Clinical trial NCT03430843
Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
Keywords: Unresectable metastatic second-line squamous esophagus chemotherapy paclitaxel docetaxel irinotecan
Sponsor: BeiGene
Start date: 2018-01-26; Completion date: 2022-12-28
Enrollment: 512 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of tislelizumab as second line treatment in participants with advanced unresectable/metastatic ESCC that had progressed during or after first line therapy.

Detailed description:

Arms: arm 1: Tislelizumab on Day 1, given every 21 days arm 2: Paclitaxel on Day 1, given every 21 days or on a weekly schedule; OR Docetaxel on Day 1, given every 21 days; OR Irinotecan on Days 1 and 8, given every 21 days
Interventions: intervention 1: Tislelizumab intervention 2: Paclitaxel intervention 3: Docetaxel intervention 4: Irinotecan
Intervention descriptions: intervention 1: 200 mg administered intravenously (IV) intervention 2: 135-175 mg /m² administered IV , or 80-100 mg/m\^2 administered IV according to local guidelines for standard of care intervention 3: 75 mg/m\^2 administered IV or 70 mg/m\^2 IV in Japan intervention 4: 125 mg/m\^2 administered IV

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
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 studies. 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. 
Protocol Title:  
A Randomized, Controlled, Open-label, Global Phase 3 Study 
Comparing the Efficacy of the anti-PD-1 Antibody Tislelizumab 
(BGB-A317) versus Chemotherapy as Second Line Treatment in 
Patients with Advanced Unresectable/Metastatic Esophageal 
Squamous Cell Carcinoma 
Protocol Identifier: 
BGB-A317-302 
Phase: 
3 
Investigational Product: 
Tislelizumab (BGB-A317) 
Indication: 
Advanced Unresectable/Metastatic Esophageal Squamous Cell 
Carcinoma (ESCC) 
EudraCT: 
2017-003699-30 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1900 Powell Street, 5th Fl., Suite 500  
Emeryville, CA 94608 
USA 
Sponsor Medical Monitors: 
 
Phone number: 
 
Email
 
 
Phone number: 
 
Email: 
 
 
Phone number: 
 
Email: 
 
Original Protocol: 
13Jul2017 
Amendment 1.0: 
07Nov2017 
Amendment 2.0: 
06Dec2017 
Amendment 3.0: 
08Nov2018 
Amendment 4.0: 
20Mar2020 




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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Randomized, Controlled, Open-label, Global Phase 3 Study Comparing 
the Efficacy of the anti-PD-1 Antibody Tislelizumab (BGB-A317) versus 
Chemotherapy as Second Line Treatment in Patients with Advanced 
Unresectable/Metastatic Esophageal Squamous Cell Carcinoma 
Protocol Identifier: BGB-A317-302 
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 the entire protocol and agree to carry out the study according to this protocol. 
 
Investigator’s Signature:   
_____________________________ 
Investigator’s Printed Name:  _____________________________ 
Date (dd mmm yyyy): 
 
_____________________________ 
Name of the center in which  
the study will be conducted:  _____________________________ 


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SYNOPSIS 
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Randomized, Controlled, Open-label, Global Phase 3 Study Comparing the 
Efficacy of the anti-PD-1 Antibody Tislelizumab (BGB-A317) versus Chemotherapy as Second 
Line Treatment in Patients with Advanced Unresectable/Metastatic Esophageal Squamous Cell 
Carcinoma 
Protocol Identifier: BGB-A317-302 
Phase of Development: 3 
Number of Patients: Approximately 500 
Study Centers: Approximately 140 global centers 
Study Objectives: 
Primary: 
 To compare the overall survival (OS) in the Intention-to-Treat (ITT) population 
following treatment with tislelizumab versus investigator chosen chemotherapy (ICC) 
when given as second line treatment in patients with advanced unresectable/metastatic 
Esophageal Squamous Cell Carcinoma (ESCC)   
Secondary: 
Key Secondary:  
 To compare the OS in programmed cell death protein ligand-1 (PD-L1) positive 
population following treatment with tislelizumab versus ICC 
Other Secondary: 
 The following will be compared between tislelizumab and ICC based on assessment by 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria: 
o Overall response rate (ORR)  
o Progression-free survival (PFS) 
o Duration of response (DOR) 
 To compare patient reported outcomes of health-related quality of life (HRQoL) 
between the tislelizumab and the chemotherapy treatments 
 To compare the safety and tolerability between tislelizumab and the chemotherapy 
treatments 
Exploratory: 


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 To characterize the disease control rate (DCR) with tislelizumab compared to 
chemotherapy 
 To characterize the pharmacokinetics (PK) of tislelizumab 
 To determine host immunogenicity to tislelizumab 
 To explore potential predictive biomarkers (including but not limited to PD-L1 
expression, gene expression profiling, tumor mutation burden, microsatellite instability 
(MSI), tumor-infiltrated immune cells) and resistance mechanism 
Study Endpoints: 
Primary: 
 OS in the ITT analysis set- defined as the time from the date of randomization until the 
date of death due to any cause in all randomized patients 
Secondary: 
Key Secondary:  
 OS in the PD-L1 positive analysis set - defined as the time from the date of 
randomization until the date of death due to any cause in the PD-L1 positive population 
Other Secondary: 
 ORR in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
proportion of patients who had complete response (CR) or partial response (PR) 
assessed by the investigators per RECIST v1.1 
 PFS in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
time from the date of randomization to the date of first documentation of disease 
progression assessed by the investigators per RECIST v1.1 or death, whichever occurs 
first 
 DOR in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
time from the first determination of an objective response until the first documentation 
of progression as assessed by the investigator per RECIST v1.1, or death, whichever 
comes first 
 HRQoL assessment of the subject’s overall health status using European Organisation 
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-
C30 index, the EORTC QLQ esophageal cancer module OES18, and the generic health 
state instrument Euroqol 5D (EQ-5D-5L) in both the ITT analysis set and the PD-L1 
positive analysis set 
 The incidence and severity of adverse events according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 
Exploratory: 
 Disease control rate (DCR) in both the ITT analysis set and the PD-L1 positive 
analysis set - defined as the proportion of patients who have CR, PR, and stable disease 


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(SD) assessed by the investigators per RECIST v1.1 
 Pharmacokinetic endpoints: summary of serum concentration of tislelizumab to include 
but not limited to trough serum concentration (Ctrough) 
 Assessments of immunogenicity of tislelizumab to determine the incidence of anti-drug 
antibodies (ADA) 
 Predictive biomarkers (including but not limited to PD-L1 expression, gene expression 
profiling, tumor mutation burden, MSI, and tumor-infiltrated immune cells) and 
resistance mechanism 
Study Design: 
This is a randomized, controlled, open-label, global Phase 3 study comparing overall survival 
following treatment with the anti-PD-1 monoclonal antibody tislelizumab to ICC given as a 
second line treatment in patients with advanced unresectable/metastatic ESCC that has 
progressed during or after first line therapy. 
Before initiating this Phase 3 study in Japan, a substudy investigating the safety, tolerability, 
PK and preliminary efficacy in Japanese patients is planned (see Appendix 13 for details). 
After providing written informed consent, completing all screening assessments, and being 
confirmed as eligible for study participation, approximately 500 patients will be randomized 
1:1 to receive either tislelizumab monotherapy or investigator chosen chemotherapy 
(paclitaxel/docetaxel/irinotecan). The choice of chemotherapy must be determined prior to 
randomization.  
At randomization, patient enrollment will be stratified by the following 3 factors: 
 Region (Asia [excluding Japan] vs Japan vs United States [US]/European Union [EU]) 
 Eastern Cooperative Oncology Group performance status (0 vs 1) 
 ICC option (paclitaxel vs docetaxel vs irinotecan) 
After randomization, patients will then begin open-label treatment with one of the following 
regimens.  
 Arm A:  Tislelizumab 200 mg intravenously (IV) on Day 1, given every 21 days  
 Arm B:  One of the following three single-agent chemotherapies as determined by the 
investigator 
o paclitaxel 135-175 mg/m² IV on Day 1, given every 21 days 
 NOTE: paclitaxel may also be given in doses of 80-100 mg/m2 IV on a 
weekly schedule, according to local and/or country specific guidelines 
for standard of care 
 Japan: 100 mg/m2 IV on Day 1, 8, 15, 22, 29, and 36, followed by one 
week of rest 
o OR docetaxel 75 mg/m2 IV on Day 1, given every 21 days 
 Japan: 70 mg/m2 IV on Day 1, given every 21 days 
o OR irinotecan 125 mg/m2 IV on Days 1 and 8, given every 21 days 


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Cross-over between chemotherapy treatments or between chemotherapy and tislelizumab 
treatment arms during the study treatment period will not be allowed. 
Study treatment will be administered until disease progression, intolerable toxicity, or another 
treatment discontinuation criterion is met. Tislelizumab treatment beyond initial 
investigator-assessed RECIST v1.1 defined progression is permitted if the patient has evidence 
of “pseudo-progression” (Section 7.17.1). 
The study design schema is as follows: 
 
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ESCC, Esophageal squamous cell carcinoma; ICC, investigator 
chosen chemotherapy;  ITT, Intention-to-treat; OS, Overall survival; ORR, Overall response rate; PD-L1, Programmed cell 
death protein ligand-1; PFS, Progression-free survival; DOR, Duration of response; HRQoL, Health Related Quality of Life; 
DCR, Disease control rate;  
ADA, Anti-drug antibody. 
a. The initial infusion (Cycle 1, Day 1) will be administered over a period of 60 minutes. If this infusion is well tolerated, 
subsequent infusions may be administered over 30 minutes. After tislelizumab infusion, patients will be further monitored 
for at least 1 hour during Cycles 1 and 2. From Cycle 3 onward, a post-infusion monitoring period of at least 30 minutes 
will be required. 
b. At the discretion of the investigator, patients randomized to receive tislelizumab may be treated beyond progression under 
protocol defined conditions. See Section 7.17.1. 
Study Assessments: 
PFS and tumor response will be assessed by the investigator using RECIST v1.1 criteria 
(Eisenhauer EA, 2009). Tumor imaging (CT with or without contrast or MRI) must be 
performed within 28 days prior to randomization. On-study tumor assessments will occur 
approximately every 6 weeks (± 7 days) for 6 months, then every 9 weeks (± 7 days) until 


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disease progression. If a patient discontinues study treatment due to reasons other than disease 
progression or death, tumor assessments will continue to be performed as scheduled until the 
start of new anti-cancer therapy, disease progression, loss to follow-up, withdrawal of consent, 
death, or until study completion, whichever occurs first.  
Patient reported outcomes will be collected using the EORTC QLQ-C30, EORTC 
QLQ-OES18 and the EQ-5D-5L at baseline, Cycles 1-6 Day 1 or at the End-of-Treatment 
Visit (whichever occurs first), and at the Safety Follow-up Visit. 
Patients will be evaluated for any AEs and serious adverse events (SAEs) occurring up to 
30 days after the last dose of study drug (all severity grades, per NCI-CTCAE v.4.03) or 
initiation of a new anticancer therapy, whichever occurs first, and immune-related AEs (irAEs) 
occurring up to 90 days after the last dose of study drug regardless of initiation of a subsequent 
anticancer therapy. All drug-related SAEs will be recorded by the investigator after treatment 
discontinuation until patient death, withdrawal of consent, or loss to follow-up, whichever 
occurs first. All study drug related SAEs will be followed until they resolve to baseline or 
≤ Grade 1, the investigator assesses the AE as stable and unlikely to improve, or the patient is 
lost to follow-up, whichever occurs first.  
Safety and efficacy monitoring will be performed by an Independent Data Monitoring 
Committee (IDMC). The IDMC may recommend modifications to the study, including 
termination due to safety and/or efficacy concerns. The functions and membership of the 
IDMC will be described in an IDMC Charter. 
Key Eligibility Criteria: 
The population under study is adult patients (>18 years of age or acceptable age according to 
local regulations, whichever is older at the time of voluntarily signing of informed consent) 
with histologically confirmed diagnosis of ESCC with tumor progression during or after 
first-line treatment for advanced unresectable/metastatic disease. All patients are also required 
to have ≥ 1 evaluable lesion per RECIST v1.1 within 28 days prior to randomization, an 
Eastern Cooperative Oncology Group Performance Status score of ≤1, and adequate organ 
function. 
Investigational Product, Dose, and Mode of Administration:   
Tislelizumab will be administered at a dose of 200 mg IV on Day 1, given every 21 days. 
Reference Therapy, Dose, and Mode of Administration:   
 Paclitaxel will be administered at a dose of 135-175 mg /m² IV on Day 1, given every 
21 days 
o NOTE: paclitaxel may also be given in doses of 80-100 mg/m2 IV on a weekly 
schedule, according to local and/or country specific guidelines for standard of 
care  
o Japan: 100 mg/m2 IV on Days 1, 8, 15, 22, 29, and 36, followed by one week of 
rest 
 Docetaxel will be administered at a dose of 75 mg/m2 IV on Day 1, given every 
21 days 
o Japan: 70 mg/m2 IV on Day 1, given every 21 days 
 Irinotecan will be administered at a dose of 125 mg/m2 IV on Days 1 and 8, given 


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every 21 days 
Statistical Methods: 
Analysis Sets: 
 The Intention-to-Treat (ITT) analysis set includes all randomized patients. It will be the 
primary analysis set for the efficacy analysis  
 Safety analysis set includes all patients who received ≥ 1 dose of study treatment. It 
will be the primary analysis set for safety analysis 
 Per-Protocol (PP) analysis set includes patients who have received ≥ 1 dose of study 
medications and had no major protocol deviations that impact efficacy evaluation. 
Major protocol deviations will be determined and documented before the database lock 
for the primary analysis  
 The PD-L1 positive analysis set includes patients whose tumor and immune cell score 
(TIC score) met the pre-defined cutoff (specified in the statistical analysis plan) using 
VENTANA PD‑L1 (SP263) Cdx Assay. TIC score is the total percentage of the tumor 
area covered by tumor cells with PD-L1 membrane staining and tumor‑associated 
immune cells with PD-L1 staining at any intensity. 
 The PK analysis set includes all patients who received ≥ 1 dose of tislelizumab per the 
protocol, for whom any post-dose PK data are available 
 The ADA analysis set includes all patients who have a baseline and ≥ 1 post-baseline 
ADA result 
Statistical and Analytical Methods: 
The primary endpoint (OS) will be tested at a one-sided alpha of 0.025. If the null hypothesis 
for overall survival in the ITT analysis set is rejected, the key secondary endpoint will be 
tested sequentially for OS in the PD-L1 positive analysis set. The inferential test for OS in the 
PD-L1 positive analysis set will be stopped at the non-significant endpoint of OS in the ITT 
analysis set. The familywise type I error will be strongly controlled at one-sided level 0.025. 
Primary Efficacy Analysis: 
The primary efficacy endpoint is overall survival (OS) in the ITT analysis set as defined in the 
primary endpoint section. In the absence of death, patients will be censored either at the date 
that the patient was last known to be alive or the date of data cut-off, whichever comes earlier. 
OS will be compared between the tislelizumab and ICC arms in a stratified log-rank test using 
a significance level of one-sided 0.025.  
The null hypothesis to be tested is: 
H0:  OS in tislelizumab = OS in ICC 
against the alternative: 
H1:  OS in tislelizumab ≠ OS in ICC 
This will be the primary analysis once the targeted event number of approximately 400 is 
reached. The p-value from one-sided log-rank test will be calculated, stratified by selected 
stratification factors of ECOG performance status (0 vs 1) and ICC option (paclitaxel vs 


