the CNS. Palliative (limited-field) radiation therapy is permitted, 
but only for pain control or prophylaxis of bone fracture to sites of bone disease present at 
baseline provided the following criteria are met: 
- 
Repeat imaging demonstrates no new sites of bone metastases 
- 
The lesion being considered for palliative radiation is not a target lesion for RECIST 
v1.1. 
- 
The case is discussed with the medical monitor, and the medical monitor agrees that 
the conditions required to receive palliative radiation are met. 
Additionally, palliative radiation or other focally ablative therapy for other non-target sites of the 
disease is permitted if clinically indicated per investigators’ discretion and after consultation with 
the medical monitor. Whenever possible, these patients should have a tumor assessment of the 
lesion(s) before receiving the radiotherapy in order to rule out progression of disease. 
6.2.2. 
Prohibited Concomitant Medications/Procedures 
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 medicines and Chinese patent medicines] for the treatment of cancer 
is not allowed. 


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• 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.  
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.2.1. 
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 
antibody. Because tislelizumab is expected to be degraded into amino acids and recycled into 
other proteins, it is unlikely to influence drug metabolizing enzymes or transporters. 
The major route of elimination of cisplatin is renal excretion. Cisplatin produces cumulative 
nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood 
urea nitrogen, creatinine clearance, and magnesium, sodium, potassium, and calcium levels 
should be measured prior to initiating therapy, and prior to each subsequent course. 
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. In a 
randomized trial in advanced ovarian cancer, response duration was adversely affected when 
pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate will sign the ICF prior to undergoing any screening procedure. The screening 
period begins on the first day a screening procedure is conducted. Patients who are suspected or 
known to have serious respiratory concurrent illness or exhibit significant respiratory symptoms 
unrelated to underlying cancer should take a pulmonary function test (refer to Appendix 1 for 
details). Screening evaluations may be repeated as needed within the screening period; the 
investigator will 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 7.5), Tumor and Response Evaluations (Section 7.6), 
and Biomarkers (Section 7.8).  
Rescreening under limited conditions may be allowed after consultation with BeiGene: eg, when 
a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression. Rescreening is allowed only once. 
7.1.1. 
Demographic Data and Medical History  
Demographic data will include 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); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before randomization.  
Cancer history will include an assessment of prior surgery, prior radiotherapy, and prior drug 
therapy including start and stop dates, best response, and reason for discontinuation. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator.  


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7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 9 for contraception guidelines and definitions of “Women of Childbearing 
Potential” and “No Childbearing Potential.”  
7.1.3. 
Informed Consent and Screening Log 
Voluntary, written, informed consent for participation in the study must be obtained before 
performing any study-specific procedures. The ICFs for enrolled patients and for patients who 
are screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before 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. 
Patient Numbering 
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant. 
7.1.5. 
Pulmonary Function Tests 
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit 
significant respiratory symptoms unrelated to the underlying cancer will undergo pulmonary 
function testing (Pellegrino et al 2005) which may include, but is not limited to: spirometry and 
assessment of diffusion of oxygenation (at a minimum pulse oximetry at rest and with exercise), 
or alternatively, assessment of diffusion capacity, during the Screening period to assist the 
determination of suitability on the study. 
Tests may be repeated as clinically indicated while on study (refer to Appendix 1 for details). 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility 
The investigator will assess, and the sponsor will 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 (or enrollment), study site personnel will complete an Eligibility Authorization 
Packet 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 
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7.2.2. 
Randomization 
Site personnel will access the IRT system to randomize the patient to treatment assignment and 
assign study drugs. Study treatment must commence within 2 business days after 
randomization/treatment assignment. 
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensation 
Tislelizumab or placebo and chemotherapy treatments will be dispensed and administered as 
described in Section 5.2. 
7.4. 
Crossover 
7.4.1. 
Crossover for Patients in Chemotherapy in Arm B With Documented and IRC 
Confirmed Disease Progression  
For patients who experience disease progression, unblinding is indicated. Patients who are 
randomized into the chemotherapy arm (Arm B) will have the opportunity to cross over to 
receive tislelizumab if they experience radiographic disease progression on chemotherapy; that 
is, if disease progression per RECIST v1.1 has been confirmed by the IRC and approval by the 
medical monitor has been obtained. Patients who permanently discontinue chemotherapy due to 
an AE, withdrawal of consent, or for any reason other than progressive disease will not be 
eligible for crossover. Crossover patients should not initiate treatment with tislelizumab prior to 
resolution of treatment-related toxicities to ≤ Grade 1 (NCI-CTCAE) or baseline, with the 
exception of select chemotherapy-related toxicities such as hair loss, but should be initiated 
within 42 days (if applicable), and upon consultation with the medical monitor. 
Patients who develop radiographic disease progression per RECIST v1.1 will be allowed to cross 
over to start tislelizumab provided that patients meet all the following criteria: 
1. ECOG performance status ≤ 1 
2. Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, CNS disease) that cannot be managed by protocol-allowed medical interventions 
3. Patient provided written consent to acknowledge that tislelizumab is an experimental 
treatment used after failure of prior first-line platinum-containing regimen 
Crossover is optional and is at the discretion of the investigator with the sponsor’s agreement. 
7.4.2. 
Crossover Assessments and Procedures 
If a patient experiences radiographic disease progression per RECIST v1.1 while on 
chemotherapy (Arm B) the investigator should discuss treatment options with the patient, 
including the option to continue chemotherapy until confirmation of progression (Section 3.3), 
and determine whether there is desire and the patient meets criteria to cross over to tislelizumab 
monotherapy. If that is the case, the patient’s informed consent needs to be obtained. Note that 
radiographic imaging scans must be the most recent at time of progressive disease and, if not 
already transmitted, at minimum at time of baseline and sum of the longest diameter nadir.  
Procedures and assessments obtained at the time of assessing progressive disease may be used as 
appropriate for the start of the crossover phase of the study.  


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The tumor imaging used to determine progressive disease can be used as the new baseline 
imaging for the crossover phase if: 
1. 
it occurred within 28 days prior to receiving the first dose of tislelizumab monotherapy, and  
2. 
no study treatment was administered between the imaging and the first dose of tislelizumab 
monotherapy,  
Otherwise a new baseline imaging must be performed prior to tislelizumab monotherapy 
treatment. 
All the visits and safety assessments for patients who cross over to tislelizumab monotherapy 
should follow the schedule upon previously original Cycle 1 Day 1 before crossover; data for 
biomarkers other than EBV-DNA, as well as PK and ADA, will be nevertheless not required to 
be collected. 
Patients who permanently discontinue the crossover phase will follow the same Safety Follow-up 
and Survival Follow-up periods. 
7.5. 
Safety Assessments 
7.5.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic) while the patient is in a seated position after resting for 10 minutes.  
Height (baseline only) and weight should be measured and recorded in the eCRF. 
For the first 2 infusions of tislelizumab or placebo, the patient’s vital signs should be determined 
within 60 minutes before starting the infusion, at least once during the infusion, and 30 minutes 
following completion of the infusion. For subsequent infusions, vital signs will be collected 
within 60 minutes before infusion and, if clinically indicated, during and 30 minutes after the 
infusion. Patients will be informed about the possibility of delayed postinfusion symptoms and 
instructed to contact their study physician if they develop such symptoms. Refer to Section 5.2.1 
regarding precautionary monitoring of patients postinfusion of tislelizumab or placebo.  
7.5.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including 
evaluation 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 Medical History eCRF with appropriate disease/condition terms.  
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance 
(Appendix 7). 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. Changes from baseline will be recorded. New or worsened 


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clinically significant abnormalities are to be recorded as AEs on the eCRF. Refer to Section 8.3 
regarding AE definitions and reporting and follow-up requirements. 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG performance status (Appendix 3) will be assessed during the study.  
7.5.4. 
Laboratory Safety Tests 
Laboratory assessments of serum chemistry, hematology, coagulation, cardiac enzymes, and 
urinalysis will be conducted, of which certain elements will be collected as specified in 
Appendix 2.  
If laboratory tests for serum chemistry, hematology, coagulation, cardiac enzymes, and urinalysis 
at screening are not performed within 7 days prior to the administration of study drug(s) on 
Cycle 1 of Day 1, these tests should be repeated and reviewed before study drug(s) 
administration. Hematology and serum chemistry (including liver function tests) as specified in 
Appendix 2 should be performed and reviewed prior to dosing of each treatment cycle, as 
clinically indicated during the treatment cycle, and upon discontinuation of chemotherapy. After 
Cycle 1, results are to be reviewed within 48 hours before study drug administration, and a 
minimum laboratory test to support dosing decision must include hematology and serum 
chemistry parameters. 
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. 
Total creatinine kinase and creatinine kinase cardiac isoenzyme will be assessed for all patients 
(including patients who will be receiving tislelizumab after crossover) at screening and, at 
scheduled visits during treatment cycles and at the end of treatment and safety follow up visits. 
ECG, serum troponins, and other investigations as clinically indicated and as appropriate, if 
significant abnormalities are detected.  
7.5.5. 
Electrocardiograms  
The ECG recordings will be obtained during screening, the Safety Follow-up Visit, and as 
clinically indicated. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. 
When coinciding with blood draws at the same timepoint, ECG assessment should be performed 
prior to blood draws. Patients should rest in semi-recumbent supine position for at least 
10 minutes prior to ECG collection.  
7.5.6. 
Adverse Events 
AEs will be graded and recorded throughout the study according to NCI-CTCAE Version 5.0. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6.  


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7.5.7. 
Hepatitis B and C Testing 
Testing will be performed by a central laboratory and/or the local laboratory at screening and 
will include HBV/HCV serology (HBsAg, hepatitis B surface antibody (HBsAb), hepatitis B 
core antibody (HBcAb), and HCV antibody) and viral load assessment (HBV DNA and HCV 
RNA). Hepatitis B and C testing will be monitoring during study conduct as clinically needed. 
7.6. 
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 6 weeks 
(± 7 days) for the first 6 months, every 9 weeks (± 7 days) for the remainder of Year 1, every 12 
weeks (± 7 days) from Year 2 onwards based on RECIST v1.1. 
Screening assessments and each subsequent assessment must include contrast-enhanced 
magnetic resonance imaging (MRI) of the nasopharynx and neck, and CT scans (with oral/IV 
contrast, unless contraindicated) or MRI of the chest, abdomen, and pelvis. Other known or 
suspected sites of disease must be included in the imaging assessments (brain, etc). 
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 MRI and CT scans). All known sites of disease must be documented at 
screening and reassessed at each subsequent tumor evaluation. 
• Imaging of the brain (MRI or CT) at baseline (≤ 28 days of informed consent) is 
required for all screened patients.  
• For a patient with known and previously treated brain metastases the MRI scan 
should be within 14 days of planned Cycle 1, Day 1. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.  
• If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full-
contrast diagnostic CT scan. 
• Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening if 
clinically indicated. If bone metastases are present at screening and cannot be seen on 
CT or MRI scans afterwards, or clinically indicated, TC-99m or PET bone scans 
should be repeated when a CR is suspected in target lesion or when progression in 
bone is suspected. 
• CT scans of the extremities should also be performed if clinically indicated and 
followed throughout the study, if there is evidence of metastatic disease in these 
regions at screening. At the investigator’s discretion, other methods of assessment of 
target lesion and nontarget lesions per RECIST v1.1 may be used. 


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Response will be assessed by the IRC and the investigator using RECIST v1.1 (see Appendix 4). 
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.  
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 progressive disease is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment with tislelizumab 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 investigator-assessed progression must be 
agreed with the sponsor medical monitor and documented in the study records. 
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, withdraws consent, is 
lost to follow up, or dies, or until the study terminates, whichever occurs first.  
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. 
7.7. 
Pharmacokinetic and Antidrug 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 antidrug antibodies (ADAs) at multiple timepoints throughout the 
study (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 bioanalysis 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. 
7.8. 
Biomarkers 
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling.  
Patients must be able to provide fresh or archival tumor tissues (FFPE blocks or approximately 
10 [≥ 5] freshly cut unstained FFPE slides) with an associated pathological report. In the absence 
of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is mandatory. 
However, fresh biopsy should not be collected from the target lesion only unless there are other 
sites of measurable disease. 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. Tumor tissue should be of good quality based on total and 
viable tumor content. Fine-needle aspiration, brushing, cell pellets from pleural effusion, and 
lavage samples are not acceptable. 
Tumor tissues are to be sent to central laboratory for assessment of PD-L1status. In addition, 
other biomarkers, including but not limited to tumor-infiltrating lymphocyte, tumor mutation 
analysis and immune-mediated gene expression profiling, that are related to response or the 
clinical benefit of tislelizumab may also be evaluated. 
Optional biopsies will also be taken for the patients who have confirmed disease progression 
during the study from accessible tumor sites to obtain samples to explore resistance 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. 
Blood samples will be collected at specified time points as described in the Schedule of 
Assessments (Appendix 1) to be used for the evaluation of biomarkers, including blood based 
germline genomic analysis and plasma EBV DNA level as a surrogate biomarker for antitumor 
efficacy measurement. 
Optional blood samples will be collected for biomarker analysis such as cytokine and soluble 
protein analysis at specified times as described in the schedule of assessment (Appendix 1).  