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docetaxel vs irinotecan). 
The median OS and the cumulative probability of OS at every 3 months if estimable, will be 
calculated for each treatment arm and presented with 2-sided 95% confidence intervals (CIs). 
Kaplan-Meier survival probabilities over time for each arm will be plotted. 
The treatment effect will be estimated by fitting a Cox regression model with treatment arm as 
a factor and with ICC and ECOG performance status as strata. From this model, the hazard 
ratio (HR) of OS will be estimated and presented with a 2-sided 95% CI. 
These analyses will be performed in the ITT analysis set as the primary analysis. Outcomes in 
the Per Protocol analysis set will be evaluated as a sensitivity analysis. 
Secondary Efficacy Analysis 
The key secondary endpoint is OS in the PD-L1 positive analysis set. 
The OS in the PD-L1 positive analysis set will be analyzed similarly as described in the 
primary analysis for OS in the ITT analysis set. 
Cochran-Mantel-Haenszel (CMH) test adjusting for selected stratification factors (ECOG and 
ICC option) in the ITT analysis set and the PD-L1 positive analysis set will be provided for 
ORR per RECIST v1.1. The 2-sided 95% CIs for the odds ratio in ORR will be calculated, as 
well as Clopper-Pearson 95% CIs of ORR for each treatment arm. 
PFS based on assessment by investigator per RECIST v1.1 will be estimated using the 
Kaplan-Meier (KM) method in the ITT analysis set and the PD-L1 positive analysis set. PFS 
censoring rule will follow United States (US) Food and Drug Administration (FDA) Guidance 
for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and Biologics (2007). 
Data for patients without disease progression or death at the time of analysis will be censored 
at the time of the last tumor assessment. Data for patients who are lost to follow-up prior to 
documented disease progression will be censored at the last tumor assessment date when the 
patient is known to be progression-free. Data for patients who start to receive new anti-cancer 
therapy prior to disease progression will be censored at the last tumor assessment date prior to 
the introduction of new therapy.  
A log-rank test stratified by selected stratification factors (ECOG and ICC option) will be used 
to test the PFS differences between two treatment arms. The stratified Cox regression will be 
used to estimate the hazard ratios of PFS. A 95% confidence interval (CI) of HR in PFS will 
be constructed. Median PFS and PFS at every 3 months for each treatment arm, if estimable, 
will be presented. 
Duration of response based on assessment by investigator will be analyzed similarly as PFS in 
the responders. 
EORTC QLQ-C30 and EORTC QLQ-OES18 will be summarized using functional 
scale/symptom scale/single item. Observed values and changes from baseline for functional 
scale/symptom scale/single item will be summarized using descriptive statistics. Time to 
clinically meaningful worsening in HRQoL domains will be estimated using Kaplan-Meier 
method. Log-rank test will be employed for testing treatment difference.  
EQ-5D-5L will be compared between tislelizumab and ICC arms. Descriptive statistics will be 
used to show the changes from baseline in each arm. These HRQoL assessments will be 
analyzed in both the ITT analysis set and the PD-L1 positive analysis set. 
Exploratory Efficacy Analysis 
Best overall response (BOR) is defined as the best response per RECIST v1.1 recorded from 
randomization until data cut or start of new anti-cancer treatment. Patients with no 
post-baseline response assessment (for any reason) will be considered non-responders for 


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BOR. The proportion and its corresponding Clopper-Pearson 95% CI for each of the response 
categories (CR, PR, SD and PD) will be presented by treatment arm.  
DCR will be analyzed similarly to ORR in the ITT analysis set and the PD-L1 positive 
analysis set. 
PD-L1 expression, gene expression profiling, tumor mutation burden, MSI, and tumor 
infiltrated immune cells may be examined in the ITT analysis set. Efficacy analyses, including 
but not limited to OS, PFS, and ORR, may be explored according to biomarker status. Other 
potential predictive markers may also be assessed. 
Safety Analysis 
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), dose intensity, and relative dose intensity. 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA®) terms and graded per NCI-CTCAE v.4.03. All treatment-emergent 
AEs (TEAEs) will be summarized. A TEAE is defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the first dose of study drug up to 
30 days following study drug discontinuation or initiation of a new anticancer therapy. TEAEs 
also include all irAEs and drug-related serious AEs recorded up to 90 days after the last dose 
of study drug regardless of whether or not the patient starts a new anticancer therapy.  
Clinical laboratory data with values outside of the normal ranges will be identified. Select 
laboratory data will be summarized by grade. Changes in vital signs will also be summarized 
by visit. 
Pharmacokinetic Analysis 
PK samples will be collected in this study as outlined in the schedule of assessments 
(Appendix 1).  
Tislelizumab serum concentration data, including but not limited to Ctrough, will be tabulated 
and summarized for each cycle at which pharmacokinetics are to be measured. Descriptive 
statistics will include means, medians, ranges, and standard deviations, as appropriate.  
Additional PK analyses may be conducted as appropriate. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
Immunogenicity Analysis 
Immunogenicity samples will be collected in this study as outlined in schedule of assessments.  
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. 
Sample Size 
The sample size calculation is based on the primary efficacy analysis of OS comparison 
between tislelizumab and ICC arms in the ITT analysis set. Assuming an OS-HR (Arm 
Tislelizumab/Arm ICC) of 0.75 and a dropout rate of 5% per year, approximately 500 patients 
will be enrolled and randomized in a 1:1 ratio to Arm Tislelizumab and Arm ICC over a 
26-month period to accumulate approximately 400 deaths, which is estimated to occur 
approximately 30.2 months after the first patient is enrolled when median OS in the 


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tislelizumab and ICC arms are 8 months and 6 months, respectively. Assuming OS-HR is 0.75, 
based on recently published results of anti-PD-1 therapies in second line treatment of ESCC 
(Kojima et al 2019; Kato et al 2019; Huang et al 2019), the study will have a power of 82% 
with a one-sided alpha of 0.025. 


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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................13 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Esophageal Carcinoma ...............................................................................................25 
1.1.1. 
Treatment Options for Esophageal Carcinoma ...........................................................25 
1.2. 
Background Information on Tislelizumab ..................................................................29 
1.2.1. 
Pharmacology .............................................................................................................29 
1.2.2. 
Clinical Pharmacology ................................................................................................30 
1.2.3. 
Summary of Relevant Clinical Experience With Tislelizumab ..................................31 
1.2.4. 
Benefit-Risk Assessment ............................................................................................33 
1.3. 
Study Conduct ............................................................................................................33 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................34 
2.1. 
Objectives ...................................................................................................................34 
2.1.1. 
Primary Objective .......................................................................................................34 
2.1.2. 
Secondary Objectives .................................................................................................34 
2.1.3. 
Exploratory Objectives ...............................................................................................34 
2.2. 
Endpoints ....................................................................................................................35 
2.2.1. 
Primary Endpoint ........................................................................................................35 
2.2.2. 
Secondary Endpoints ..................................................................................................35 
2.2.3. 
Exploratory Endpoints ................................................................................................35 
3. 
STUDY DESIGN .......................................................................................................36 
3.1. 
Summary of Study Design ..........................................................................................36 
3.2. 
Study Schematic .........................................................................................................36 
3.3. 
Duration of Study .......................................................................................................37 
3.3.1. 
Screening Phase ..........................................................................................................37 
3.3.2. 
Treatment Phase ..........................................................................................................37 


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3.3.3. 
End of Treatment ........................................................................................................39 
3.3.4. 
Safety Follow-up Phase ..............................................................................................39 
3.3.5. 
Survival Follow-up Phase ...........................................................................................40 
3.3.6. 
End of Study ...............................................................................................................40 
3.4. 
Study Rationale ...........................................................................................................41 
3.4.1. 
Rationale for Tislelizumab in the Treatment of ESCC ...............................................41 
3.4.2. 
Rationale for Selection of Tislelizumab Fixed Dose ..................................................41 
3.4.3. 
Rationale for Selection of Paclitaxel/Docetaxel/Irinotecan as Comparator ...............42 
3.4.4. 
Rationale of Stratification Factors ..............................................................................42 
4. 
MATERIALS AND METHODS ...............................................................................44 
4.1. 
Selection of Study Population ....................................................................................44 
4.1.1. 
Inclusion Criteria ........................................................................................................44 
4.1.2. 
Exclusion Criteria .......................................................................................................45 
5. 
STUDY TREATMENT ..............................................................................................49 
5.1. 
Formulation, Packaging, Handling, and Storage ........................................................49 
5.1.1. 
Tislelizumab ...............................................................................................................49 
5.1.2. 
Paclitaxel .....................................................................................................................49 
5.1.3. 
Docetaxel ....................................................................................................................49 
5.1.4. 
Irinotecan ....................................................................................................................50 
5.2. 
Dosage, Administration, and Compliance ..................................................................50 
5.2.1. 
Tislelizumab ...............................................................................................................50 
5.2.2. 
Paclitaxel .....................................................................................................................51 
5.2.3. 
Docetaxel ....................................................................................................................52 
5.2.4. 
Irinotecan ....................................................................................................................52 
5.3. 
Handling of Overdose .................................................................................................53 
5.4. 
Investigational Medicinal Product Accountability .....................................................53 
5.5. 
Disposal and Destruction ............................................................................................54 
6. 
PRIOR, CONCOMITANT AND SUPPORTIVE THERAPY ...................................55 
6.1. 
Prior Therapy ..............................................................................................................55 
6.2. 
Concomitant Therapy .................................................................................................55 
6.2.1. 
Permitted Therapy ......................................................................................................55 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................56 


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6.3. 
Rescue Medication and Supportive Care ....................................................................57 
6.3.1. 
Supportive Care guidelines for Tislelizumab .............................................................57 
6.3.2. 
Supportive Care guidelines for Paclitaxel, Docetaxel and Irinotecan ........................58 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................59 
7.1. 
Informed Consent Form and Screening Log Completion...........................................59 
7.2. 
Medical History and Demographic Data Collection ..................................................59 
7.3. 
Eastern Cooperative Oncology Group Performance Status Grading .........................60 
7.4. 
Antitumor Activity and Response Assessment...........................................................60 
7.5. 
Adverse Event Collection ...........................................................................................61 
7.6. 
Physical Examinations ................................................................................................61 
7.7. 
Ophthalmologic Examinations ...................................................................................61 
7.8. 
Vital Signs Assessment...............................................................................................62 
7.9. 
Electrocardiograms .....................................................................................................62 
7.10. 
Clinical Laboratory Tests and Pharmacokinetic Blood Sampling ..............................62 
7.11. 
Anti-drug Antibody Evaluation Procedures ...............................................................63 
7.12. 
Tumor Tissue and Biomarker Assessment Procedures ..............................................63 
7.13. 
Health-Related Quality of Life Assessment ...............................................................64 
7.14. 
Timing of Assessments during the Treatment Phase ..................................................64 
7.15. 
Safety Follow-up ........................................................................................................65 
7.16. 
Survival Follow-up .....................................................................................................65 
7.17. 
Patient, Treatment, Study, and Site Discontinuation ..................................................65 
7.17.1. 
Discontinuation of Patients .........................................................................................65 
7.17.2. 
Study Termination and Study Site Closure ................................................................67 
8. 
SAFETY MONITORING AND REPORTING .........................................................68 
8.1. 
Risks Associated With Study Drugs ...........................................................................68 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................68 
8.1.2. 
Risks Associated with Chemotherapy (Paclitaxel/Docetaxel/Irinotecan) ..................68 
8.1.3. 
General Plan to Manage Safety Concerns ..................................................................69 
8.2. 
Adverse Events ...........................................................................................................71 
8.2.1. 
Definition and Reporting Guidelines ..........................................................................71 
8.2.2. 
Assessing Severity ......................................................................................................71 
8.2.3. 
Definition of a Serious Adverse Event .......................................................................72 


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8.2.4. 
Assessing Causality ....................................................................................................73 
8.2.5. 
Laboratory Test Abnormalities ...................................................................................73 
8.2.6. 
Follow up of Adverse Events .....................................................................................74 
8.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................74 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events .................................74 
8.4.1. 
Reporting All Adverse Events ....................................................................................74 
8.4.2. 
Reporting Serious Adverse Events .............................................................................75 
8.4.3. 
Eliciting Adverse Event Information ..........................................................................76 
8.4.4. 
Recording Disease Progression ..................................................................................76 
8.4.5. 
Recording Deaths ........................................................................................................76 
8.4.6. 
Recording Pregnancies ...............................................................................................76 
8.4.7. 
Recording Post-Study Adverse Events .......................................................................77 
8.4.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................77 
8.5. 
Independent Data Monitoring Committee ..................................................................77 
8.6. 
Dose Delays or Modifications ....................................................................................78 
8.6.1. 
Dose Delay or Modification for Tislelizumab ............................................................78 
8.6.2. 
Dose Delay, Interruption or Modification for Paclitaxel, Docetaxel and 
Irinotecan ....................................................................................................................78 
8.7. 
Criteria for Permanent Discontinuing Chemotherapy Regimens ...............................84 
8.8. 
Management of AE of Special Interest .......................................................................85 
8.8.1. 
Assessing and Recording Immune-Related Adverse Events ......................................85 
8.8.2. 
Managing Immune-Related Adverse Events ..............................................................86 
8.8.3. 
Managing Infusion-Related Reactions due to Tislelizumab .......................................86 
8.8.4. 
Medical Management Guidelines for Infusion-Related Reactions (All 
Grades) ........................................................................................................................87 
8.8.5. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................88 
8.8.6. 
Renal Function Abnormalities ....................................................................................88 
9. 
STATISTICAL METHODS AND ANALYSIS PLAN .............................................90 
9.1. 
Analysis Sets ...............................................................................................................90 
9.2. 
Patient Disposition ......................................................................................................90 
9.3. 
Demographic and Other Baseline Characteristics ......................................................90 
9.4. 
Prior and Concomitant Therapies ...............................................................................91 


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9.5. 
Efficacy Analyses .......................................................................................................91 
9.5.1. 
Primary Efficacy Analyses .........................................................................................91 
9.5.2. 
Secondary Efficacy Analyses .....................................................................................92 
9.5.3. 
Exploratory Efficacy Analyses ...................................................................................93 
9.6. 
Safety Analyses ..........................................................................................................93 
9.6.1. 
Extent of Exposure .....................................................................................................93 
9.6.2. 
Adverse Events ...........................................................................................................93 
9.6.3. 
Clinical Laboratory Analyses .....................................................................................94 
9.6.4. 
Vital Signs Analyses ...................................................................................................94 
9.6.5. 
Ophthalmologic Examination .....................................................................................94 
9.7. 
Pharmacokinetic Analyses ..........................................................................................94 
9.8. 
Immunogenicity Analyses ..........................................................................................95 
9.9. 
Determination of Sample Size ....................................................................................95 
9.10. 
Interim Analysis ..........................................................................................................95 
10. 
DATA HANDLING AND QUALITY ASSURANCE ..............................................96 
10.1. 
Data Collection ...........................................................................................................96 
10.2. 
Data Management/Coding ..........................................................................................96 
10.3. 
Quality Assurance .......................................................................................................97 
10.4. 
Data Integrity Protection Plan and In-house Blinding ................................................97 
10.5. 
Study Records Retention ............................................................................................97 
10.6. 
Publication and Data Sharing Policy ..........................................................................98 
11. 
ETHICAL CONSIDERATIONS..............................................................................100 
11.1. 
Compliance with Laws and Regulations ..................................................................100 
11.2. 
Informed Consent .....................................................................................................100 
11.3. 
Institutional Review Board/Independent Ethics Committee ....................................100 
11.4. 
Confidentiality ..........................................................................................................101 
11.5. 
Financial Disclosure .................................................................................................101 
12. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .......103 
12.1. 
Study Documentation ...............................................................................................103 
12.1.1. 
Access to Information for Monitoring ......................................................................103 
12.1.2. 
Access to Information for Auditing or Inspections ..................................................103 
12.2. 
Case Report Forms ...................................................................................................103 


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12.3. 
Protocol Deviations ..................................................................................................104 
12.4. 
Study Site Inspections...............................................................................................104 
12.5. 
Protocol Amendments ..............................................................................................104 
13. 
REFERENCES .........................................................................................................105 
14. 
APPENDICES ..........................................................................................................110 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................110 
APPENDIX 2. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................115 
APPENDIX 3. ECOG PERFORMANCE STATUS-GRADING SYSTEM ............................124 
APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................125 
APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL” AND “WOMEN OF NO 
CHILDBEARING POTENTIAL” ............................................................................127 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................129 
APPENDIX 7. EORTC-QLQ-C30 QUESTIONNAIRE ..........................................................130 
APPENDIX 8. EORTC QLQ-OES18 QUESTIONNAIRE ......................................................132 
APPENDIX 9. EQ-5D-5L QUESTIONNAIRE........................................................................133 
APPENDIX 10. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................135 
APPENDIX 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................148 
APPENDIX 12. DETERMINING LINE OF THERAPY IN ESCC 1 ......................................149 
APPENDIX 13. SAFETY RUN-IN SUBSTUDY INVESTIGATING SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND PRELIMINARY 
ANTITUMOR ACTIVITY OF ANTI-PD-1 MONOCLONAL ANTIBODY 
TISLELIZUMAB IN JAPANESE PATIENTS WITH ADVANCED 
UNRESECTABLE/METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA ..........................................................................................................150 
SYNOPSIS FOR SUBSTUDY ....................................................................................................151 
1. 
INTRODUCTION ....................................................................................................156 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................156 
2.1. 
Objectives .................................................................................................................156 
2.1.1. 
Primary Objectives ...................................................................................................156 
2.1.2. 
Secondary Objectives: ..............................................................................................156 