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7.9. 
Patient-Reported Outcomes 
Patients will be asked to complete the EORTC QLQ-C30 and EORTC QLQ-H&N35 modules 
questionnaires before any clinical activities are performed during on-study clinic visits according 
to the schedule in Appendix 1. The questionnaires will be provided in the patient’s preferred 
language. 
7.10. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted 
(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 of Day1.  
7.11. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination, ECOG performance status, AE 
review, concomitant medications and procedures review, radiographic assessments, physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms, and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation.  
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 


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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated With Study Drugs 
8.1.1. 
Risks Associated With Tislelizumab 
Tislelizumab is an investigational agent that is currently in clinical development. Limited safety 
data are available in patients, and the full safety profile has not been characterized. The 
following recommendation is based on results from nonclinical and clinical studies with 
tislelizumab and 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 7. 
8.1.2. 
Risks Associated With Cisplatin in Combination With Gemcitabine 
For NPC patients who were treated with cisplatin in a first-line setting, frequent (> 5%) Grade 3 
or 4 drug-related toxicities were neutropenia, anemia, nausea, vomiting, and fatigue (Scagliotti et 
al 2008). Although not life-threatening, these AEs can severely impact the physical, 
psychological, and social well-being of patients receiving chemotherapy and can lead to dose 
reductions and discontinuations.  
Please refer to Table 3 below for the reported toxicity of the respective chemotherapeutic agents. 
The investigator should refer to the respective prescribing information for additional details. 
Table 3. 
Commonly and Specifically Reported Toxicity of the Chemotherapeutic 
Agents 
Agents  
Common toxicity 
Specific toxicity 
Cisplatin 
Myelosuppression with leukopenia, 
thrombocytopenia and anemia; infectious 
Nephrotoxicity; ototoxicity and 
peripheral neuropathies 


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Gemcitabine 
complications; nausea/vomiting and other 
gastrointestinal toxicity; hepatic 
impairment; fatigue; anorexia; 
constipation 
Pulmonary toxicity; rash; peripheral 
edema; nephrotoxicity; hemolytic 
uremic syndrome; exacerbation of 
radiation therapy toxicity; capillary 
leak syndrome; posterior reversible 
encephalopathy syndrome 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered. Specifically, 
patients at risk for study-emergent active autoimmune diseases, or with a history of autoimmune 
diseases that may relapse, patients who have undergone allogenic stem cell or organ 
transplantation and patients who have received a live viral vaccine within 28 days before 
randomization are excluded from the study. Patients with contraindications for chemotherapy 
treatment are also excluded from the study. Refer to 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.  
Serum samples will be drawn for determination of ADAs to tislelizumab in all randomized 
patients but will only be tested for patients randomized to the tislelizumab arm. Administration 
of tislelizumab will be performed in a setting where emergency medical equipment and staff who 
are trained to respond to medical emergencies are available (see Section 5.2.1).  
Investigators are instructed to report all AEs (including pregnancy-related AEs).  
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections.  


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8.3. 
Adverse Events 
8.3.1. 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not.  
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome  
• New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor.  
8.3.2. 
Assessment of Severity 
The investigator will assess the severity 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 follow: 
• 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 


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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 drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab Investigator’s Brochure in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always makes an assessment of causality for every SAE prior to transmission of the 
SAE report to the sponsor, since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements. The investigator may change his/her opinion of 
causality considering follow-up information, amending the SAE report accordingly.  
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment, 
including:  
• Temporal relationship of the AE to the administration of study treatment/study 
procedure  
• Whether an alternative etiology has been identified  
• Mechanism of action of the study drug  
• Biological plausibility  
An AE should be considered "related" to study drug if any of the following 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. 


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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 
post-mortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that:  
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation.  
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF.  
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the adverse event. For example, an elevated 
serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.”  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 


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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) 
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 (ADR), the specificity or severity of which is not 
consistent with those noted in the tislelizumab Investigator’s Brochure. 


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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 treatment or initiation of new anticancer 
therapy, whichever occurs first. An imAE (serious or nonserious) 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 should be reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in  
Table 4. 
Table 4. 
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 SAE 
SAE Report 
As 
expeditiously as 
possible 
SAE Report 
Email or fax 
SAE form or 
Pregnancy 
form 
Abbreviations: 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 for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 


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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. 
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. 
Disease Progression  
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, 
the symptoms, signs or clinical sequelae that result from disease progression should be reported 
as the AE term(s). 
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of disease 
progression. If a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression.”  
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. 
Recording Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab or within the 30 
days after the last dose of chemotherapy, a pregnancy report form is required to be completed 


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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. 
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 label 
• Gemcitabine label 
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 (Section 8.7.3) should be classified as imAEs and identified 
as such in the eCRF AE page until 90 days after treatment discontinuation. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune CPIs, in Appendix 7. 
An extensive list of potential imAEs appears in Section 8.7.3, Table 6. 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 7. 
8.7. 
Management of Adverse Events of Special Interest 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for ≥ 1 hour afterwards in an area with resuscitation equipment and 
emergency agents before chemotherapy. From Cycle 3 onward, a minimum of a 30-minute 
monitoring period is required in an area with resuscitation equipment and emergency agents 
before chemotherapy.  
The management of infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined below. 


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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, IV antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions.  
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 5. 
Table 5. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s)  
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 h. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 - severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4 - life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: h, hours; IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued, and the patient should be withdrawn from 
tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per type of the reaction. This includes but is not limited to an 


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antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen. 
In the next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
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 AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but are not limited to serologic, immunologic, 
and histologic (biopsy) data. If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy and is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 6. All conditions similar to those listed should 
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Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017; Brahmer et al 2018), and common immune-mediated toxicities 
are detailed in Appendix 7. For any AEs not included in Appendix 7, please refer to the ASCO 
Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-mediated toxicities.  
Table 6. 
Immune-Mediated Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase (ALT/AST) 
elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent diabetes 
mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 7. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor. Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released. Details of the statistical analyses will be included in a 
separate Statistical Analysis Plan. 
9.1. 
Statistical Analysis 
9.1.1. 
Randomization Methods 
As discussed in Section 7.2.2, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization with gender and metastatic status (with or without liver 
metastases).  
9.1.2. 
Analysis Sets  
The ITT analysis set includes all randomized patients. Patients will be analyzed according to 
their randomized treatment arms. This will be the primary analysis set for all efficacy analysis, 
including analyses of PFS and OS endpoints.  
The Safety analysis set includes all randomized patients who received any dose of any 
component of study drug; it will be the analysis set for the safety analyses. Patients will be 
analyzed according to the actual treatment regimen received. 
The PK analysis set includes all patients who receive any dose of tislelizumab per the protocol, 
for whom any postdose PK data are available. 
The Immunogenicity analysis set includes all patients who receive any dose of tislelizumab for 
whom both baseline ADA and ≥ 1 postbaseline ADA results are available.  
9.1.3. 
Patient Disposition 
The number of patients randomized, treated, and discontinued from study drug and/or study and 
those with major protocol deviations will be counted. The primary reason for study drug and/or 
study discontinuation will be summarized according to the categories in the eCRF. The 
end-of-study status (alive, dead, withdrew consent or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF.  
Major protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics of the ITT analysis set will be summarized using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial 
cancer diagnosis, and time since metastatic/recurrent disease diagnosis, EBV DNA viral load. 
Categorical variables include histology, prior neoadjuvant or adjuvant therapy, stage of disease, 
PD-L1 expression in TC, gender, ECOG performance status, race, smoking status, prior systemic 
therapies, and metastatic site.  


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9.1.5. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary drug codes. 
Concomitant medications will be further coded to the appropriate Anatomical Therapeutic 
Chemical (ATC) code indicating therapeutic classification. Prior and concomitant medications 
will be summarized and listed by drug and drug class in the clinical study report (CSR) for this 
protocol. Prior medications will be defined as medications that stopped before the day of first 
dose of study drug. Concomitant medications will be defined as medications that 1) started 
before the first dose of study drug and were continuing at the time of the first dose of study drug 
or 2) started on or after the date of the first dose of study drug up to 30 days after the patient’s 
last dose (as of the 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 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 immune-mediated AE at a telephone follow-up contact, the 
investigator should arrange an unscheduled visit if further assessment is indicated. 
9.2. 
Efficacy Analyses 
9.2.1. 
Primary Efficacy Analysis 
PFS per the IRC in ITT Analysis Set: 
PFS per the IRC is defined as the time from randomization to the first documented disease 
progression as assessed by the IRC with the use of RECIST v1.1, or death from any cause, 
whichever occurs first. The actual tumor assessment visit date will be used to calculate PFS. 
Data for patients without disease progression or death at the time of analysis will be censored at 
the time of the last valid tumor assessment. Data for patients without postbaseline tumor 
assessment will be censored at the time of randomization. Data for patients who start to receive 
new anticancer therapy or are lost to follow-up will be censored at the last valid tumor 
assessment date prior to the introduction of new therapy or loss to follow-up. 
PFS per the IRC will be compared between tislelizumab + gemcitabine + cisplatin (Arm A) and 
placebo + gemcitabine + cisplatin (Arm B) at a 1-sided α of 2.5% using stratified log-rank test 
methodology. The hypothesis test is formed as follows: 
The null hypothesis to be tested is: 
H0: PFS in Arm A ≤ PFS in Arm B 
Against the alternative hypothesis: 
Ha: PFS in Arm A > PFS in Arm B 
The p-values from a stratified log-rank test will be presented using stratification factors with 
actual values as recorded in the electronic data capture (EDC) system at randomization. The 
median PFS will be calculated for each treatment arm and presented with two-sided 95% CIs. 
Kaplan-Meier survival probabilities for each arm will be plotted over time. The HR for PFS will 
be estimated using a stratified Cox regression model, with treatment arm as a factor and stratified 
by the actual value of the stratification factors as recorded in eCRF. The 95% CI for the HR will 
be provided. Unstratified analysis will also be presented for descriptive purposes. 


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Subgroup Analysis for PFS per the IRC 
Subgroup analysis of primary endpoint of PFS per the IRC will be conducted to determine 
whether the treatment effect is consistent across various subgroups, and the HR estimates of PFS 
and its 95% CI will be estimated and plotted within each category of the following variables: 
metastatic status (liver versus other organ), ECOG performance status (0 versus 1), age (≤ 65 
versus > 65 years), gender (female versus male), smoking status (former versus current versus 
never), etc.  
9.2.2. 
Secondary Efficacy Analyses 
Objective Response Rate per the IRC  
ORR (confirmation not required according to RECIST v1.1) is the proportion of patients who 
had a CR or PR as assessed by the IRC per RECIST v1.1 in all randomized patients with 
measurable disease at baseline. Patients without any postbaseline assessment will be considered 
nonresponders. The difference in ORR between Arm A and Arm B in the ITT analysis set will be 
evaluated using the Cochran-Mantel-Haenszel chi-square test with the actual stratification factors 
as strata. The two-sided 95% CIs for the odds ratio and the difference in ORR will be calculated, 
as well as Clopper-Pearson 95% CIs for the ORR within each arm. 
Duration of Response per the IRC 
DOR per the IRC is defined as the time from the first documented objective response to 
documented disease progression as assessed by the IRC using RECIST v1.1, or death from any 
cause, whichever occurs first. Data for patients who are alive and who have not experienced 
disease progression at the time of analysis will be censored at the date of the last tumor 
assessment. If no tumor assessments were performed after the date of the first occurrence of the 
objective response (CR or PR), DOR will be censored at the date of the first occurrence of the 
objective response. DOR will be estimated using Kaplan-Meier methodology. Comparison 
between Arm A and Arm B will be made using the stratified and unstratified log-rank test for 
descriptive purposes only.  
Overall Survival  
OS is defined as the time from randomization to death from any cause. Data for patients who are 
not reported as having died at the time of analysis will be censored at the date last known to be 
alive. Data for patients who do not have postbaseline information will be censored at the date of 
randomization. Similar methodology used to evaluate PFS per the IRC will be applied to OS 
analysis.  
Progression-Free Survival per the Investigator 
PFS per the investigator is defined as the time from randomization to the first objectively 
documented disease progression, or death from any cause, whichever occurs first, as determined 
per RECIST v1.1 in an ITT analysis set. Similar methodology used to evaluate PFS per the IRC 
will be applied to analysis of PFS per the investigator.  
Second Progression-free Survival per the Investigator 
Analysis of PFS2, defined as the time from randomization to second/subsequent disease 
progression after initiation of new anticancer therapy, or death from any cause, whichever occurs 


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first, will be carried out. Patients alive and for whom a second objective disease progression has 
not been observed will be censored at the last time known to be alive and without second 
objective disease progression. Descriptive analysis of PFS2 will be performed as needed.  
Health-Related Quality of Life  
HRQoL is measured via PRO questionnaires using the EORTC QLQ-C30 and EORTC QLQ-
H&N35. 
Observed values and changes from baseline in global health status/quality of life (GHS/QoL) and 
functional/symptom scales of QLQ-C30 and the symptom scales and index score of H&N35 will 
be descriptively summarized by visit and by treatment arm. 
Time to deterioration (TTD) is defined as the time from randomization to first onset time at 
which deterioration is clinically meaningful (≥ 10 points in the direction of worsening) in the 
score of QLQ-C30’s GHS and the QLQ-H&N35’s index score for 2 executive assessments or 1 
assessment followed by death from any cause within 3 weeks. TTD will be calculated using 
Kaplan-Meier estimates and presented with 2-sided 95% CIs.  
9.2.3. 
Exploratory Efficacy Analyses 
Objective Response Rate per the Investigator 
ORR (confirmation not required according to RECIST v1.1) is the proportion of patients who 
had CR or PR as assessed by the investigator per RECIST v1.1 in all randomized patients with 
measurable disease at baseline. Patients without any postbaseline assessment will be considered 
as nonresponders. Similar methodology used to evaluate ORR per the IRC will be applied to 
analysis of ORR per the investigator. 
Duration of Response per the Investigator 
DOR per the investigator is defined as the time from the first documented objective response to 
documented disease progression as assessed by the investigator using RECIST v1.1, or death 
from any cause, whichever occurs first. Data for patients who are alive and who have not 
experienced disease progression at the time of analysis will be censored at the date of the last 
tumor assessment. If no tumor assessments were performed after the date of the first occurrence 
of the objective response (CR or PR), DOR will be censored at the date of the first occurrence of 
the objective response. Similar methodology used to evaluate DOR per the IRC will be applied 
to analysis of DOR per the investigator. 
Disease Control Rate per the Investigator  
DCR is defined as the proportion of patients with objective response (CR or PR) or SD 
maintained for ≥ 6 weeks as assessed by the investigator using RECIST v1.1. The analysis 
methods for DCR will be the same as those for ORR per the investigator. 
Time to Response per the Investigator 
Time to response (TTR) per the investigator is defined for patients with an objective response by 
the investigator as the time from randomization to the first occurrence of a CR or PR as assessed 
by the investigator using RECIST v1.1. TTR will be summarized for descriptive purposes. The 
mean, standard error, median, and range of TTR will be provided.  