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2.1.3. 
Exploratory Objectives .............................................................................................156 
2.2. 
Endpoints ..................................................................................................................156 
2.2.1. 
Primary Endpoints ....................................................................................................156 
2.2.2. 
Secondary Endpoints ................................................................................................157 
2.2.3. 
Exploratory Endpoints ..............................................................................................157 
3. 
STUDY DESIGN .....................................................................................................158 
3.1. 
Summary of Study Design ........................................................................................158 
3.2. 
Schedule of Study Assessments................................................................................158 
3.3. 
Duration of Study .....................................................................................................164 
3.4. 
Dose-Limiting Toxicities ..........................................................................................164 
3.5. 
Study Rationale .........................................................................................................164 
4. 
MATERIALS AND METHODS .............................................................................165 
4.1. 
Selection of Study Population ..................................................................................165 
4.1.1. 
Inclusion Criteria ......................................................................................................165 
4.1.2. 
Exclusion Criteria .....................................................................................................166 
5. 
STUDY TREATMENT ............................................................................................169 
5.1. 
Formulation, Packaging, Handling, and Storage ......................................................169 
5.2. 
Dosage, Administration, and Compliance ................................................................169 
5.3. 
Handling of Overdose ...............................................................................................169 
5.4. 
Investigational Medicinal Product Accountability ...................................................169 
5.5. 
Disposal and Destruction ..........................................................................................169 
6. 
PRIOR AND CONCOMITANT THERAPY ...........................................................169 
7. 
STUDY ASSESSMENTS AND PROCEDURES ....................................................170 
8. 
SAFETY MONITORING AND REPORTING .......................................................171 
9. 
STATISTICAL METHODS AND ANALYSIS PLAN ...........................................173 
9.1. 
Analysis Sets .............................................................................................................173 
9.2. 
Patient Disposition ....................................................................................................173 
9.3. 
Demographic and Other Baseline Characteristics ....................................................173 
9.4. 
Prior and Concomitant Therapies .............................................................................173 
9.5. 
Analyses ....................................................................................................................173 
9.5.1. 
Primary Analyses ......................................................................................................173 
9.5.2. 
Secondary Analyses ..................................................................................................174 


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9.5.3. 
Exploratory Analyses ................................................................................................174 
9.6. 
Safety Analyses ........................................................................................................174 
9.7. 
Pharmacokinetic Analyses ........................................................................................174 
9.8. 
Immunogenicity Analyses ........................................................................................175 
10. 
DATA HANDLING AND QUALITY ASSURANCE ............................................175 
11. 
ETHICAL CONSIDERATIONS..............................................................................175 
12. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .......175 
 


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LIST OF TABLES 
Table1: 
Second-Line Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma ...................................................................................................................27 
Table 2: 
Treatment Plan ............................................................................................................38 
Table 3: 
Selection and Timing of Dose for Each Patient ..........................................................50 
Table 4: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................75 
Table 5: 
Immune-Related Adverse Events Associated with Anti-PD-1 Drugs ........................86 
Table 6: 
Treatment Modification Guidelines for Symptoms of Infusion-Related 
Reactions Due to Tislelizumab ...................................................................................87 
Table 7: 
Japan Substudy Schedule of Assessments ................................................................159 
Table 8: 
Schedule of Japan Substudy Pharmacokinetic Sampling and 
Anti-Tislelizumab Antibody Sampling .....................................................................163 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................36 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve-time curve 
BGB-A317 
Tislelizumab, a humanized monoclonal antibody directed at PD-1 
BOR 
Best overall response 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CSR 
Clinical Study Report 
DCR 
Disease control rate 
DOR 
Duration of response 
EAC 
Esophageal adenocarcinoma 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EORTC QLQ-OES18 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Oesophagus Cancer Module 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life 5-Dimensions (EQ-5D-5L Version) 
ESCC 
Esophageal squamous cell carcinoma 
Fc 
Fragment crystallizable region  
FcγR 
Fc Gamma receptor (eg, Fcγ-RI, Fcγ-R2I) 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HRQoL 
Health Related Quality of Life 
ICC 
Investigator chosen chemotherapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonization  
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  
IMP 
Investigational medicinal product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
IV 
Intravenous (Intravenously) 
KD 
Dissociation constant 
KM 
Kaplan-Meier 
LDH 
Lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PD-L1 
Programmed cell death protein ligand-1 
PET 
Positron emission tomography 


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Abbreviation 
Definition 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PT  
Preferred term 
Q2W 
Once every 2 weeks 
Q3W 
Once every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
 


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1. 
INTRODUCTION 
1.1. 
Esophageal Carcinoma 
Esophageal cancer is the eighth most common cancer worldwide and the sixth most common 
cause of death from cancer (GLOBOCAN, 2012). The incidence, prevalence, and histologic type 
of esophageal cancer varies between geographic regions, particularly between Western countries 
(US and Europe) and an area commonly referred to as the “esophageal cancer belt”, which is a 
geographic area stretching across Central-Eastern Asia from the Caspian region to northern 
China (Arnold M, 2015). To illustrate, an estimated 16,940 people in the US will be diagnosed 
with esophageal cancer and 15,690 people will eventually die of their disease in 2017 
(Siegel RK, 2017). The predominant histologic type of these new diagnoses in the US will be 
adenocarcinoma. The 5-year survival rates are 18.4% in the United States (Siegel RK, 2017) and 
12 % in Europe (De Angelis R, 2014). In contrast, in China, an estimated 477,900 people will be 
diagnosed with esophageal cancer, 90% of which will be of the squamous cell carcinoma 
histology, and 375,000 people will die of this disease (Chen W, 2016; Arnold M, 2015). The 
age-standardized five-year relative survival rate for patients in China diagnosed in 2003–2005 is 
20.9% (Li M, 2017). 
Recognized risk factors for developing both adenocarcinoma and squamous cell esophageal 
carcinoma include poor nutritional status, low intake of fruits and vegetables, drinking alcohol, 
smoking tobacco, chewing betel quid, and drinking liquids, such as mate, at high temperatures, 
obesity, and chronic gastroesophageal reflux disease (GERD). Esophageal cancer of either 
histology is much more prevalent in men and more common in an older patient population  
(Shah MA, 2015).   
Advanced esophageal cancer is a rapidly fatal disease. Approximately 40% of patients diagnosed 
with esophageal cancer will have advanced or metastatic disease, with a median survival of 8-10 
months and an expected 5-year survival rate < 5% (Lin M, 2016; Drahos J, 2013). These data, 
combined with the relative lack of highly effective treatment, are indicative of the large unmet 
medical need in patients diagnosed with esophageal cancer.  
1.1.1. 
Treatment Options for Esophageal Carcinoma 
Esophageal cancer treatment is based on the extent of disease at presentation and tumor 
histology. International treatment guidelines are consistent in the approach to the treatment of 
this disease. Therapeutic treatment modalities include endoscopic resection for focal disease or 
esophagectomy with lymph node resection for larger tumors in patients who are considered 
medically fit (Lordick F, 2016; NCCN Guidelines Version 1, 2017; Japanese Gastric Cancer 
Association Gastric Cancer, 2017; Stahl M, 2009). Chemoradiation therapy may be given to 
those with larger tumors in the neo-adjuvant, peri adjuvant or in the adjuvant setting. 
Post-operative chemotherapy or chemoradiation is commonly given to patients who have 
positive lymph nodes after R0 resection, or those with microscopic or macroscopic residual 
cancer (R1 and R2 resection, respectively) after surgery. Systemic regimens given in the 
pre-operative or peri-operative setting commonly include chemotherapy doublets which include 
taxanes, platinum agents, fluorouracil, or irinotecan. Triplet combinations may also be 
considered, such as epirubicin, oxaliplatin and fluorouracil/capecitabine, but are more toxic and 
restricted to those patients with good performance status. In the pre-operative or peri-operative 


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setting, the choice of chemotherapy regimen is made independent of the tumor histology 
(Lordick F, 2016; NCCN Guidelines Version 1, 2017; Japanese Gastric Cancer Association 
Gastric Cancer, 2017; Stahl M, 2009). 
The choice of systemic chemotherapy agents for patients who are not surgical candidates or 
those who have recurrent or metastatic disease that cannot be adequately treatment with local 
therapy are similar to those described above, and also similar to those treatments given to 
patients with advanced gastric cancer (Lordick F, 2016). The choice of agents or regimen may be 
based on the patient’s performance status, and underlying comorbidities. Fluoropyrimidines 
(either 5-Flourouracil or capecitabine) as monotherapy or in combination with either cisplatin or 
oxaliplatin, taxanes (either paclitaxel or docetaxel) given as monotherapy or with platinum 
agents, or irinotecan in combination with 5-fluorouracil are suitable front-line treatments. The 
only difference in treatment recommendations between different esophageal histologic subtypes 
is the use of ramucirumab, which is indicated in combination with paclitaxel for patients with 
adenocarcinoma of the esophagus. 
The overall response rate (ORR) to first-line chemotherapy for advanced or metastatic disease 
ranges from 20% to 48% and 5 -year survival rates of lower than 30% with significant toxicity 
rates (Grunberger B, 2007). There is no global consensus on the optimal second-line treatment. 
Very few prospective clinical studies have been completed evaluating second line treatments in 
esophageal carcinoma. Clinical studies have not shown that combination chemotherapy impart 
an overall survival advantage compared to monotherapy, and have shown that combination 
chemotherapies are associated with more toxicities (Song ZB, 2014; Thallinger CM, 2011; 
Albertsson M, 2007). Chemotherapy monotherapy is typically given, and include paclitaxel, 
docetaxel or irinotecan (Thallinger CM, 2011). There are regional preferences for the 
chemotherapy of choice and may be based on the toxicity profile of each agent. The following 
table (Table1) summarizes the efficacy outcomes between the 3 chemotherapies allowed in this 
protocol. It should be noted that some publications are summarizing data from retrospective 
analyses (Shirakawa T, 2014; Song ZB, 2014; Mizota A, 2011; Fukushima R, 2014). Given these 
caveats, the ORR and median survival appear comparable amongst paclitaxel, docetaxel, and 
irinotecan. 


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Table1: 
Second-Line Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma 
Agent 
(Reference) 
Sample Size 
by Histology 
 (n) 
Treatment 
setting 
Regimen 
ORR (%) 
OS 
(median 
months) 
Paclitaxel 
(Ilson DH, 2007) 
ESCC  
(n=32) 
 
1st/2nd line 
80 mg/m2 weekly x 
4 weeks every 28 days 
13% (1L);  
8% (2L) 
NR for ESCC 
subset 
Paclitaxel 
(Mizota A, 2011) 
ESCC (n=35) 
EAC (n=3) 
2nd line 
80 -100 mg/m2 Day 1, 8, 
15 every 28 days 
25.7%* 
7.2* 
Paclitaxel 
(Kato K, 2011) 
ESCC (n=52) 
EAC (n=1) 
NR** 
100 mg/m2 Days 1,8, 15, 
22, 29, and 36 every 49 
days 
44% 
10.4 
Paclitaxel 
(Shirakawa T, 2014) 
ESCC 
(n= 31) 
2nd line 
100 mg/m2 weekly x 6  
1-week rest 
19.4% 
 
6.1 
 
Docetaxel 
(Song ZB, 2014) 
ESCC  
(n=41) 
2nd line 
Not specified 
19.5% 
 
5.2 
Docetaxel 
(Mizota A, 2011) 
ESCC (n=84) 
EAC (n=2) 
2nd line 
60- 70 mg/m2  
Q3W 
10.3%* 
6.1* 
Docetaxel 
(Shirakawa T, 2014) 
ESCC  
n=132 
2nd line 
70 mg/m2   
Q3W 
5.3% 
5.5 
Docetaxel 
(Muro K, 2004) 
ESCC (n=46) 
EAC (n=1) 
Other (n=1) 
Advanced 
70 mg/m2   
Q3W 
20% 
8.1 
Irinotecan 
(Mühr-Wilkenshoff 
F, 2003) 
ESCC (n=10) 
EAC (n=3) 
1st/2nd line 
125 mg/m2 Weekly x 
4 with 2 weeks’ rest 
20% 
ESCC only 
6.4* 
Irinotecan 
(Burkart C, 2007) 
ESCC (n=7) 
EAC (n=7) 
2nd line 
100 mg/m2 Weekly x 
3 every 4 weeks 
15%* 
5* 
Irinotecan 
(Fukushima R, 2014) 
ESCC 
n=29 
NR** 
Not specified 
4% 
4.1 
Abbreviations: ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma. 
*Combined ESCC and EAC histology 
** line of therapy not specified; all patients received prior treatment for esophageal cancer 
1.1.1.1. 
Anti-PD-1/Anti-PD-L1 Therapy for Advanced Esophageal Squamous Cell 
Carcinoma  
Clinical outcome data are available from early phase studies evaluating tislelizumab, nivolumab, 
and pembrolizumab in patients with advanced esophageal carcinoma. 
Tislelizumab 
As of 20 May 2019, there are 22 ongoing clinical studies with tislelizumab with over 1705 
patients treated. Of these, 13 studies have preliminary data available in the Investigator’s 
Brochure (IB): 7 monotherapy studies, 2 chemotherapy combination therapy studies, and 4 
investigational agent combination therapy studies. Information about the safety and efficacy 
signals in these clinical studies may be found in the Tislelizumab Investigator’s Brochure. 


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Tislelizumab in advanced esophageal carcinoma 
As of 20 May 2019, 54 patients with advanced esophageal carcinoma (adenocarcinoma, n=23; 
squamous, n=26; other, n=5; missing, n=1) were enrolled in a Phase 1 clinical study (Study 
BGB-A317_Study_001). The median age of these enrolled patients is 62 years (range 30-80 
years), 41 patients are men and 28 patients are white, 21 patients are Asian, and 5 are other races.  
Prior to study enrollment, these patients had received a median of 2 (range 0-7) prior treatment 
regimens for their esophageal cancer, with 12 patients having received at least 3 prior treatments.   
Tislelizumab was administered for a median of 2.1 months (range 0.2-31.7 months) in this 
patient cohort. Patients received BGB-A317 at a variable dose of 5 mg/kg; 1 patient was treated 
at the 2 mg/kg dose or a fixed dose of 200 mg.  
The majority (n=52 [96.3%]) of patients experienced at least 1 treatment-emergent adverse 
event. Twenty-eight (51.9%) patients experienced a treatment-related adverse event. The most 
common treatment-emergent adverse events reported in ≥ 5% of patients in the esophageal 
cohort of any grade or causality included fatigue (27.8%); decreased appetite (22.2%); nausea 
(20.4%); cough and constipation (18.5% each); back pain (13.0%); diarrhoea, vomiting, 
dyspnoea and pyrexia (11.1% each); abdominal pain upper, anaemia, arthralgia, 
gastroesophageal reflux disease, hypercalcaemia, hypothyroidism, pneumonia, upper respiratory 
infection, and weight decreased (9.3% each); abdominal pain and musculoskeletal pain (7.4% 
each); dysphagia, headache, hypokalaemia, infusion-related reaction, insomnia, myalgia, neck 
pain, oedema peripheral, oesohageal obstruction, pleural effusion, proteinuria, and pruritus (5.6% 
each). 
Serious adverse events were reported in 19 patients (35.2%). The serious adverse events that 
occurred in more than 1 patient included esophageal obstruction in 2 patients (3.7%), pneumonia 
in 4 patients (7.4%), and lower respiratory tract infections in 2 patients (3.7%). One patient 
experienced a treatment-related NCI-CTCAE Grade 3 event of dermatitis. 
Three patients reported adverse events with fatal outcome: mediastinitis (1), sepsis (1), and 
hemoptysis (1). These events are recognized complications of esophageal carcinoma; none were 
considered related to study treatment. 
Of 54 esophageal carcinoma patients, 53 patients were evaluable for response. Confirmed 
complete and partial responses were observed in 1 patient (1.9%) and 5 patients (9.4%), 
respectively. The resulting ORR was 11.3%. In addition, 14 patients (26.4%) had a best overall 
response of stable disease (SD). A total of 24 patients (45.3%) had a best response of progressive 
disease (PD) in this cohort, and the assessments for 8 patients (15.1%) were missing. 
Nivolumab 
Efficacy results in ESCC patients treated with nivolumab, an anti-PD-1 monoclonal antibody, 
were reported from an open-label, single-arm, multi-center phase 2 study (Kudo T, 2017). This 
study enrolled 65 patients with squamous cell esophageal carcinoma even though the study was 
designed to recruit patients with squamous, adenocarcinoma, or adeno-squamous cell histologies. 
These patients were considered refractory or intolerant to fluoropyrimidine, platinum, and 
taxane-based chemotherapies. Patients were treated with nivolumab 3 mg/kg given intravenously 
once every 2 weeks (Q2W). Tumor response was assessed approximately every 6 weeks. Median 
follow-up was 10.8 months (Interquartile range 4.9–14.3) and patients received a median of 


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3 nivolumab cycles (range 1-10). The ORR by central radiology assessment was 17% (95% 
CI:10-28) and 22% (95% CI:14-33) by investigator assessment. The DCR, defined as the number 
of patients with a complete or partial response, and those with stable disease of any duration was 
42% (95% CI: 31-54) by centrally assessment and 53% (95% CI:41-65) patients by investigator 
assessment. The median duration of overall survival was 10.8 months (95% CI 7.4–13.3). The 
median durations of progression-free survival were 1.5 (95% CI: 1.4-2.8) and 2.3 (95% CI:1.5–
3.0) months, by central and investigator assessment, respectively. IrRECIST objective response 
and disease control were reported in 16 patients (25%, 95% CI: 16-37) and 43 patients (67%, 
95% CI: 55-77), respectively, and median irRECIST progression-free survival was 2.9 months 
(95% CI:1.9-5.6).  
Pembrolizumab 
KEYNOTE-028 (NCT02054806), a multicohort, phase 1b study recruited advanced esophageal 
squamous cell carcinoma and adenocarcinoma patients with disease progression following 
standard therapy. Patients received pembrolizumab 10 mg/kg Q2W. Response was assessed 
every 8 weeks for the first 6 month and every 12 weeks thereafter. Primary endpoint was ORR 
per RECIST v1.1 by investigator review. In this cohort of 23 patients, 87% received ≥ 2 prior 
therapies for metastatic disease and 17 patients had esophageal squamous cell carcinoma. After a 
median follow-up of 7.1 months (range, 1.3-19.4 months), ORR was 30% (95% CI: 13%-53%) 
(five patients with a response had ESCC and 2 patients had adenocarcinoma) and the stable 
disease rate was 9% (95% CI, 1%-28%). The median duration of response was not reached 
(range, 5.5-11.8 months). The median time to response was 3.7 months (range, 1.8-8.3 months) 
(Doi T, 2016). 
1.2. 
Background Information on Tislelizumab 
1.2.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against programmed cell death protein-1 (PD-1) under clinical 
development for the treatment of certain 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 by 
both programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-
2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T-cells. In in vitro cell-based 
assays, tislelizumab was observed to consistently and dose-dependently enhance the functional 
activity of human T-cells and pre-activated, primary peripheral blood mononuclear cells. In 
addition, tislelizumab has demonstrated antitumor activity in several allogeneic xenograft 
models, in which peripheral blood mononuclear cells were co-injected with human cancer cells 
(A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
In addition, tislelizumab is an IgG4 variant antibody to gamma fragment crystallizable region 
(Fc) receptors (FcγR) such as FcγRI and FcγRIIIA, and has very low binding affinity to 
Complement 1q (C1q), a subunit of complement 1. In vitro assays with tislelizumab suggest 
either low or no antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular 


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phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC) effects in humans  
(Labrijn et al 2009; Zhang et al 2018). 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab.  
1.2.2. 
Clinical Pharmacology 
1.2.2.1. 
Pharmacokinetics 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim pharmacokinetics 
(PK) analysis (data cutoff date of 28 August 2017) was conducted using noncompartmental 
methods, using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, and 
10 mg/kg Q2W, and 2.0 mg/kg, 5.0 mg/kg, and 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 (AUC) 
increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both after 
single-dose administration and 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 plasma clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution 
(Vd) in the central and peripheral compartments of 2.89 L and 1.76 L, respectively, and half-life 
(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. 
1.2.2.1.1. Lack of Ethnic Differences in Exposure 
Based on the information available to date, tislelizumab exposure in Asian and Caucasian 
patients is similar, and the safety profile at clinically relevant doses is tolerable and manageable. 
Preliminary PK data from Study BGB-A317_Study_001 are summarized in Section 1.2.2.1 
above. Comparison of PK parameters indicates that after a single intravenous (IV) infusion of 
tislelizumab, dose-normalized exposure (AUC0-14day) was consistent between Study 001 with 
non-Chinese (n=91 mostly Caucasian) and Study 102 with Chinese (n=20) patients in the study, 
which was conducted in the US, Australia, New Zealand, Korea, and Taiwan. Additionally, 
dose-normalized exposure (AUC0-14day) was consistent between BGB-A317_Study_ 001 across 
Asian (n=27, including 20 Chinese and 7 non-Chinese Asian) and Caucasian (n=80). 
These preliminary findings indicate that ethnic differences are unlikely to affect the exposure of 
tislelizumab.  
Furthermore, these data are consistent with findings of limited ethnic differences in studies of 
therapeutic monoclonal antibodies (Chiba et al 2014, Matsushima et al 2015, Zhou et al 2012). In 
addition, there do not appear to be clinically relevant differences in PK exposures from studies of 
2 other anti-PD-1 antibodies, nivolumab and pembrolizumab (Shimizu et al 2016; Yamamoto et 
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1.2.3. 
Summary of Relevant Clinical Experience With Tislelizumab 
As of 20 May 2019, there are 22 ongoing studies with tislelizumab, 13 ongoing with available 
preliminary data: monotherapy studies BGB-A317_Study_001, BGB-A317-102, 
BGB-A317-203, BGB-A317-204, BGB-A317-207, BGB-A317-208, and BGB-A317-209; 
chemotherapy combination therapy studies BGB-A317-205 and BGB-A317-206; and 
investigational agent combination therapy studies BGB-A317/BGB-290_Study_001 
(tislelizumab in combination with BGB-290 [also known as pamiparib, a poly (ADP-ribose) 
polymerase (PARP) inhibitor]), BGB-3111_BGB-A317_Study_001 (tislelizumab in combination 
with zanubrutinib [also known as BGB-3111, a Bruton’s tyrosine kinase (BTK) inhibitor]), and 
BGB-900-101 (BGB-A333 [an anti-PD-L1 monoclonal antibody] alone and in combination with 
tislelizumab), and BGB-900-103 (tislelizumab in combination with sitravatinib [also known as 
MGCD516, a receptor tyrosine kinase inhibitor]).  
The 9 ongoing studies without available clinical data include BGB-A317-301, BGB-A317-302, 
BGB-A317-303, BGB-A317-304, BGB-A317-305, BGB-A317-306, BGB-A317-307, 
BGB-900-102, and BGB-900-104. 
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy. For monotherapy, the safety profile is similar 
across tumor types. There is no pattern in the incidence, severity, or causality of adverse events 
(AEs) to tislelizumab dose level. The safety profile for single-agent tislelizumab is similar to 
those observed in other PD-1 inhibitors. The initial data collected in these studies suggest that 
tislelizumab can result in antitumor activity across a variety of tumor types. Antitumor activity 
has been observed across the dose ranges evaluated in patients. In Phase 3 controlled studies, the 
safety profile of tislelizumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. Please find the overview of safety 
and efficacy in Section 1.2.3.1 and Section 1.2.3.2. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on 
efficacy and safety of tislelizumab. 
1.2.3.1. 
Overview of Safety 
There were 1,273 patients in the Pooled Monotherapy studies. Of the 1,273 enrolled, 
544 patients (42.7%) remained on study as of 20 May 2019; 272 patients (21.4%) were still 
receiving tislelizumab treatment, and 272 patients (21.4%) were in follow-up. At the time of data 
cut-off, 785 patients had a dosing period of ≥ 2 months, ie, evaluable for treatment assessment 
beyond 2 months. Among them, 261 patients (33.2%) continued to receive tislelizumab 
treatment.  
All patients in the pooled monotherapy analysis had a median treatment exposure duration of 
3.58 months (range: 0.1 to 43.6) and median study follow-up duration of 8.34 months (range: 0.1 
to 47.5). Overall, the total pooled monotherapy population had a median age of 59 years and was 
66.9% male. 
The median number of prior systemic anti-cancer therapy regimens for the solid tumor, 
hematologic malignancy, and total populations were 1.0 (range: 0 to 12), 3.0 (range: 0 to 11), 
and 1.0 (range: 0 to 12), respectively. 


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Preliminary Safety 
Of the 1,273 total patients treated in the Pooled Monotherapy studies, 846 (66.5%) experienced 
at least one treatment-related TEAE. The most commonly occurring TEAEs assessed as related 
to tislelizumab were aspartate aminotransferase (AST) increased (128 patients, 10.1%), alanine 
aminotransferase (ALT) increased (123 patients, 9.7%), hypothyroidism (113 patients, 8.9%), 
rash (96 patients, 7.5%), and pyrexia (94 patients, 7.4%). 
Related TEAEs by Severity 
Of the 1,273 total patients treated in the Pooled Monotherapy studies, 163 (12.8%) experienced 
at least one Grade 3 or higher TEAE assessed as related to tislelizumab. The only Grade 3 or 
higher TEAEs that occurred in ≥ 1% (12 or more patients) in the total study population were 
AST increased (19 patients, 1.5%) and ALT increased (15 patients, 1.2%). 
As of the data cutoff 20 May 2019, 105 patients (8.2% of the total population) died within 30 
days of the last study drug dose in the Pooled Monotherapy studies. Of these 105 patients, there 
were 21 patients (1.6% of the total population) who had an AE with a fatal outcome within 30 
days of the last study drug dose. Of the 536 patients (42.1% of the total population) who died 
more than 30 days after the last study drug dose, 14 patients (1.1% of the total population) died 
as a result of an AE. 
1.2.3.2. 
Overview of Efficacy 
1.2.3.2.1. Study BGB-A317_Study_001 (Data Cutoff 20 May 2019) 
Study BGB-A317_Study_001 was a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts to establish the maximum tolerated dose (MTD), if any, a 
recommended Phase 2 dose (RP2D) for the Phase 1b, and a flat dose (fixed dose) followed by a 
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 the data cutoff 20 May 2019, there were 451 patients treated in the study and 441 patients 
were included in the efficacy evaluable set. 
Across all disease cohorts, there were 5 patients (1.1%) with a complete response (CR). A total 
of 55 patients (12.5%) had a confirmed partial response (PR). The resulting overall clinical 
response rate was 13.6%. Additionally, there were 142 patients (32.2%) with a best overall 
response of SD. A total of 199 patients (45.1%) had a best response of PD in this study.  
1.2.3.2.2. Study BGB-A317-102 (Data Cutoff 20 May 2019) 
This is a two-phase, non-randomized, Phase 1/2 study of tislelizumab monotherapy in Chinese 
patients with advanced solid tumors. Phase 1 includes a dose verification substudy and a 
substudy of PK evaluation of the investigational products derived from 2 manufacturing 
processes and scales. Phase 2 is an indication expansion study. 
As of the data cutoff 20 May 2019, of the 300 patients treated in Study BGB-A317-102, 249 
patients were included in the Efficacy Evaluable Analysis Set. Across all disease cohorts and 
study phases, there was 1 patient (0.4%) with a CR. A total of 44 patients (17.7%) had a 
confirmed PR. The resulting overall clinical response rate was 18.1%. Additionally, there were 


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91 patients (36.5%) with a best overall response of SD. A total of 113 patients (45.4%) had a 
best response of PD in this study. 
1.2.3.3. 
Immune-Related Reactions  
Of the 1273 total patients for the Pooled Monotherapy studies, 602 (47.3%) experienced at least 
one immune-related adverse events (irAEs) of any grade. The most commonly occurring irAEs 
of any grade were AST increased (129 patients, 10.1%), ALT increased (124 patients, 9.7%), 
hypothyroidism (113 patients, 8.9%), rash (97 patients, 7.6%), and pruritus (78 patients, 6.1%). 
Analysis of the total patients with at least one irAE that also was ≥ Grade 3 in severity showed 
that 121 patients (9.5%) experienced such events.  The most commonly occurring irAEs 
≥ Grade 3 in severity were AST increased (21 patients, 1.6%), gamma-glutamyltransferase 
increased (17 patients, 1.3%), ALT increased (16 patients, 1.3%), pneumonitis and pneumonia (9 
patients each, 0.7%). 
Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in 
combination with paclitaxel and cisplatin. The patient’s initial symptoms were dyspnea and 
tea-colored urine 2 weeks after starting treatment. Elevated urine and serum cardiac and skeletal 
muscle enzymes were reported. The patient died of multi-organ failure 6 days later. 
1.2.4. 
Benefit-Risk Assessment 
Patients with advanced unresectable/metastatic ESCC represent a population with a high unmet 
medical need. There is no globally accepted standard of care regimen for patients with 
previously treated unresectable/metastatic ESCC. Single-agent chemotherapy is typically 
administered, but the choice of agent differs by geography and is often tailored to patient needs. 
Data from clinical studies of immune checkpoint inhibitors and the data collected in the Phase 1 
Study BGB-A317_ Study_001 suggest that evaluating tislelizumab in ESCC may have potential 
benefit for these patients. The safety profile across immune checkpoint inhibitors is consistent, 
supporting an acceptable tolerability profile. 
Given the unmet medical need and limited treatment options for this indication, the benefit/risk 
assessment based on available tislelizumab Phase 1 data and published data from the PD-1 
antibodies may be considered acceptable and support the conduct of this study.  
An Independent Data Monitoring Committee (IDMC) will be established to regularly monitor 
the safety of tislelizumab when compared with investigator chosen chemotherapy (ICC).  
1.3. 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To compare the overall survival (OS) in the Intention-to-Treat (ITT) population following 
treatment with tislelizumab vs. investigator chosen chemotherapy (ICC) when given as second 
line treatment in patients with advanced unresectable/metastatic esophageal squamous cell 
carcinoma (ESCC) 
2.1.2. 
Secondary Objectives 
Key Secondary Objective: 
 To compare the OS in the PD-L1 positive population following treatment with 
tislelizumab versus investigator chosen chemotherapy (ICC).  
Other Secondary Objectives: 
 The following will be compared between the tislelizumab and the chemotherapy 
treatments based on assessment by investigator per RECIST v1.1 criteria: 
 ORR  
 Progression-free survival (PFS) 
 Duration of response (DOR) 
 To compare HRQoL endpoints between the tislelizumab and the chemotherapy 
treatments as assessed by patient reported outcome (PRO) measures: European 
EORTC QLQ-C30 index (EORTC QLQ-C-30), the European esophageal cancer 
specific module OES18 (EORTC QLQ-OES18), and the generic health state 
instrument Euroqol 5D (EQ-5D-5L) 
 To compare the safety and tolerability between tislelizumab and the chemotherapy 
treatments 
2.1.3. 
Exploratory Objectives 
 To characterize the disease control rate (DCR) with tislelizumab compared to 
chemotherapy 
 To characterize the PK of tislelizumab  
 To determine host immunogenicity to tislelizumab  
 To explore potential predictive biomarkers (including but not limited to PD-L1 
expression, gene expression profiling, tumor mutation burden, microsatellite 
instability [MSI], and tumor-infiltrated immune cells) and resistance mechanism 


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2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
 Overall survival (OS) in the ITT analysis set- defined as the time from the date of 
randomization until the date of death due to any cause in all randomized patients. 
2.2.2. 
Secondary Endpoints 
Key Secondary Endpoint: 
 OS in the PD-L1 positive analysis set - defined as the time from the date of 
randomization until the date of death due to any cause in PD-L1 positive population 
Other Secondary Endpoints: 
 ORR in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
proportion of patients who had CR or PR assessed by the investigator per RECIST 
v1.1. 
 PFS in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
time from the date of randomization to the date of first documentation of disease 
progression assessed by the investigator per RECIST v1.1 or death, whichever occurs 
first 
 DOR in both the ITT analysis set and the PD-L1 positive analysis set - defined as the 
time from the first determination of an objective response until the first 
documentation of progression as assessed by the investigator per RECIST v1.1, or 
death, whichever comes first 
 HRQoL assessment of the subject’s overall health status using EORTC QLQ-C-30, 
EORTC QLQ-OES18, and EQ-5D-5L in both the ITT analysis set and the PD-L1 
positive analysis set 
 The incidence and severity of adverse events according to NCI-CTCAE v4.03 
2.2.3. 
Exploratory Endpoints 
 Disease control rate (DCR) in both the ITT analysis set and the PD-L1 positive 
analysis set - defined as the proportion of patients who have CR, PR and SD assessed 
by the investigator per RECIST v1.1 
 Pharmacokinetic endpoints: summary of serum concentration of tislelizumab to 
include but not limited to Ctrough  
 Assessments of immunogenicity of tislelizumab to determine the incidence of 
anti-drug antibodies (ADA) 
 Predictive biomarkers (including but not limited to PD-L1 expression, gene 
expression profiling, tumor mutation burden, MSI, and tumor-infiltrated immune 
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a randomized, controlled, open-label, global Phase 3 study of the PD-1 monoclonal 
antibody tislelizumab compared to investigator chosen chemotherapy given as second line 
treatment in patients with advanced unresectable/metastatic ESCC that has progressed during or 
after first line therapy. A substudy investigating the safety, tolerability, PK, and preliminary 
efficacy in Japanese patients is planned; preliminary safety and tolerability will be evaluated 
before Japanese patients are recruited in this Phase 3 study (see Appendix 13). 
Patient randomization and enrollment will be stratified by region (Asia [excluding Japan] vs 
Japan vs US/EU), ECOG performance status (0 vs 1), and ICC option (paclitaxel vs docetaxel vs 
irinotecan).  
3.2. 
Study Schematic 
The study design schematic is presented in Figure 1 
Figure 1: 
Study Design Schematic 
 