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PD-L1 Expression as a Predictive Biomarker for Response 
PD-L1 expression level will be examined in the ITT analysis set. Association between PD-L1 
expression and treatment effect over control (PFS, OS, ORR, DOR, DCR) will be explored. 
EBV DNA Level as a Predictive Biomarker for Response 
Distribution of EBV DNA level will be examined in the ITT analysis set. Association between 
EBV DNA level and tislelizumab treatment effect over control (PFS, OS, ORR, DOR, DCR) will 
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, urinalysis), 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 drug 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), and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to MedDRA 
(Version 20.0 or higher) by lowest level term, preferred term, and primary system organ class 
(SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pre-treatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever 
occurs first. For the tislelizumab arm, the TEAE classification also applies to imAEs that are 
recorded up to 90 days after discontinuation from tislelizumab, regardless of whether the patient 
starts a new anticancer therapy. Only those AEs that were treatment-emergent will be included in 
summary tables. All AEs, treatment-emergent or otherwise, will be presented in patient data 
listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and preferred term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v5.0 within an SOC and preferred term, even if the patient experienced > 1 TEAE 
within a specific SOC and preferred term. The number (percentage) of patients with TEAEs will 
also be summarized by relationship to the study drug. Treatment-related AEs include those 
events considered by the investigator to be related to study treatment or with missing assessment 


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of the causal relationship. SAEs, deaths, TEAE with ≥ Grade 3 severity, imAE, treatment-related 
TEAEs and TEAEs that led to treatment discontinuation, dose interruption, dose reduction, or 
dose delay will be summarized. 
9.3.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry) 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, heart rate, 
respiratory rate, temperature, 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 
Pharmacokinetic samples will be collected in this study as outlined in Appendix 1. 
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 or 
safety endpoints) analyses may be conducted as appropriate and the results of such analysis may 
be reported separately from the CSR. 
9.5. 
Immunogenicity Analysis 
Samples to assess anti-tislelizumab antibodies will be collected in all randomized patients and in 
sites that are able to adequately perform sampling, handling and processing procedures outlined 
in the laboratory manual. ADA test will be performed for the 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 ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 


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9.6. 
Sample Size Consideration 
The sample size calculation is based on the number of PFS 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 with 
regard to PFS based on the following assumptions: 
1. Median PFS of 7 months in Arm B. 
2. At a 1-sided α of 0.025, 82% power to detect a, HR of 0.65, corresponding to an 
improvement in median PFS from 7 months to 10.8 months, in the PFS of A versus B 
comparison. 
3. Randomization ratio: 1:1. 
4. PFS evaluation dropout rate of 5% per 12 months. 
5. A steady-state enrollment rate of 20 patients per month and enrollment ramp up duration 
of three months, ie, enrollment rate of 5 patients per month from study month 0 to month 
1, 10 patients per month from month 1 to 2, 15 patients per month from month 2 to month 
3, and 20 patients per month afterwards. 
6. One interim analysis is planned when approximately 70% of total PFS events occurred, 
with Lan-DeMets O'Brien-Fleming approximation spending function. 
With these assumptions, a total of 181 PFS events are required for final analysis of PFS. 
Assuming 256 patients are to be enrolled over a 14.3-month period, the final analysis will occur 
at approximately 21.5 months after first patient randomized. 
Sample size is calculated by EAST (version 6.0). 
9.7. 
Interim Analyses  
There will be one interim efficacy analysis of PFS performed in the ITT analysis set. The interim 
efficacy analysis will be performed when approximately 127 PFS events (70% of the target 
number of 181 PFS events) are observed. It is estimated that it will take approximately 15.6 
months to reach time of interim analysis. The interim boundary for each comparison is based on 
Lan-DeMets O'Brien-Fleming approximation spending function. The interim and final analysis 
timing, and stopping boundaries are summarized in Table 7 below. 
Table 7. 
Analysis Timing and Stopping Boundaries for PFS in Each of the Primary 
Tests at a 1-sided α = 0.025  
Type of analysis 
Time (months) 
Number of 
events 
Testing boundary 
p-value boundary 
Approximate hazard ratio 
threshold 
Interim analysis 
15.6 
127 
0.007 
0.649 
Final analysis 
21.5 
181 
0.023 
0.743 


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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Blinded Independent Central Review 
A Blinded Independent Central Review (BICR) committee will be established to perform an 
independent review of all radiological images for the efficacy analysis and to determine all 
instances of response and disease progression based on RECIST v1.1 criteria, in addition to the 
local investigator review of radiographs. The results from the investigator’s review of 
radiographic images will be used to determine whether patients should be enrolled or should 
continue study treatment. The tumor assessment by the BICR 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 BICR are outlined separately in the Imaging 
Manual and the BICR Charter. 
10.2. 
Independent Data Monitoring Committee 
Safety monitoring and interim efficacy data review will be performed by an Independent Data 
Monitoring Committee (IDMC). The first IDMC safety monitoring and review will occur after 
the first 30 patients recruited have been on treatment for ≥ 1 month or completed at least 1 cycle 
of study treatment. Thereafter, IDMC will review data approximately every 6 months, or more 
frequently if indicated or requested by the medical monitor based on ongoing safety monitoring 
of patients on study. The IDMC may recommend study modification including early termination 
of the study due to safety concerns, or for evidence of compelling efficacy at a preplanned 
interim analysis. 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 take place based on new 
information.  
Following IDMC review and discussion, the sponsor will make all final decisions regarding any 
change 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) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation to verify the data 
recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected while these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 


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12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that 
country/region. 
12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be made 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 (if allowed), 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 requirements specified in the 
Pharmacy Manual. At the end of the study, or at appropriate times during the conduct of the 
study, following drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet 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 principal 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 principal 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 principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
investigational new drug safety reports or other safety-related communications from the sponsor. 
Investigators are responsible for ensuring that such reports are reviewed and processed in 
accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file.  
13.2.1. 
Protocol Amendments 
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming 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 prior to participation in the study.  
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality 
The sponsor will maintain confidentiality and privacy standards by coding each patient enrolled 
in the study through assignment of a unique patient identification number. This approach ensures 
that patients’ names are not included in any data set transmitted to any sponsor location.  
Patient medical information obtained by 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.  
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated during this study must be available for inspection upon request by representatives 
of the US Food and Drug Administration, China Health Authority, and all other national and 
local health authorities; by sponsor monitors, representatives, and collaborators; and by the 
IRBs/IECs for each study site, as appropriate.  
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the Investigator’s Brochure, this protocol, 
eCRFs, the investigational new drug, and any other study information, remains the sole and 
exclusive property of 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. 


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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 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.  
14.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at 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 which includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
AEs will be coded using the MedDRA Version 20.0 or higher. Concomitant medications will be 
coded using the World Health Organization Drug Dictionary. Concomitant diseases/medical 
history will be coded using the MedDRA Version 20.0 or higher. 
14.3. 
Data Integrity and In-house Blinding 
In this double-blind, placebo-controlled, randomized 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. 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 personnel per SOPs until the time of unblinding. 


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14.4. 
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 the following 2 categories: 1) the investigator’s study file and 2) the 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, 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 regenerating a hard copy, if required. Furthermore, the investigator must 
ensure that there is an acceptable backup of these reproductions and that an acceptable quality-
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 5 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to archival at an off-site facility or transfer of ownership of or responsibility for 
the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and 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. 
14.5. 
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 that they will apply 
due diligence to avoid protocol deviations. 


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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.  
14.6. 
Publication and Data-Sharing Policy 
CSRs 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. As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint, multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation in 
accordance with the clinical study agreement. This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The process of 
reviewing manuscripts and presentations that are based on the data from this study is detailed in 
the investigator’s clinical study agreement. Each investigator agrees that, in accordance with the 
terms of the clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings in advance of the publication/presentation. 
14.7. 
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, 


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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. 
14.8. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study are the sole property of the sponsor and are hereby 
assigned to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel.  
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor.  
These restrictions do not apply to: 
• Information which becomes publicly available through no fault of the investigator or 
study center personnel 
• Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information which is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results which may be published as described in Section 14.6 
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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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; IRC, Independent Review Committee; IRT, interactive response technology; IV, intravenous; MRI, 
magnetic resonance imaging; PET, position emission tomography; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; 
PK, pharmacokinetic; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; TSH, thyroid stimulating 
hormone; v, version. 
1. Written informed consent is required prior to performing any study-specific tests or procedures. Results of standard of care tests or examinations performed 
prior to obtaining informed consent and within 28 days prior to randomization may be used for screening assessments rather than repeating such tests.  
2. The End of Treatment Visit is conducted when the Investigator determines that tislelizumab or placebo and/or chemotherapy 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. 
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of tislelizumab or placebo and/or chemotherapy, or before the 
initiation of a new anticancer treatment, whichever occurs first. 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 or more after the last study treatment. 
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. 
5. Patients will be randomized into either Arm A or Arm B via IRT. All patients are required to receive study treatment within 2 business days of 
randomization. 
6. Includes age or year of birth, gender, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior medication, loco-
regional treatment(s), and surgical treatment(s). Information on radiographic studies performed prior to study entry may be collected for review by the 
Investigator. 
7. Vital signs collected on study include temperature, pulse rate, and blood pressure. For the first 2 infusions of tislelizumab or placebo, the patient’s vital signs 
are required to be recorded within 60 minutes before starting the infusion, at least once during the infusion, and 30 minutes following the completion of the 
infusion. For subsequent infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 30 minutes after the 
infusion. Height should only be measured and recorded during screening. 
8. During the Screening Visit, a complete physical examination will be conducted. At subsequent visits (and as clinically indicated), limited, symptom-directed 
physical examinations will be performed.  
9. The ECG recordings will be obtained during screening, the Safety Follow-up Visit, and as clinically indicated at other timepoints. When coinciding with 
blood draws, ECG assessment should be performed prior to blood draws. Patients should be resting in semi-recumbent supine position for ≥ 10 minutes prior 
to each ECG measurement. 
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 drug, only SAEs should be reported. After the first dose of study drug, all AEs and SAEs, regardless 
of their assessed relationship to study drug, are to be reported until either 30 days after the last dose of study treatment (including chemotherapy) or the 
initiation of new anticancer therapy, whichever occurs first. Weekly review of AEs and concomitant medications, may be conducted by telephone on 
non-infusion days, ie, Day 15. In addition, telephone contacts with patients should be conducted to assess immune-mediated AEs and concomitant 
medications (if appropriate, ie, associated with an immune-mediated AE or is a new anticancer therapy) at 60 days, and 90 days (± 14 days) after the last 
dose of study treatment, regardless of whether the patient starts a new anticancer therapy. Immune-mediated AEs (serious or nonserious) will be reported 
until 90 days after the last dose of tislelizumab (or placebo), regardless of whether the patient starts a new anticancer therapy. 
11. Laboratory assessments on serum chemistry, hematology, coagulation, total CK and CK-MB, and urinalysis will be conducted, of which certain elements 
will be collected as specified in Section 7.5.4. These laboratory assessments preferentially should be performed at the clinical trial site. However, 