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ESCC, Esophageal squamous cell carcinoma; 
ICC, investigator chosen chemotherapy; ITT, Intention-to-treat; OS, Overall survival; ORR, Overall response rate; 
Study Population: 
advanced unresectable/metastatic 
ESCC that has progressed during 
or after first line therapy 
Arm A 
Tislelizumab treatmenta 
 
Screening 
• Treatment until disease 
progression, intolerable 
toxicity, or withdrawal for 
other reasons b 
• Safety Follow-up & Survival 
Follow-up 
---------------------------------- 
Primary endpoint: OS in the 
ITT analysis set 
 
Secondary endpoints: 
• OS in the PD-L1 positive 
analysis set (Key secondary) 
• ORR 
• PFS 
• DOR 
• HRQoL 
• Adverse events  
 
Exploratory endpoints: 
• DCR 
• Pharmacokinetic assessment 
of tislelizumab  
• Immunogenicity of 
tislelizumab (ADA) 
• Predictive biomarkers analysis 
and resistance mechanism 
Arm B 
ICC treatment 
• Paclitaxel  
• OR Docetaxel  
• OR Irinotecan  
 
Randomization & 
Stratification: 
n=500 eligible patients 
1:1 randomization to 
Tislelizumab treatment or 
ICC treatment 
Stratification by region 
(Asia [excluding Japan] vs 
Japan vs US/EU), ECOG 
performance status (0 vs 1), 
and ICC option (paclitaxel 
vs docetaxel vs irinotecan) 


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PD-L1, Programmed cell death protein ligand-1; PFS, Progression-free survival; DOR, Duration of response; 
HRQoL, Health Related Quality of Life; DCR, Disease control rate; ADA, Anti-drug antibody. 
a. 
The initial infusion (Cycle 1, Day 1) will be administered over a period of 60 minutes. If this infusion is well 
tolerated, subsequent infusions may be administered over 30 minutes. After tislelizumab infusion, patients will 
be further monitored for at least 1 hour during Cycles 1 and 2. From Cycle 3 onward, a post-infusion 
monitoring period of at least 30 minutes will be required. 
b. At the discretion of the investigator, patients randomized to receive tislelizumab may be treated beyond 
progression under protocol defined conditions. See Section 7.17.1. 
3.3. 
Duration of Study 
Total duration of study participation will vary by patient. Each study phase is further discussed 
below. 
3.3.1. 
Screening Phase 
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
voluntarily agree to participate will be required to sign the informed consent form (ICF) prior to 
undergoing any screening procedure (refer to Appendix 1 for details). 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. The investigator is to assess patient eligibility 
according to the latest screening assessment results. 
Patients who are suspected to have serious respiratory illness or exhibit significant respiratory 
symptoms should undergo pulmonary function testing (refer to Appendix 1 for details).  
Archival tissue is required to be collected for the purpose of biomarker analysis if available. If 
archival tumor tissue samples are not available, collection of a fresh tumor biopsy at baseline is 
requested if accessible. Please refer to Section 7.12 for details. 
Radiologic images performed within 28 days prior to randomization will be reviewed by the 
investigators for tumor characterization according to RECIST v1.1 criteria. 
3.3.2. 
Treatment Phase 
After completing all screening activities, patients confirmed eligible will be randomized in a 1:1 
ratio to receive either tislelizumab or ICC treatment (paclitaxel/docetaxel/irinotecan).  
Investigator chosen chemotherapy (ICC, paclitaxel/docetaxel/irinotecan) should be determined 
prior to randomization. The treatment plan is presented in Table 2. 


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Table 2: 
Treatment Plan 
Arm 
Drug 
Treatment Regimen 
Treatment 
Discontinuation 
Tislelizumab 
Tislelizumab 
200 mg IV on Day 1, given every 21 days 
until disease 
progression, 
intolerable 
toxicity, or 
withdrawal for 
other reasons 
ICC 
Paclitaxel 
135-175 mg/m² IV on Day 1, given every 
21 days 
 NOTE: Paclitaxel may also be given 
in doses of 80-100 mg/m2 IV on a 
weekly schedule according to local 
and/or country specific guidelines for 
standard of care 
 Japan: 100 mg/m2 IV on Day 1, 8, 15, 
22, 29, and 36, followed by one week 
of rest 
Docetaxel 
75 mg/m2 IV on Day 1, given every 21 
days 
 Japan: 70 mg/m2 IV on Day 1, given 
every 21 days 
Irinotecan 
125 mg/m2 IV on Days 1 and 8, given 
every 21 days 
Tislelizumab treatment beyond initial investigator-assessed, RECIST v1.1 defined progression 
may be permitted if, in the judgement of the investigator, the patient is anticipated to benefit 
from continued treatment, eg, the patient has evidence of “pseudo-progression”. Specific 
requirements for post-progression continuation of patients treated with tislelizumab are described 
in Section 7.17.1. 
Radiologic assessment of tumor-response status will be performed approximately every 6 weeks 
(± 7 days) for 6 months, then every 9 weeks (± 7 days) until disease progression. Tumor 
response will be assessed by the investigator using RECIST v1.1 (see Appendix 2) (Eisenhauer 
EA, 2009). Details are provided in Section 7.4. 
Patients randomized to tislelizumab treatment will undergo blood sampling for PK assessment at 
predetermined timepoints, as outlined in Appendix 1. Procedures for collection of tislelizumab 
PK samples are described in the Laboratory Manual. 
The HRQoL measurement will be performed using the EORTC-QLQ-C30, EORTC 
QLQ-OES18 and the EQ-5D-5L at baseline, prior to study treatments on Day 1 of Cycles 1 
through 6 or at the End-of-Treatment Visit (whichever occurs first), and at the Safety Follow-up 
Visit. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] 
v4.03), new physical examination findings, and clinically significant changes in laboratory 
assessments. Adverse events of special interest in this study will include the incidence and 
severity of irAEs. Vital signs, Eastern Cooperative Oncology Group (ECOG) performance status 
change, and electrocardiogram (ECG) results will also be used for safety assessment. Safety 
assessments are further detailed in Section 7 and the Schedule of Assessments (Appendix 1). 


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Optional blood samples will be taken to explore the association of blood-based biomarkers. 
Please refer to Section 7.12 for details. 
3.3.3. 
End of Treatment 
The End-of-Treatment (EOT) Visit is conducted when the investigator determines that 
tislelizumab or ICC will no longer be used, at which time all of the assessments listed for the 
EOT Visit will be performed. If a patient withdraws from treatment at a study visit when all 
assessments required for EOT have been completed, EOT assessments do not need to be 
repeated.  
Patients randomized to tislelizumab treatment who have RECIST-defined PD by investigator 
assessment, but who, in the opinion of the investigator, have evidence of continued clinical 
benefit from tislelizumab may continue to receive this drug only after review and agreement by 
the medical monitor. In such cases, patients must complete the EOT visit only after permanent 
discontinuation of tislelizumab.  
If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before 
the End of Treatment Visit, tests need not be repeated. In subjects who discontinue study 
treatment, tumor imaging should be performed at the time of treatment discontinuation 
(± 4 weeks window). If a previous scan was obtained within 6 weeks prior to the date of 
discontinuation, then a scan at treatment discontinuation is not required.   
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them to determine the survival status. 
Optional biopsies and/or blood samples will be taken for the patients who have confirmed 
disease progression to explore resistance mechanism as outlined in Section 7.12. 
3.3.4. 
Safety Follow-up Phase 
In both study arms, patients who discontinue treatment for any reason will be asked to return to 
the clinic for the Safety Follow-up Visit within 30 days (± 7 days) after the last dose of study 
drug or before the initiation of a new anticancer therapy (whichever occurs first) to collect AEs 
or SAEs that may have occurred after the patient discontinued from the study treatment. All 
drug-related SAEs will be recorded by investigator after treatment discontinuation until patient 
death, withdrawal of consent, or lost to follow-up, whichever occurs first. In addition, telephone 
contacts with patients should be conducted to assess irAEs and concomitant medications (if 
appropriate, ie, associated with an irAE or is a new anticancer therapy) at 60 days (± 14 days), 
and 90 days (± 14 days) after the last dose of study drug, regardless of whether or not the patient 
starts a new anticancer therapy. If patients report a suspected irAE at a telephone follow-up 
contact, the investigator should arrange an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.4.  
The End of Treatment (EOT) Visit may be combined with the Safety Follow-up visit, provided 
that the EOT occurred 30 days (± 7 days) after the last study treatment; the assessments for both 
visits should be performed. Patients who discontinue study treatment prior to disease progression 
will have their tumors assessed as outlined in Section 7.4. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 


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3.3.5. 
Survival Follow-up Phase 
Patients who discontinue study drug for reasons other than radiographically confirmed disease 
progression (eg, toxicity) will continue to undergo tumor assessments according to Section 7.4 
and the Schedule of Assessments (Appendix 1), until radiographically confirmed disease 
progression, withdrawal of 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 contact, email, or other communications; review 
of patient medical records; and/or in-person clinic visits approximately 1 month (4 weeks ± 7 
days) after the Safety Follow-up Visit and every month thereafter (Section 7.16). 
3.3.6. 
End of Study 
The end of study is defined as the timepoint when the final data for a clinical study were 
collected, which is after the last study patient has made the final visit to the study location.  
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following:  
 The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients  
 Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. 
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 notified to the site in 
advance. Reasons for closing a site may include but are not limited to the following:  
 Excessively slow recruitment  
 Poor protocol adherence  
 Inaccurate or incomplete data recording  
 Noncompliance with Good Clinical Practice (GCP), applicable laws and regulations  
 Study activity is completed (ie, all patients have completed and all obligations have 
been fulfilled)] 


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3.4. 
Study Rationale 
3.4.1. 
Rationale for Tislelizumab in the Treatment of ESCC 
High levels of FcγR-expressing myeloid derived cells (eg, M2 macrophage, MDSC) in tumor 
tissues predict a poor survival of tumor-bearing animals after anti-PD-1 monoclonal antibody 
treatment; this is possibly due to Fc-FcγR-mediated ADCC or antibody-dependent cellular 
phagocytosis (ADCP) depletion of effector T cells (Gül and van Egmond 2015; Prieto et al 2015; 
Makarova-Rusher et al 2015; Beers et al 2016; Dahan et al 2015). As a no- to low-FcγR-binding 
agent (thus causing minimal ADCC/ADCP effect), tislelizumab may show superior efficacy and 
lower toxicity in esophageal carcinoma. Available data from a clinical study with other 
anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have shown drugs targeting 
the PD-1 pathway to have both a manageable safety profile and promising antitumor activity in 
patients with advanced unresectable or metastatic ESCC (Section 1.1.1.1). 
Finally, according to the latest data collected from the Phase 1 Study BGB-A317_Study_001, 
tislelizumab monotherapy has established a manageable safety profile, with the most common 
side effects consistent with known class effects of other anti-PD-1 antibodies (Section 1.2.3). 
Given the unmet medical need and limited treatment options in this indication, the benefit/risk 
assessment based on available tislelizumab Phase 1 data and published data from the PD-1 
antibodies may be considered acceptable and support continued development. 
3.4.2. 
Rationale for Selection of Tislelizumab Fixed Dose 
The PK, safety, and efficacy data obtained from the first-in-human study 
BGB-A317_Study_001, as well as other clinical study data, were analyzed in aggregate to 
determine the recommended dose for pivotal studies of tislelizumab. The flat dose of 200 mg IV 
Q3W was selected for further evaluation.  
Rates of treatment-related adverse events (AEs) and serious adverse events (SAEs) observed in 
patients receiving 2 mg/kg and 5 mg/kg Q2W and Q3W were comparable, suggesting no clear 
dose-dependence across these regimens. Similarly, confirmed overall response rates (ORRs) in 
patients treated with tislelizumab 2 mg/kg and 5 mg/kg Q2W ranged between 10% and 15%, 
compared to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg Q3W. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender, and the observed serum exposure of a 
200 mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose range 
with comparable safety and efficacy rates).  
Additionally, no unexpected treatment-related AEs occurred in 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 partial response (PR), 
4 patients (31%) had a BOR of stable disease (SD), and 6 patients (46%) had a BOR of 
progressive disease (PD). Therefore, clinical activity with a manageable and tolerable safety 
profile is expected to be maintained in patients receiving tislelizumab 200 mg Q3W. 
In conclusion, tislelizumab 200 mg Q3W is the recommended dose for this Phase 3 global study. 


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3.4.3. 
Rationale for Selection of Paclitaxel/Docetaxel/Irinotecan as Comparator 
Current guidelines recommend the combination of fluorouracil and cisplatin, either alone or in 
combination with a third drug such as epirubicin or a taxane, as the most effective first-line 
treatment option (Ando N, 2015). In China, cisplatin with a taxane is also preferred to treat 
ESCC as first-line therapy. Approximately 40% of patients for whom first-line treatment fails 
will be potential candidates for second line therapy (Thallinger CM, 2011). In a relapsed or 
refractory disease setting, however, data in the second-line ESCC treatment setting are scarce, 
and there is no established consensus on the optimal second-line chemotherapy treatment so far.  
National Comprehensive Cancer Network (NCCN, 2017) guidelines endorse use of docetaxel, 
paclitaxel and irinotecan in the second-line treatment of esophageal carcinoma. While these 
agents are widely used, there are recognized geographic differences in the choice of treatment in 
this disease setting despite the lack of clinically significant differences in response rates, PFS and 
OS between agents. In Japan, taxanes are widely used as second-line treatment of esophageal 
carcinoma (Kuwano H, 2015). In China, irinotecan is often chosen as second-line treatment. 
As discussed in Section 1.1.1, ORR to single-agent chemotherapy with paclitaxel, docetaxel, or 
irinotecan range between 4% and 44% (Table1). Progression-free survival, being less than 4 
months, in the 13 single-agent studies reviewed by Thallinger et al (2011). In addition, 
combination chemotherapy as second line therapy showed more serious adverse events than 
single regimen, suggesting an unfavorable risk benefit profile. So, new well-designed, 
adequately powered clinical second-line studies may lead to improved outcome, but Phase 3 
studies for comparison of the different forms of therapy are indispensable. 
3.4.4. 
Rationale of Stratification Factors 
Patient enrollment will be stratified by geographic region of enrollment (Asia excluding Japan vs 
Japan vs US/EU), ECOG performance status (0 vs 1), and by ICC option (paclitaxel vs docetaxel 
vs irinotecan). 
The highest incidence of esophageal cancer is seen along two geographical belts, one from north 
central China through the central Asian republics to northern Iran, and one from eastern to 
southern Africa (Arnold M, 2015). Patient enrollment will be stratified by geographic region of 
enrollment to account for potential differences in the prior standard medical care that are not 
easily quantifiable, as well as other factors associated with those geographic regions (ie betel 
quid exposure, nutritional factors). 
Patients with an ECOG performance score (PS) of 0 or 1 may be enrolled to this study if other 
entry criteria are met. As with many other malignancies, performance status has been shown to 
be prognostic for survival in patients with both limited and advanced squamous esophageal 
carcinoma (Tustumi F, 2016; Uchinami Y, 2016). In a retrospective analysis, Tustumi et al 
(2016) observed a 1-year survival rate of 62.3% in patients with an ECOG PS <2 vs. 31.7% in 
patients with an ECOG PS ≥2. These results are consistent with that published by Nomura et al 
(2016) who found a significant association of PS with outcome in a univariate analysis, but not 
in a multi-variate analysis, as well as data published by Shirakawa et al (2014). 
The ICC option will be determined for all patients prior to the randomization. Since 
3 comparator drugs are included in the control arm to reflect the real-world choices made by 
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as a stratification factor in the randomization and statistical analysis to adjust any potential 
confounding factors due to the heterogeneity of these three drugs used in the control arm. 