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recognizing that this might pose a hardship on patients traveling from afar, BeiGene agrees that visits on non-infusion days, if indicated, may be done at an 
alternate site upon agreement with study principal investigator, and the medical monitor needs to be informed. In the event that CK-MB fractionation is not 
available, please assess troponin I and/or troponin T instead. If laboratory tests for serum chemistry, hematology, coagulation, cardiac enzymes, and 
urinalysis at screening are not performed within 7 days prior to the administration of study drug(s) on Cycle 1 of Day 1, these tests should be repeated and 
reviewed before study drug(s) administration. Hematology and serum chemistry (including liver function tests) will be performed and reviewed prior to 
dosing of each treatment cycle, as clinically indicated, and upon discontinuation of chemotherapy. Total CK and CK-MB will be assessed for all patients 
(including the patients who will be receiving tislelizumab after crossover) at screening, at scheduled visits during treatment cycles and at the end of treatment 
and safety follow-up visits (data collected as specified in Section 7.5.4). After Cycle 1, results are to be reviewed within 48 hours before study drug 
administration, and a minimum laboratory test to support dosing decision must include hematology and serum chemistry parameters. 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. Includes international normalized ratio, prothrombin time, and activated partial thromboplastin time or partial thromboplastin time. 
13. Urine or serum pregnancy (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 of each cycle. A serum pregnancy test 
must be performed if the urine pregnancy test is positive or equivocal. 
14. Analysis of free T3, free T4, and TSH will be performed by a central laboratory or the local study site laboratory. Thyroid function tests will be performed at 
screening and every 3 cycles (ie, Cycles 4, 7, 10, etc.), and at the Safety Follow-up Visit. 
15. Testing will be performed by a central laboratory and/or the local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, 
and HCV antibody) and viral load assessment (HBV DNA and HCV RNA). 
16. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the underlying 
cancer will undergo pulmonary function testing which may include, but is not limited to, spirometry and assessment of diffusion of oxygenation, at a 
minimum pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity done during the Screening period to assist the 
determination of suitability on the study. 
17. PK samples will be collected for all randomized patients and in sites that are able to adequately perform PK sampling and handling. For tislelizumab, 
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 or 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 mandatory 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. These tests are required for patients randomized to receive tislelizumab when it is allowed by local 
regulations/IRBs/IECs.  
18. ADA samples will be collected for all randomized patients and in sites that are able to adequately perform ADA sampling and handling. 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 are required for patients 
randomized to receive tislelizumab when it is allowed by local regulations/IRBs/IECs. 
19. Radiologic 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, provided they meet the protocol specifications. All measurable and evaluable lesions are required to be assessed and documented at the 
Screening Visit and reassessed at each subsequent tumor evaluation. An MRI (or CT scan if MRI is contraindicated or not readily available) of the head is 
required at screening; bone scan or PET is required if clinically indicated. The same radiographic procedure must be used throughout the study for each 
patient.  
The Investigator must review radiograph results before dosing at the next cycle. Patients will undergo tumor assessments approximately every 6 weeks 
(± 7 days) for the first 6 months, every 9 weeks (± 7 days) for the remainder of Year 1, and every 12 weeks (± 7 days) from Year 2 onwards (based on 


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RECIST v1.1 assessment). The Investigator may perform additional scans or more frequent assessments if clinically indicated. See Section 7.6 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 experiences disease progression, withdraws consent, dies, or until the study terminates, whichever 
occurs first. 
20. Patients are to provide archival tumor tissues (FFPE blocks or approximately 10 [≥ 5] unstained slides) for biomarker analysis. Fresh biopsy: In the absence 
of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is mandatory (written informed consent is required prior to fresh tumor 
biopsies). However, fresh biopsy should not be collected from the target lesion only unless there are other sites of measurable disease. See Section 7.8 for 
more information. Patients who have progressive disease will be asked to provide optional biopsy samples for the assessment of mechanism of resistance 
(written informed consent is required prior to fresh tumor biopsy). 
21. Mandatory blood sample will be collected for biomarker analysis including plasma EBV DNA measurement and germline genomic analysis. Blood samples 
for plasma EBV analysis will be taken at baseline (both screening and predose on Cycle 1 Day 1); after Cycle 1 Day 1, the following samples will be 
collected within the visit window and coincide with tumor assessment. On the day of tumor assessment, the blood sample for plasma EBV DNA analysis 
need to be collected before MRI or CT scan. If a dose has been planned, the blood sample would be recommended to be taken prior to dosing. Blood sample 
for germline genomic analysis will be collected at screening.  
22. Tislelizumab will be given IV Q3W for patients in Arm A. The initial infusion (Cycle 1, Day 1) will be delivered for over 60 minutes, and then can be 
administered for over 30 minutes for subsequent infusions if well tolerated. Patients must be monitored for ≥ 1 hour after infusion of tislelizumab on Day 1 
of Cycle 1 and Cycle 2; from Cycle 3 onward, a monitoring period of ≥ 30 minutes is required. Treatment could continue beyond progression if clinical 
benefit is seen and treatment is tolerated per the investigator’s discretion. Patients should sign an informed consent form for continued treatment beyond 
RECIST v1.1. Patients in Arm B who will be receiving tislelizumab following crossover after IRC confirmed radiographic disease progression on 
chemotherapy should not initiate treatment with tislelizumab prior to resolution of treatment-related toxicities to ≤ Grade 1 or baseline, with the exception of 
select chemotherapy-related toxicities such as hair loss, but should be initiated within 42 days (if applicable), and upon consultation with the medical 
monitor. Patients in Arm B should follow the same schedule of assessments. Refer to Section 7.4 for further specifications regarding crossover.  
23. Chemotherapy will be given as IV infusions for all patients for 4 to 6 cycles. Cisplatin: 80 mg, Day 1 of each cycle; gemcitabine 1 g/m2, Day 1, Day 8 of 
each cycle. Refer to Section 5.2 for detail dose and schedule. 
24. To be completed prior to any clinical activities during on-study site visits. EORTC QLQ-C30 and EORTC QLQ-H&N35 will be completed at screening, at 
every other cycle through Cycle 12, then every 4 cycles thereafter, and at the end of treatment.  
25. Optional blood sample will be collected for biomarker analysis such as cytokine and soluble protein analysis. The blood sample will be collected at Cycle 1 
Day 1 (predose), Cycle 2 Day 1 (predose) and Cycle 3 Day 1 (predose) (written informed consent is required prior to blood collection), and at time of 
confirmed PD as assessed by the investigator. 
26. Day 8 and Day 15 of the first 6 cycles after crossover are not required. 


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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS 
Serum Chemistry 
Hematology 
Coagulation 
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Creatinine 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Magnesium 
Potassium 
Sodium 
Chloride 
Corrected calcium  
Total protein 
Albumin 
Creatinine Kinasea 
CK-MBa 
CBC including  
RBC  
Hematocrit  
Hemoglobin  
Platelet counts 
WBC count with 
differential  
 
Prothrombin time 
Partial thromboplastin time or 
activated partial thromboplastin time 
International normalized ratio  
 
Urinalysisb 
Pregnancy Test 
Thyroid Function 
Specific gravity pH 
Glucose 
Protein  
Ketones 
RBC 
WBC 
Urine or serum pregnancy 
test 
TSH 
Free T3 
Free T4 
Abbreviations: CBC, complete blood count; CK-MB, creatine kinase cardiac isoenzyme; pH, negative of the 
logarithm to base 10 of the activity of the (solvated) hydronium ion; RBC, red blood cell; T3, triiodothyronine; T4, 
thyroxine; TSH, thyroid stimulating hormone; WBC, white blood cells. 
a. 
In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
b. On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein 
and a random urine sample for total protein and creatinine to determine a protein to creatinine ratio.  
 
 


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APPENDIX 3. ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
> 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair > 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 MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55. 
 


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APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference:  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):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 non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan and MRI (no less than double the slice thickness and a minimum of 
10 mm) 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 


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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 non-measurable) since they 
are, by definition, simple cysts 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next.  If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 


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• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such 
as germ cell tumors, where known residual benign tumors can remain).  When effusions 
are known to be a potential adverse effect of treatment (eg, with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or SD in order to differentiate between 
response (or SD) 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 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This means 
that when lymph nodes are included as target lesions, the “sum” of lesions may not be 
zero even if CR criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  Case report recorded in a separate section where, in order to qualify 


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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”. 
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 


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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 non-measurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in “volume” (which is equivalent to a 20% increase diameter in a measurable 
lesion).  
• Examples include an increase in a pleural effusion from “trace” to “large”, an increase 
in lymphangitic disease from localized to widespread, or may be described in protocols 
as “sufficient to require a change in therapy”.  If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point.  While it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes 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 CR.  For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on trial has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
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 


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FDG-PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on 
a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment taking into account any requirement for confirmation.  On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and nontarget disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “best overall response”. 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of CR or PR 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. 


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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.” 
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 CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 


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the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (phase 2 or 3) or trials where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
results.  However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases.  If the 
proportion of patients achieving SD 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 SD. 
Note: The duration of response and SD 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. 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 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) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 


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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If 
any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin 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 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any immune-mediated AE 
(imAE) are intended as a guidance.  This document should be used in conjunction with expert 
clinical judgement (by specialist physicians experienced in the treatment of cancer using 
immunological agents), and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs.  In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis:  
• What was the temporal relationship between initiation of tislelizumab and the 
adverse event? 
• How did the patient respond to withdrawal 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: CBC, 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. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatinine kinase; CK-MB, creatinine kinase cardiac isoenzyme; CNS, central nervous 
system; CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; CBC, complete blood count; HIV, human 
immunodeficiency virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; 
LKM, liver kidney microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, 
magnetic resonance imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle 
antibody; T4, thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC,  urea electrolytes and 
creatinine. 


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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-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 
3-4 
Severe or life-
threatening symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  
Initiate pulse IV methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation.  Convert to 
oral prednisolone and taper over at 
least 1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
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 IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 2 
months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day.  Taper over at least 4 
weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
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: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment)  
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 


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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 
IV (methyl)prednisolone 
2 mg/kg/day.  When LFTs improve 
to Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day.  Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed IV methylprednisolone 
• 
If on IV, add 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 IV 
(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 IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
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 
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 IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
Admit to hospital for emergency 
care.  Consider IV corticosteroids if 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
complications or 
dehydration 
not contraindicated by infection. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia.  If symptoms do not 
improve add immunosuppressant 
therapy.  Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatinine kinase; CK-MB, creatinine kinase cardiac isoenzyme; 
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 8. COCKCROFT-GAULT FORMULA AND CALVERT 
FORMULA 
 
Abbreviation: CLcr, creatinine clearance; SCr, serum creatinine concentration. 
 
CALVERT FORMULA: 
(GFR*+25) x  AUC= dose in mg. 
* glomerular filtration rate (GFR) calculation formula is same as ClCr formula as shown above. 


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APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of exposure associated with the study treatment). 
− NOTE: Total sexual abstinence should only be used as a contraceptive method if it is 
in line with the patient’s usual and preferred lifestyle.  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with a highly effective form of birth control, listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 


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− < 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 an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
 
Adapted from Clinical Trials Facilitation Group (CTFG).  Recommendations related to contraception and pregnancy 
testing in clinical trials.  September 15, 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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APPENDIX 10. DOSE MODIFICATION GUIDELINES FOR 
CHEMOTHERAPY 
For the purposes of this protocol, the sponsor defines a chemotherapy cycle as the administration 
of at least one chemotherapy component (ie, cisplatin or gemcitabine). Cycles in which no 
chemotherapy component is given do not count toward the total number of chemotherapy cycles. 
If only tislelizumab but no chemotherapeutic partner has been administered during a cycle, the 
cycle does not count toward the total number of chemotherapy cycles. For example, if 4 cycles of 
chemotherapy were planned, but no component of chemotherapy could be administered during 
Cycle 4, Cycle 5 counts as the fourth cycle of chemotherapy. Because of the complex nature and 
possible permutations of such dosage interruptions and reintroductions, site personnel should 
contact the monitor, and the monitor will instruct the site on how to open the appropriate visits 
and electronic Case Report Form (eCRF) so that the site can then record the interruption and 
reintroduction accordingly on the eCRF. 
Dose modification should be made in accordance to prescribing information and as per 
institutional guidelines. 
• If considered in the best interest of the patient and consistent with local practice, 
investigators may decide to use supportive measures/treatment, and/or secondary 
prophylaxis instead of dose reductions for the next cycle.  
• These provided triggers for dose modifications are recommendations only.  
• Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to that of the preceding 
administration. 
• All dose modifications should be made based on the worst grade toxicity. 
Table 8. 
Chemotherapy Dose Modification for Hematological Toxicity for 
Gemcitabine and Cisplatin 
Adverse Event 
Treatment   
Febrile neutropenia; documented 
infection 
1) The first episode of febrile neutropenia or documented infection 
will result in antibiotic treatment and reduction by 25% of both drugs 
doses 
2) If there is a second episode despite dose reduction, the patient must 
receive prophylactic antibiotics during the subsequent cycles 
3) If there is a third episode, the chemotherapy will be discontinued. 
Neutropenia 
Grade 3 
(0.5-0.99 x 
109/L) 
Chemotherapy delay until ≤ Grade 1 (≥ 1.5 x 109/L); restart with the full 
dose 
Grade 4 
(< 0.5 x 109/L) 
Chemotherapy delay until recovered to ≤ Grade 1; dose reduction of all 
further doses by 25% 


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Adverse Event 
Treatment   
Thrombocytopenia 
Grade 1 
Chemotherapy delay until recovered to normal; restart with the full dose 
≥ Grade 2 
Chemotherapy delay until recovered to normal; dose reduction of all 
further doses by 25% 
Note: If considered in the best interest of the patient and consistent with local practice, investigators may decide 
to use supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle. 
The provided triggers for dose modifications are recommendations only.  
 
Recommended Dose Modifications for Non-hematologic Toxicities 
The dose adjustments of chemotherapy for non-hematologic toxicity are described in the 
following table. All dose modifications should be made based on the worst grade toxicity. 
Table 9. 
Chemotherapy Dose Modifications for Non-Hematological Toxicity for 
Gemcitabine and Cisplatin 
Toxicity 
Grade 
Treatment 
Renal 
toxicity  
≥ Grade 1 
Delay chemotherapy until recovered to Grade 0 or baseline, dose reduction by 
25% for other drug; if recur, stop chemotherapy 
Ototoxicity  
Grade 2 
dose reduction of all further doses of cisplatin by 25% 
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 2  
Sensory 
neuropathy 
Grade 2 
Dose reduction for all further doses of cisplatin by 25% 
Grade 3 
Stop cisplatin, stop gemcitabine 
Grade 4 
Stop cisplatin, and/or gemcitabine 
Other organ 
toxicity 
Grade 2 
Delay chemotherapy until ≤ Grade 1 or baseline*. 
 
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 1 or baseline*, dose reduction of 
all further dose by 25% 
Note: If considered in the best interest of the patient and consistent with local practice, investigators may decide to 
use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. The 
provided triggers for dose modifications are recommendations only.  
*Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting which may have resolved to Grade 2 or baseline. 
 


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