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4. 
MATERIALS AND METHODS 
4.1. 
Selection of Study Population 
The specific eligibility criteria for selection of the approximately 500 patients planned for 
randomization (1:1 to tislelizumab or ICC treatment) are provided in Section 4.1.1 and 
Section 4.1.2, respectively.  
4.1.1. 
Inclusion Criteria 
To be eligible to participate in this study, a patient must meet all of the following criteria: 
1. Is male or female, aged ≥ 18 years on the day the patient voluntarily agrees to participate 
in the study (or acceptable age according to local regulations, whichever is older) 
2. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments 
3. Histologically confirmed diagnosis of esophageal squamous cell carcinoma (ESCC) 
4. Tumor progression during or after first-line systemic treatment for advanced 
unresectable/metastatic ESCC (Appendix 12) 
NOTE: Patients with disease progression that occurs during treatment or within 
≤ 6 months (180 days) of cessation of neoadjuvant/adjuvant treatment (chemotherapy or 
chemoradiotherapy) are eligible provided all other criteria are met  
NOTE: A line of treatment begins with the administration of the first agent in a regimen 
and ends with disease progression. A line of therapy is preserved when chemotherapy is 
switched due to toxicities 
5. At least one measurable/evaluable lesion by RECIST v1.1 as determined by local site 
investigator/radiology assessment within 28 days prior to randomization 
NOTE: Lesions that have been previously irradiated may be considered evaluable 
provided there is evidence of disease progression following the completion of radiation 
therapy. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (Appendix 3) of 0 or 1 
prior to randomization 
7. Laboratory data meeting the criteria below within 14 days prior to randomization. 
Laboratory data will not be valid if the patient has received growth factors or blood 
transfusion for prophylactic use within 7 days before the laboratory testing: 
 Absolute neutrophil count (ANC) ≥1500 cells/mm3  
 Platelet count ≥100,000 cells/mm3  
 Hemoglobin ≥9 g/dL or ≥5.6 mmol/L  
 Estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 11)  


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 Serum total bilirubin ≤1.5 x upper limit of normal (ULN) (or < 3 x ULN in patients 
with Gilbert’s syndrome) 
 Prothrombin time/International normalized ratio (PT/INR) ≤1.5 x ULN unless the 
patient is receiving anti-coagulant therapy  
 Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (or 
≤ 5.0 x ULN in patients with liver metastases)  
8. HBV or HCV infection and meets the following criteria as applicable to the infection 
type:  
For patients with inactive/asymptomatic carrier, chronic, or active HBV: 
HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at screening.  
NOTE: Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV 
DNA should be managed per treatment guidelines. Patients receiving antivirals at 
screening should have been treated for > 2 weeks and HBV < 500 IU/ml prior to 
randomization and should continue treatment for at least 6 months after study drug 
treatment discontinuation.  
For patients with HCV:  
Patients with detectable HCV RNA and who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study.  
9. Females of childbearing potential must have a negative serum pregnancy test within 
7 days of randomization and must be willing to have additional pregnancy tests during 
the study. Females of childbearing potential must be willing to use highly effective 
methods of birth control for the duration of the study, and for at least 120 days after the 
last dose of tislelizumab and 180 days after the last dose of ICC  
10. Non-sterile males who have female sexual partner(s) of childbearing potential 
(Appendix 5) must use highly effective form of birth control for the duration of the study, 
and for at least 120 days after the last dose of tislelizumab and 180 days after the last 
dose of ICC  
 A sterile male is defined as one for whom known azoospermia, in a semen sample 
examination, has been previously demonstrated as definitive evidence of infertility.  
 Males with known ‘low sperm counts’ (consistent with ‘sub-fertility) are not to be 
considered sterile for purposes of this study.  
4.1.2. 
Exclusion Criteria 
To be eligible to participate in this study, a patient cannot meet any of the following exclusion criteria: 
1. Ineligible for treatment with any of the treatments of protocol-specified chemotherapy 
2. Receipt of 2 or more prior lines of systemic treatments for advanced/metastatic 
unresectable ESCC 
3. Palliative radiation treatment for ESCC within 14 days of study treatment initiation 
(C1D1) 


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4. History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 
months prior to randomization  
5. Tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or 
respiratory tract) at an increased risk of fistula in the study treatment assessed by 
investigator  
6. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 2 weeks of intervention) 
7. Current or past history of severe hypersensitivity reactions to other humanized 
monoclonal antibodies 
8. Received prior therapies targeting PD-1 or PD-L1 
9. Has 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) exceptions are to be determined by 
investigator in consultation with the medical monitor 
10. Prior malignancy active within the previous 2 years before randomization (exceptions 
include the tumor under investigation in this study and surgically excised non-melanoma 
skin cancer, curatively treated carcinoma in situ of the cervix, localized prostate cancer 
treated with curative intent, curatively treated low-stage bladder cancer, ductal carcinoma 
in situ treated surgically with curative intent, or a malignancy diagnosed >2 years ago, 
with no current evidence of disease and no therapy ≤ 2 years prior to randomization) 
11. Active brain or leptomeningeal metastasis. Patients with equivocal findings or with 
confirmed brain metastases are eligible for enrollment provided that they are 
asymptomatic and radiologically stable without the need for corticosteroid treatment for 
at least 4 weeks prior to randomization. CT/MRI of the head at baseline is required for 
patients who are suspected to have central nervous system (CNS) metastases.  
12. Has active autoimmune disease or history of autoimmune diseases at high risk for relapse   
NOTE: Patients with following diseases may be enrolled if they meet all other eligibility 
criteria: controlled type I diabetes, hypothyroidism managed with hormone replacement 
therapy only, controlled celiac disease, skin diseases not requiring systemic treatment 
(such as vitiligo, psoriasis or alopecia), or diseases not expected to recur in the absence of 
external triggering factors. 
13. Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalents) or other immunosuppressive medications within 14 days prior 
to randomization  
 Patients who have a history of organ transplant, including stem cell allograft are not 
permitted to enroll  
 Adrenal replacement steroid dose ≤ 10 mg daily prednisone equivalents are permitted 
in the absence of active autoimmune disease 
 Patients are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  


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 A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
14. Undergone surgery requiring general anesthesia or epidural anesthesia within 28 days 
prior to randomization  
15. Undergone surgery involving local anesthesia within 14 days prior to randomization. 
Exceptions to this exclusion criteria include:  
a. Placement of a central venous access device that requires up to a 3-day surveillance 
period. 
b. A biopsy procedure performed under local anesthesia during the screening period that 
require a 7-day post procedure surveillance period. 
16. Received any radiopharmaceuticals - (except for examination or diagnostic use of 
radiopharmaceuticals) within 42 days prior to randomization.  
17. Has received: 
a. Within 28 days or 5 half-lives (whichever is shorter but at least 14 days) of the first 
study drug administration: any chemotherapy, any immunotherapy (eg, interleukin, 
interferon, or thymoxin) or any investigational therapies 
b. Within 14 days of the first study drug administration: any Chinese herbal medicine or 
Chinese patent medicines used to control cancer or boost immunity 
18. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that could interfere 
with the subject’s safety, obtaining informed consent, or compliance with study 
procedures  
19. Receipt of a live vaccine within 4 weeks prior to Cycle 1 Day 1 
NOTE: Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live viruses and are not allowed.  
20. Known history of, or any evidence of interstitial lung disease, non-infectious 
pneumonitis, pulmonary fibrosis diagnosed based on imaging or clinical findings, or 
uncontrolled systemic diseases, including diabetes, hypertension, acute lung diseases, etc 
NOTE: Patients with radiation pneumonitis may be randomized if the radiation 
pneumonitis has been confirmed as stable (beyond acute phase) and is unlikely to recur. 
Patients with severe but stable radiation-induced pneumonitis may be required to undergo 
routine pulmonary function studies   
21. Has severe chronic or active infection (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal or antiviral therapy, within 14 days prior to Cycle 1 
Day 1 
NOTE: Patients who require systemic antiviral therapy for HBV are excepted 
22. Known history of Human Immunodeficiency Virus (HIV) 


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23. Has any of the following cardiovascular risk factors: 
 Ongoing cardiac chest pain, defined as moderate pain that limits instrumental 
activities of daily living 
 Symptomatic pulmonary embolism within 28 days before randomization 
 Any history of acute myocardial infarction within 6 months before randomization 
 Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 6) within 6 months before randomization 
 Any event of ventricular arrhythmia > Grade 2 in severity within 6 months before 
randomization  
 Any history of cerebrovascular accident or transient ischemic attack within 6 months 
before randomization 
 Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 
mmHg despite anti-hypertension medications ≤ 28 days before randomization or first 
dose of study drug 
Any episode of syncope or seizure ≤ 28 days before randomization 
24. Severe malnutrition despite enteral or parenteral nutritional supplementation 
25. Known, active alcohol or drug abuse or dependence 
26. Pregnant or breastfeeding woman. 


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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, Handling, and Storage 
The interactive response technology (IRT) system will be used for drug supply management. The 
study drug will be dispatched to a study center only after receipt of the required documents in 
accordance with applicable regulatory requirements and the sponsor’s procedures. The 
investigator or pharmacist/designated personnel is responsible for maintaining the drug supply 
inventory and acknowledgement receipt of all study drug shipments. All study drugs must be 
stored in a secure area with access limited to the investigator and authorized study center 
personnel and under physical conditions that are consistent with study drug-specific 
requirements. 
Only patients enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements. Only authorized study center personnel may supply or administer study 
drug. 
5.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg 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. One vial is packaged in a single 
carton box.  
The study drug must be kept at the temperature condition as specified on the label. 
Please refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal. Please also refer to the Investigator’s Brochure for other details regarding tislelizumab.  
5.1.2. 
Paclitaxel 
Paclitaxel will be provided in vials for infusion. The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
Paclitaxel must be kept at room temperature in original package as specified on the label. 
Please refer to the Pharmacy Manual for details regarding administration, accountability, and 
disposal. 
5.1.3. 
Docetaxel 
Docetaxel will be provided in vials for infusion. The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
Docetaxel must be kept at 20 to 25℃ in original package to protect from light as specified on the 
label. 
Please refer to the Pharmacy Manual for details regarding administration, accountability, and 
disposal. 


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5.1.4. 
Irinotecan 
Irinotecan will be provided in vials for infusion. The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
Irinotecan must be kept at room temperatures condition and protected from light as specified on 
the label. 
Please refer to the Pharmacy Manual for details regarding administration, accountability, and 
disposal. 
5.2. 
Dosage, Administration, and Compliance 
Dosing schedules for both arms, broken out by individual arm, are provided in Table 3. The first 
dose of study drug should be administered within 3 business days of randomization. The day of 
the 1st dose treatment will be documented as Cycle 1 Day 1. All patients will be monitored 
continuously for AEs. Treatment modifications (eg, dose delay, reduction, interruption, or 
discontinuation) will be based on specific laboratory assessment and AE criteria, as described in 
Section 8.6. 
Table 3: 
Selection and Timing of Dose for Each Patient 
5.2.1. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 1, given every 21 days.  
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment 
Tislelizumab 
200 mg 
Day 1, 
given every 21 days 
IV 
See Section 3.3.2 
Paclitaxel 
135-175 mg/m² 
Day 1, 
given every 21 days 
IV 
 
See Section 3.3.2 
Paclitaxel 
80-100 mg/m2 
Weekly in accordance 
with local/country 
treatment guidelines 
IV 
Paclitaxel 
(Japan) 
100 mg/m² 
Day 1, 8, 15, 22, 29, and 
36, followed by one week 
of rest 
IV 
Docetaxel 
75 mg/m2 
Day 1, 
given every 21 days 
IV 
Docetaxel 
(Japan) 
70 mg/m2 
Day 1, 
given every 21 days 
IV 
Irinotecan 
125 mg/m2 
Days 1 and 8, 
given every 21 days 
IV 


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Tislelizumab will be administered by IV infusion, using a volumetric pump through an 
intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron 
in-line or add-on filter. Specific instructions for product preparation and administration are 
provided in the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterwards in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, at least a 30-minute monitoring period is required in 
an area with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes. If this is well-tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion. Tislelizumab must not be concurrently administered with any 
other drug.  
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of irAEs and infusion-related reactions are provided in detail in Section 8.6 and 
Section 8.8, respectively. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.2. 
Paclitaxel 
After all procedures/assessments have been completed as detailed in Appendix 1 and 
Section 3.3.1, paclitaxel will be administered on Day 1, given every 21 days at a dose of 135 to 
175 mg/m2 by IV infusion over 3 hours or 1 hour, or in doses ranging between 80 to 100 mg/m2 
IV on a weekly basis consistent with local or country-specific treatment guidelines, or according 
to manufacturer standards or institutional standards. The labeled dose and schedule for paclitaxel 
in Japan is 100 mg/m2 IV infusion over 1 hour on Days 1, 8, 15, 22, 29, and 36, followed by one 
week of rest. The initial treatment of paclitaxel should be administered within 3 business days of 
randomization. The first dose of paclitaxel is dependent upon the patient’s baseline body surface 
area. Subsequent doses of paclitaxel must be recalculated if the change of body surface area 
(increase or decrease) from baseline ≥ 10%. Subsequent doses should not be recalculated if the 
change (increase or decrease) of body surface area from baseline < 10%. 
Premedication is recommended prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards. The premedication regimen should be determined by the 
investigator and administered as close to randomization as possible. Premedication may consist 
of an oral steroid (such as dexamethasone 8-20 mg or equivalent administered 6-12 hours orally 
or 30-60 minutes intravenously before paclitaxel), an antihistamine (H1 antagonist) such as 
diphenhydramine hydrochloride 50 mg IV or equivalent or H2 antagonist, such as cimetidine 300 
mg IV or equivalent), and an antiemetic (such as ondansetron 8 mg/kg IV or equivalent 
administered 30 to 120 minutes before paclitaxel). Premedication may be provided per local 
guidance and all medications will be documented on the case report form (CRF). 
There is a 3-day window for all treatments in subsequent cycles if the cycle length is 21 days. If 
paclitaxel is given on a weekly schedule, there will be a 2-day treatment window. If dosing is 
delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), the 
subsequent dosing visit should be scheduled as clinically appropriate. 


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Patients will be monitored continuously for adverse events and will be instructed to notify their 
physician for new adverse events, such as worsening of pre-existing conditions, or adverse 
events that cause any change in performance status or activities of daily living. Management of 
suspected adverse drug reactions may require temporary interruption and/or dose reduction of 
paclitaxel therapy. Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 8.6.  
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.3. 
Docetaxel 
Docetaxel will be administered on Day 1, given every 21 days after all procedures/assessments 
have been completed as detailed in Appendix 1 and Section 3.3.1. The initial treatment of 
docetaxel should be administered within 3 business days of randomization. Docetaxel should be 
administered at a dose of 75 mg/m2 by IV infusion over 60 minutes according to manufacturer 
standards. Doses lower than 75 mg/m2 are allowed if considered appropriate for any given 
patient. The labeled dose and schedule for docetaxel in Japan is 70 mg/m2 IV on Day 1, given 
every 21 days. The first dose of docetaxel is dependent upon the patient’s baseline body surface 
area. Subsequent doses of docetaxel must be recalculated if the change of body surface area 
(increase or decrease) is ≥ 10% from baseline. Subsequent doses should not be recalculated if the 
change (increase or decrease) of body surface area is < 10% from baseline.  
Premedication might be recommended prior to infusion of docetaxel according to the 
manufacturer’s instructions and local standards. To alleviate the incidence and severity of fluid 
retention as well as the severity of hypersensitivity reactions, premedication of oral 
corticosteroids, such as dexamethasone 16 mg per day (eg, 8 mg twice daily) for 3 days should 
be given prior to infusion of docetaxel. The premedication regimen should be determined by the 
investigator and administered as close to randomization as possible. All medications will be 
documented on the appropriate CRF. 
There is a 3-day window for all treatment in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), 
the subsequent dosing visit should be scheduled as clinically appropriate. 
Patients will be monitored continuously for adverse events and will be instructed to notify their 
physician for new adverse events, such as worsening of pre-existing conditions, or adverse 
events that cause any change in performance status or activities of daily living. Management of 
suspected adverse drug reactions may require temporary interruption and/or dose reduction of 
docetaxel therapy. Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 8.6.  
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.4. 
Irinotecan 
Irinotecan will be administered on Days 1 and 8, given every 21 days after all 
procedures/assessments have been completed as detailed in Appendix 1 and Section 3.3.1. The 
initial treatment of irinotecan should be administered within 3 business days of randomization. 


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Irinotecan should be administered at a dose of 125 mg/m2 by IV infusion over 90 minutes or 
according to manufacturer standards. The first dose of irinotecan is dependent upon the patient’s 
baseline body surface area. Subsequent doses of irinotecan must be recalculated if the change of 
body surface area (increase or decrease) is ≥ 10% from baseline. Subsequent doses should not be 
recalculated if the change (increase or decrease) of body surface area is < 10% from baseline. 
Alternate doses/schedules of irinotecan according to local or country-specific standards of care 
may be used as long as the 21-day cycle length (or multiples of that) are maintained.  
Premedication is recommended prior to infusion of irinotecan according to the manufacturer’s 
introductions and local standards. The premedication regimen should be determined by the 
investigator and administered as close to randomization as possible. To reduce the incidence and 
severity of fluid loss, premedication may include atropine and antiemetic agents, such as 
dexamethasone 10 mg along with another antiemetic agent (eg, ondansetron) on the day of 
irinotecan administered. All medications will be documented on the appropriate CRF. 
There is a 3-day window for all treatment in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), 
the subsequent dosing visit should be scheduled as clinically appropriate. 
Patients will be monitored continuously for adverse events and will be instructed to notify their 
physician for new adverse events, such as worsening of pre-existing conditions, or adverse 
events that cause any change in performance status or activities of daily living. Management of 
suspected adverse drug reactions may require temporary interruption and/or dose reduction of 
irinotecan therapy. Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 8.6.  
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.3. 
Handling of Overdose 
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of any study drug should be noted on the study drug administration eCRF. AEs 
associated with an overdose or incorrect administration of study drug will be recorded on the AE 
eCRF. Any SAEs associated with an overdose or incorrect administration are required to be 
reported within 24 hours of awareness via SAE reporting process as described in Section 8.8. 
Supportive care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability 
The investigational medicinal product (IMP) required for completion of this study (tislelizumab, 
paclitaxel, docetaxel and irinotecan) will be provided by the sponsor, as required by local or 
country-specific guidance. The investigational site will acknowledge receipt of IMP. 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. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
by information provided by the patient. 


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The investigator and/or study personnel will keep accurate records of drug dispensed and used by 
each patient. This information must be captured in the source document at each patient visit. The 
investigator is responsible for tislelizumab, paclitaxel, docetaxel and irinotecan, reconciliation, 
and record maintenance. In accordance with all applicable regulatory requirements, the 
investigator or designated study center personnel must maintain tislelizumab, paclitaxel, 
docetaxel and irinotecan accountability records throughout the course of the study. This person 
will document the amount of tislelizumab, paclitaxel, docetaxel and irinotecan received from the 
sponsor, the amount supplied, and/or administered (and returned by patients, if applicable). 
5.5. 
Disposal and Destruction 
After completion of the study, all unused tislelizumab, paclitaxel, docetaxel and irinotecan will 
be inventoried and packaged for return shipment by the hospital unit pharmacist or other 
designated study center personnel. The inventoried supplies may also be destroyed on site or at 
the depot according to institutional policies, after receiving written sponsor approval. 


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6. 
PRIOR, CONCOMITANT AND SUPPORTIVE THERAPY 
6.1. 
Prior Therapy 
All prior cancer treatments and treatments for underlying active medical conditions must be 
recorded on the appropriate case report form. 
6.2. 
Concomitant Therapy 
6.2.1. 
Permitted Therapy 
Most concomitant medications and therapies deemed necessary in keeping with the local 
standards of medical care at the discretion of the investigator for the supportive care (eg, 
antiemetics, antidiarrheals, pain medications, and nutritional support) and in a patient’s 
well-being are allowed. All concomitant medications will be recorded on the eCRF including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids. If changes 
(stop or start) in concomitant medication occur during the study, documentation of drug and 
reason for use will be recorded on the eCRF. 
All concomitant medications received within 30 days before the first dose of study drug and 
30 days after the last infusion or dose of study treatment should be recorded. Nutritional support 
for patients with a history of weight loss is strongly recommended as a routine standard-of-care 
therapy, and such support should be recorded as a concomitant medication. 
Systemic corticosteroids given for the control of irAEs must be tapered over at least 1 month and 
be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the next 
tislelizumab administration. The short-term use of steroids as prophylactic treatments (eg, 
patients with contrast allergies to diagnostic imaging contrast dyes) is permitted.  
Patients with active hepatitis B defined as either detectable HBsAg or HBV DNA at baseline 
must initiate treatment 2 weeks prior to randomization or first dose and continue until 6 months 
after the last dose. Patients should continue effective antiviral treatment during the study to 
decrease potential viral re-activation risk. Tenofovir and entecavir are recommended in the 
American Association for the Study of Liver Disease (AASLD) guideline because they lack 
resistance with long-term use (Terrault et al 2016; AASLD/IDSA HCV Guidance Panel, 2015). 
The investigator might use other antiviral agents, if appropriate, following local guidelines. 
Management of antiviral therapy is at the discretion of the investigator; however, reason(s) must 
be provided in the CRF if a patient with active hepatitis B is not treated with antiviral 
prophylaxis.  
BeiGene does not require patients with active hepatitis C to receive treatment with antiviral 
therapy. Patients with detectable HCV RNA and who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study. Investigators can consider 
treatment with sofosbuvir alone or in combination with other antivirals following the AASLD 
guideline or the local guidelines as appropriate. However, interferon-based therapy for either 
HBV or HCV is not permitted on study. Patients who are given antiviral therapy must initiate 
treatment at least 2 weeks prior to randomization or first dose. 


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Patients may continue to receive hormone replacement or supportive care if initiated prior to 
enrollment. Bisphosphonates and RANK-L inhibitors are allowed for bone metastases if initiated 
prior to enrollment and at a stable dose. Bisphosphonates are permitted during the study for a 
non-malignant indication. 
For those patients randomized to the ICC arm of the study, premedication with steroids is 
acceptable. 
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline. If repeat imaging demonstrates new 
sites of bone metastases and the criteria for disease progression has been met, according to the 
investigator, then the patient should discontinue study treatment, and receive appropriate 
treatment 
 If the lesion being considered for palliative radiation is a target or non-target lesion 
per RECIST v1.1, it will become non-evaluable for response assessments 
 The case should be discussed with the medical monitor to ensure that the patient is 
still eligible to continue on study treatment 
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 to rule out progression of disease. 
6.2.2. 
Prohibited Concomitant Medications/Procedures 
6.2.2.1. 
Therapies Excluded during Tislelizumab Treatment 
The following medications are prohibited or restricted at the time of screening and during the 
administration of tislelizumab: 
 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 or for short-term use as prophylactic treatment 
 Live vaccines within 28 days prior to the first dose of tislelizumab and 60 days 
following the last dose of tislelizumab 
 Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with liver or other major organ functions (eg, 
hypericin). Patients must notify the investigator of all herbal remedies used during the 
study. 
6.2.2.2. 
Therapies Excluded during Paclitaxel/Docetaxel/Irinotecan Treatment 
Caution should be exercised for patients receiving paclitaxel concomitantly with substrates, 
inhibitors or inducers of CYP2C8 or CYP3A4. The metabolism of paclitaxel is catalyzed by 
cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when 
paclitaxel is concomitantly administered with known substrates (eg, midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, 


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atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of 
CYP3A4. Caution should also be exercised when paclitaxel is concomitantly administered with 
known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers 
(eg, rifampin) of CYP2C8. Potential interactions between paclitaxel, a substrate of CYP3A4, and 
protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or 
inhibitors of CYP3A4, have not been evaluated in clinical studies. 
Patients receiving docetaxel should avoid concomitant use of strong inhibitors of CYP3A4 (eg, 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin and voriconazole).; however, if strong inhibitors of CYP3A4 
cannot be avoided, the docetaxel dose should be reduced per the product label. 
Do not administer strong CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine, or St. 
John’s wort) with irinotecan unless there are no therapeutic alternatives. Do not administer 
strong CYP3A4 inhibitors (clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) and UGT1A1 inhibitor (eg, atazanavir, 
gemfibrozil, indinavir) or both CYP3A4 and UGT1A1 inhibitors (such as ketoconazole) when 
patients treated by irinotecan unless there are no therapeutic alternatives. 
6.2.2.3. 
Therapies Excluded during All Study Treatment 
The following medications are to be prohibited or restricted at the time of screening and during 
the administration of study treatment: 
 Any concurrent antineoplastic therapy (eg, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicines] for the treatment of cancer) 
 Extensive radiation therapy (except for local, palliative radiotherapy; refer to 
Section 6.2.1) 
The following guidelines should be also followed during the study: 
 Surgical procedures required during study participation will be reported as treatments 
for adverse events. If a surgical procedure is considered elective (eg, Cosmetic 
surgery), the procedure should be reported on the appropriate eCRF 
 Patients should not abuse alcohol or other drugs during the study  
6.3. 
Rescue Medication and Supportive Care  
6.3.1. 
Supportive Care guidelines for Tislelizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined in Section 8.8.2, Section 8.8.3, and 
Appendix 10. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 


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attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to tislelizumab. 
6.3.2. 
Supportive Care guidelines for Paclitaxel, Docetaxel and Irinotecan 
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to the subjects in ICC arm of this study. Supportive care measures may 
include but are not limited to antidiarrheal agents, antiemetic agents, opiate and non-opiate 
analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors. Non-drug 
supportive care procedures may be performed as medically necessary and appropriate in the 
opinion of the investigator. Details of interventions, procedures, or blood products (eg, blood 
cells, platelets, or fresh frozen plasma transfusions) should be recorded on the eCRF. 
Appropriate management of hypersensitivity reactions is described in Section 8.8.5. The use of 
other specific supportive care agents is presented as below. 
Diarrhea: In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, 
loperamide, octreotide, or other antidiarrheals. If diarrhea is severe (ie, requires intravenous 
hydration) and associated with fever or severe (Grade 3 or 4) neutropenia, broad – spectrum 
antibiotics may be prescribed as clinically necessary. Subjects with severe diarrhea or any 
diarrhea associated with severe nausea or vomiting should be hospitalized for intravenous 
hydration and correction of electrolyte imbalance. In cases of irinotecan induced diarrhea, 
antibiotic therapy should be initiated if the subject develops ileus, fever or sever neutropenia. 
Nausea/Vomiting: The use of antiemetic agents is permitted at the discretion of the investigator 
(Hesketh PJ, 2016). 
Additional Supportive Care Guidelines: 
Analgesic Agents: The use of analgesic agents is permitted at the discretion of the investigator. 
The chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with a high risk of bleeding 
(eg, indomethacin, ibuprofen, naproxen, or similar agents) is strongly discouraged unless at the 
discretion and responsibility of the investigator after careful assessment of the individual 
bleeding risk of the subject. Chronic use of analgesic agents with no or low bleeding risk (eg, 
paracetamol/acetaminophen, metamizole, dipyrone, propyphenazone) is acceptable. 
Granulocyte-Colony Stimulating Factors (G-CSF): The use of G-CSF is permitted during the 
study at the discretion of the investigator according to the standard of care practice guidelines. G-
CSF or similar agents are recommended following Grade 3 or 4 neutropenia of duration > 5 days 
or following any incidence of febrile neutropenia (ANC < 0.5 x 109/L or < 1.0 x 109/L with 
predicted decline to < 0.5 x 109/L over the next 48 hours with a single temperature ≥ 38.5°C or a 
sustained temperature ≥ 38.0°C over 1 hour) (Smith TJ, 2015). 
Erythroid Growth Factors: The use of erythroid-stimulating factors (eg, erythropoietin) is 
permitted at the discretion of the investigator based on American Society of Clinical Oncology 
(ASCO) and Food and Drug Administration (FDA) guidelines, or according to local guidelines 
(Rizzo JD, 2010; Bokemeyer et al, 2007).  
Please refer to the product label or local standards of care for additional paclitaxel, docetaxel, or 
irinotecan supportive measures. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of all study procedures is provided in the Schedule of Assessments (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 and eCRF for each 
patient.  
Dosing will occur only if the clinical assessment and laboratory test values (which must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines. 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 dosing continued on the scheduled 21-day intervals 
accordingly. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent 
and ≤ 7 days prior to randomization may be used for the purposes of screening rather than 
repeating the standard-of-care tests. 
7.1. 
Informed Consent Form and Screening Log Completion  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  
Informed consent forms for enrolled patients and for patients who are screened but not enrolled 
will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable.   
7.2. 
Medical History and Demographic Data Collection 
Medical history should include any history of clinically significant disease, surgery, reproductive 
status (ie, of childbearing potential or no childbearing potential [Appendix 5]); history of alcohol 
consumption (ie, presence or absence); history of smoking; weight loss history, and all 
medications (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 30 days before the first dose.  
Demographic data will include age, gender, and self-reported race/ethnicity.  
Cancer history will include stage at initial diagnosis using current American Joint Committee on 
Cancer criteria, tumor location, location of metastatic disease at study baseline, dates of prior 
surgery, prior radiotherapy, prior drug therapy, including start and stop dates, best response and 
the date(s) of disease progression. The presence or absence of symptoms of esophageal 
carcinoma as well as the severity grade will be collected at baseline. 
New or worsening conditions are to be recorded as adverse events on the Adverse Event eCRF. 
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7.3. 
Eastern Cooperative Oncology Group Performance Status Grading 
Eastern Cooperative Oncology Group Performance Status (Appendix 3) will be assessed at the 
Screening Visit (within 7 days prior to randomization), pretreatment on Day 1 of each treatment 
cycle, EOT Visit and Safety Follow-up Visit.  
7.4. 
Antitumor Activity and Response Assessment 
Tumor imaging will be performed within 28 days prior to randomization. Results of standard-of-
care tests or examinations (Appendix 1) 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, patients will undergo tumor assessments approximately 
every 6 weeks (± 7 days) for 6 months, then every 9 weeks (± 7 days). All radiographic 
assessments performed to assess tumor status at baseline and during study treatment to assess 
response should be performed at the same investigative site. 
Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral/IV contrast, unless contraindicated) or magnetic resonance imaging (MRI) 
of at least the neck, chest and abdomen. 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) 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.  
Subjects with previously treated brain metastases may participate provided they have stable brain 
metastases, ie, without evidence of progression by imaging (confirmed by MRI if MRI was used 
at prior imaging, or confirmed by CT imaging if CT used at prior imaging) for at least four 
weeks prior to randomization. Any neurologic symptoms must have returned to baseline and 
subjects must have no evidence of new or enlarging brain metastases, and have not used steroids 
for brain metastases for at least 28 days prior to randomization. This exception does not include 
carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of 
clinical stability. CT/MRI of the head at baseline is required for patients who are suspected to 
have central nervous system (CNS) metastases.  
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride-PET (NaF-PET) should be 
performed at screening if clinically indicated. If bone metastases are present at screening and 
cannot be seen on subsequent CT or MRI scans, or if clinically indicated, TC-99m or NaF PET 
bone scans should be repeated when either progression in bone or a CR in the target lesion is 
suspected. 
CT scans of the extremities and all other known sites should also be performed if clinically 
indicated and followed throughout the study, if there is evidence of metastatic disease in these 
regions at screening. 
For subsequent tumor assessments, the same radiographic procedure used to assess disease sites 
at screening are required to be used throughout the study (eg, the same contrast protocol for CT 
scans). All known sites of disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  


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Response will be assessed by the investigator using RECIST v1.1 (Appendix 2). The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits. 
At the investigator’s discretion, additional radiographic scans or more frequent assessments 
should be performed if clinically indicated.  
Patients who discontinue study treatment early for reasons other than disease progression or 
death will continue to undergo tumor assessments as scheduled until the patient begins a new 
anticancer treatment, experiences disease progression, withdraws consent, dies, lost to follow-up, 
or the study completes, whichever occurs first. If previous tumor imaging was obtained within 6 
weeks prior to the date of discontinuation, then additional tumor imaging at treatment 
discontinuation is not required.  
After signing a separate informed consent, patients who continue tislelizumab treatment beyond 
the initial diagnosis of radiographic disease progression (Section 7.17.1) will be monitored with 
a follow-up scan at least 4 weeks later or at the next scheduled tumor assessment (not to exceed 
6 weeks) from the prior radiographic scan date. 
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held.  
7.5. 
Adverse Event Collection 
All adverse events, including SAEs, will be collected as described in Section 8.2.  
7.6. 
Physical Examinations 
A complete physical examination, including an evaluation of the head, eyes, ears, nose, throat, 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems is required to be performed at screening. Any abnormality identified at baseline will be 
recorded on the Medical History eCRF with appropriate disease/condition terms. Height 
(baseline only) will be measured and recorded in the eCRF.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations will be performed. Changes from baseline will be recorded in patient notes.  
7.7. 
Ophthalmologic Examinations 
Eye examination, visual acuity test, and optical coherence tomography (or equivalent diagnostic 
test) will be assessed at the Screening Visit in all patients. Eye examination, visual acuity test, 
and optical coherence tomography (or equivalent diagnostic test for retinal examination) 
captured as standard of care prior to obtaining written informed consent and within 28 days of 
randomization may be used for the screening evaluation. Patients on the tislelizumab arm will 
undergo repeated assessments approximately every 15 weeks (± 7 days) during study treatment 
and a final assessment < 30 days (± 7 days) after the last dose of study treatment.   
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during tislelizumab treatment. For any 
change in vision, referral to an appropriate specialist will be made for further management 
guidance (see Appendix 10). 


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7.8. 
Vital Signs Assessment 
Vital signs will include measurements of weight, pulse rate and blood pressure (systolic and 
diastolic) while the patient is in a seated position after resting for 10 minutes, and body 
temperature (˚C). 
For all infusions of tislelizumab, vital signs will be assessed before the infusion, and between 30 
to 45 minutes after the infusion. Vital signs must be collected during the infusion if clinically 
indicated. Weight should be collected once at each of these visits. Patients will be informed 
about the possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. Refer to Section 8.8.3 regarding management of 
infusion-related reactions. 
7.9. 
Electrocardiograms 
A 12-lead ECG is required at screening, End of Treatment, and as clinically indicated. All ECG 
recordings should be performed after the patient has been resting in a sitting or supine position 
for at least 10 minutes, and a repeat ECG should be performed to confirm findings, if any.  
7.10. 
Clinical Laboratory Tests and Pharmacokinetic Blood Sampling 
Clinical laboratory assessments will include the following, of which certain elements will be 
collected:  
 Hematology (complete blood count [CBC], including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with automated differential 
[neutrophils, eosinophils, lymphocytes, monocytes, and basophils], and platelet 
count). A manual differential can be done if clinically indicated 
 Serum chemistry (glucose, blood urea nitrogen [BUN] or serum urea, creatinine, 
sodium, potassium, chloride, phosphorus, total bilirubin, ALT, AST, alkaline 
phosphatase, lactate dehydrogenase [LDH] [optional], total protein, albumin). All 
patients will have creatine kinase (CK) and creatine kinase-cardiac muscle isoenzyme 
(CK-MB) testing at screening and at all scheduled visits during the first 3 treatment 
cycles, all pre-dose assessments from Cycle 4 onwards, and at the EOT and Safety 
Follow-up Visits. 
NOTE: In the event that CK-MB fractionation cannot be evaluated in the local 
laboratory, troponin I and/or troponin T should be assessed instead; the same test 
should be administered throughout the study. 
 Prothrombin time and international normalized ratio (PT/INR)  
 Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) must be performed and documented as negative within 7 
days prior to randomization, EOT Visit and at Safety Follow-up. Urine pregnancy test 
will be performed at each visit prior to dosing; a serum pregnancy test must be 
performed if the urine pregnancy test is positive or equivocal 
 Urinalysis (complete [including, but not limited to glucose, protein, ketones, and 
blood] and/or microscopic, if clinically indicated)  


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 Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4) 
 Thyroid function testing performed during the study and at the Safety Follow-up Visit 
will only be for patients on the tislelizumab arm 
 HBV and HCV serology (HBsAg, HBcAb and HCV antibody) 
If laboratory tests at screening are not performed within 7 days prior to the administration of 
study drug(s) on Cycle 1 Day 1, these tests should be repeated and reviewed before study drug(s) 
administration. Hematology and serum chemistry (including liver function tests) as specified 
above should be performed weekly for the first 2 cycles and at the beginning of each subsequent 
cycle; results are to be reviewed within 3 business days before study drug administration. 
Weekly peripheral blood cell counts should be performed on all patients receiving paclitaxel, 
docetaxel, and irinotecan.  
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. 
The following assessments will be performed at a central laboratory:  
 ADA assays: Serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay  
 PK assay: Serum samples will be assayed for tislelizumab concentration with use of a 
validated immunoassay 
7.11. 
Anti-drug Antibody Evaluation Procedures 
Tislelizumab may elicit an immune response.  Patients with signs of any potential immune 
response to tislelizumab will be closely monitored with repeat sampling for anti-drug antibody 
(ADA detection as well as clinical evaluations.  
Validated screening and confirmatory assays will be employed to detect ADAs at multiple 
timepoints throughout the study (Appendix 1).  The immunogenicity evaluation will utilize a 
risk-based immunogenicity strategy (Bai S, 2012; Worobec A, 2004) to characterize ADA 
responses to tislelizumab in support of the clinical development program.  
7.12. 
Tumor Tissue and Biomarker Assessment Procedures 
Shipping, storage, and handling of archival tumor, fresh tumor, and residual tumor tissue for the 
assessment of biomarkers will be managed through a central laboratory. Refer to the Laboratory 
Manual for details of sample handling.  
Archival tumor tissues (representative tumor specimens in paraffin blocks (preferred) or 
approximately 10 unstained tumor specimen slides) are required to be sent to central laboratory 
for biomarker analysis such as immunohistochemistry (IHC) analysis of PD-L1 status if 
available. In addition to PD-L1 expression, other exploratory predictive biomarkers, such as gene 
expression profiling, tumor mutation burden, MSI, and tumor-infiltrated immune cells, that are 
related to response or clinical benefit of tislelizumab may also be evaluated.  


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In the absence of available archival tumor tissue samples, collection of fresh tumor biopsy at 
baseline is recommended if accessible. 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.  
Optional biopsies will also be taken from patients who have confirmed disease progression 
during the study in accessible tumor sites to explore resistance mechanism. If feasible, follow-up 
biopsies should be taken from the same tumor lesion at baseline. Written patient consent is 
required for fresh tumor biopsies. 
Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable.  
Optional blood samples (approximately 10 mL each timepoint) will be taken at the time of first 
tumor response (tumor assessment is CR or PR), and/or disease progression for all randomized 
patients, to explore the association of blood-based biomarkers (such as ctDNA, cytokine, 
immune cell profiling, etc) with response, resistance, and prognosis to tislelizumab or 
chemotherapy. Written patient consent is required for blood sample collections.  
Refer to the Schedule of Assessment (Appendix 1) for detailed schedule. 
7.13. 
Health-Related Quality of Life Assessment 
Patients will be asked to complete the EORTC-QLQ-C30 (Appendix 7), EORTC-QLQ-OES18 
(Appendix 8) and EQ-5D-5L questionnaires (Appendix 9) prior to study treatment initiation, 
Cycle 1 through Cycle 6 Day 1 (± 7 days) or at treatment discontinuation (whichever occurs 
first), and at the Safety Follow-up visit according to the schedule in Appendix 1. The 
questionnaires will be provided in the patient’s preferred language and given to the patient prior 
to being seen by a health care professional. 
7.14. 
Timing of Assessments during the Treatment Phase 
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 
unless otherwise noted. Laboratory results are required to be reviewed prior to study treatment 
administration. 
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 dosing rescheduled to meet the requirement of interval for dosing 
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7.15. 
Safety Follow-up  
In both treatment arms, patients who discontinue treatment for any reason will be asked to return 
to the clinic for a Safety Follow-up Visit within 30 days (± 7 days) after the last study treatment 
or before the initiation of a new anticancer treatment, whichever comes first. In addition, 
telephone contacts with patients should be conducted to assess irAEs and concomitant 
medications (if appropriate, ie, associated with an irAE or is a new anticancer therapy) at 60 (±14 
days), and 90 days (±14 days) after the last dose of tislelizumab, regardless of initiation of a new 
anticancer treatment. Beyond 90 days, investigators should continue to report any SAEs that are 
believed to be related to study drug(s) if they become aware of them. If patients report a 
suspected immune-related AE at a telephone follow-up contact, the investigator should arrange 
an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.4. 
The EOT Visit may be combined with the Safety Follow-up visit, provided that the EOT 
occurred 30 days (± 7 days) after the last study treatment; the assessments for both visits should 
be performed. Patients who discontinue study treatment prior to disease progression will have 
their tumors assessed as outlined in Section 7.4. 
See the study flowchart provided in Appendix 1 for assessments to be performed at the Safety 
Follow-up Visit. 
7.16. 
Survival Follow-up 
Following discontinuation of the study treatment, all patients will be followed for survival status 
and study drug-related SAEs, beginning approximately 1 month (4 weeks ± 7 days) after the 
Safety Follow-up Visit and approximately monthly thereafter or as directed by the sponsor. 
Information on Survival Follow-up and the subsequent anticancer treatment will be collected via 
telephone calls, email, or other communications; patient medical records; and/or clinic visits 
approximately every month until death, loss to follow-up, withdrawal of consent, or study 
termination by the sponsor.  
7.17. 
Patient, Treatment, Study, and Site Discontinuation  
Patients who discontinue study treatment early, but who have not withdrawn consent for 
follow-up, should be followed for assessments of antitumor activity (unless a new anti-cancer 
treatment is initiated - see Section 7.4), safety (Section 7.15), and survival (Section 7.16), if 
possible. 
7.17.1. 
Discontinuation of Patients 
Patients have the right to voluntarily withdraw from the study or 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. Reasons that a patient may be discontinued from the study 
treatment may include, but are not limited to the following:  
 Patient withdrawal of consent at any time  
 Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue in the study  


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 Investigator or sponsor determines it is in the best interest of the patient  
 Patient noncompliance 
Every effort should be made to obtain information on patients who discontinue from study 
treatment. The primary reason for discontinuation should be documented on the appropriate 
eCRF.  
Patients should discontinue study treatment if they experience any of the following:  
 Symptomatic deterioration (eg, uncontrollable pain secondary to disease or 
unmanageable ascites, etc.) attributed to disease progression  
 Patients must discontinue study treatment if they experience any of the following: 
 Intolerable toxicity related to tislelizumab, paclitaxel, docetaxel or irinotecan, 
including development of an immune-mediated or paclitaxel/docetaxel/ irinotecan-
mediated adverse event determined by the investigator to be unacceptable given the 
individual patient’s potential response to therapy and severity of the event 
 Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment  
 Use of another non-protocol anticancer therapy (Section 6.2.2)  
 Pregnancy 
Patients will be permitted to continue tislelizumab if pseudo-progression is suspected and/or 
there is a reasonable belief that the patient could derive benefit from tislelizumab after RECIST 
v1.1 criteria for progressive disease are met, and all of the following criteria are met:  
 Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening laboratory values)  
 ECOG PS ≤ 1 
 Absence of rapid progression of disease or progression at a critical anatomical site 
(eg, progression of a spinal lesion with impending cord compression) or that 
necessitates urgent alternative medical intervention 
If, in the judgement of the investigator, the patient is anticipated to benefit from continued 
treatment, the patient must re-sign an informed consent, agreeing to continue treatment beyond 
radiographical disease progression. If patients agree to continue treatment beyond radiographical 
progression, a follow-up radiographic evaluation will be performed no later than 6 weeks after 
the initial scan that diagnosed progressive disease, as outlined in Section 7.4.  
If, in the judgement of the investigator, rapid early progression is evident (“hyperprogression”), 
tislelizumab should be discontinued.  
The primary reason for study drug discontinuation will be documented in the medical chart and 
on the appropriate eCRF. Patients who discontinue study drug prior to disease progression will 
not be replaced. 


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7.17.2. 
Study Termination and Study Site Closure  
The primary analyses will be conducted when the predefined 400 death events have been 
observed (Section 9.6.1). The study will continue until the last patient has died, becomes lost to 
follow-up, or withdraws consent from the study, or until the sponsor decides to terminate the 
study (see Section 3.3.6 for End of Study). 
At the end of study, any patient assigned to tislelizumab who, in the opinion of the investigator, 
may continue to benefit from tislelizumab at study termination, will be offered the option to 
continue treatment in a company-sponsored clinical trial until tislelizumab is commercially 
available in the country of the patient’s residence. 


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8. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated With Study Drugs  
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. 
8.1.1. 
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 irAEs, specifically the induction or enhancement of autoimmune 
conditions. Immune-related AEs commonly associated with anti-PD-1 therapy are presented in 
Table 5. 
Although most irAEs 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 irAEs are provided in Appendix 10. 
8.1.2. 
Risks Associated with Chemotherapy (Paclitaxel/Docetaxel/Irinotecan) 
Most common adverse reactions across all paclitaxel indications are neutropenia, leukopenia, 
alopecia, anemia, arthralgia/myalgia, peripheral neuropathy, nausea, vomiting, diarrhea, 
mucositis, infections, alkaline phosphatase elevations, aspartate transaminase (AST) elevations, 
hypotension, infusion site reaction, or bleeding. Most frequent Grade 3 and 4 adverse events are 
neutropenia, anemia, leukopenia, infection, nausea, vomiting, hypersensitivity reactions. 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical studies. Fatal reactions have occurred in patients despite 
premedication. Patients who experience severe hypersensitivity reactions to paclitaxel should not 
be rechallenged with the drug. 
Most common adverse reactions across all docetaxel indications are infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, 
vomiting, mucositis, alopecia, skin reactions and myalgia. Most frequent grade 3 or 4 adverse 
events are neutropenia, anemia, leukopenia, infection, thrombocytopenia. Treatment-related 
mortality will increase if patients have abnormal liver function. Severe hypersensitivity, 
including very rare fatal anaphylaxis, has also been reported in patients despite receiving 
dexamethasone premedication.  
Common adverse reactions of irinotecan observed in single-agent therapy clinical studies are: 
nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia 


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(including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. 
Most frequent Grade 3 or 4 adverse events are diarrhea, nausea, vomiting, leukopenia, 
neutropenia, abdominal pain and asthenia. Early and late forms of diarrhea can occur. Early 
diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated 
by atropine. Late diarrhea can be life threatening and should be treated promptly with 
loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. If patients 
develop ileus, fever, or severe neutropenia, they should receive antibiotic therapy, per institution-
specific guidelines. If severe diarrhea and myelosuppression occur, irinotecan should be 
interrupted and either discontinued or dose reduced for subsequent cycles to subsequent doses. 
Patients should be tested locally for the UGT1A1*28 allele to determine if modifications to the 
starting dose are needed as outlined in the prescribing information or according to local 
guidelines. 
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. 
 Paclitaxel, Docetaxel and irinotecan therapy should not be given to patients with 
solid tumor who have baseline neutrophil counts of less than 1,500 cells/mm3. To 
monitor the occurrence of bone marrow suppression, primary neutropenia, which 
may be severe and result in infection, it is recommended that frequent peripheral 
blood cell counts be performed on all patients receiving paclitaxel, docetaxel, and 
irinotecan.  
 Anaphylaxis reactions: Anaphylaxis reactions and severe hypersensitivity reactions 
have occurred in 2% to 4% of subjects treated with paclitaxel. Fatal reactions have 
occurred in subjects despite premedication. All subjects should be pretreated with 
corticosteroids, diphenhydramine, and H2 antagonists. Subjects who experience 
severe hypersensitivity reactions should not be rechallenged. 
 Diarrhea: Early diarrhea (occurring during or shortly after infusion of irinotecan) is 
usually transient and infrequently severe. Late diarrhea (generally occurring more 
than 24 hours after administration of irinotecan) can be life threatening since it may 
be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Monitor 
patients with diarrhea and give fluid and electrolytes as needed. Early diarrhea may 
be accompanied by cholinergic symptoms which may be prevented or ameliorated by 
atropine. Late diarrhea can be life threatening and should be treated promptly with 
loperamide. Avoid diuretics or laxatives in patients with diarrhea. 
For toxicities not listed above, dose modifications are permitted per local standards. 
8.1.3. 
General Plan to Manage Safety Concerns 
8.1.3.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients enrolled to 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 taken into account. 


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Specifically, patients at risk for study-emergent active autoimmune diseases or 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 must be eligible for at least one of the 
chemotherapy drugs in ICC treatment arm.  
8.1.3.2. 
Safety Monitoring Plan 
Safety will be evaluated in this study through reporting and monitoring of all AEs, defined and 
graded according to NCI-CTCAE v4.03. Patients will be assessed for safety (including 
laboratory values) according to the schedule in Appendix 1. Clinical laboratory results must be 
reviewed by the investigator or appropriate delegate prior to the start of each cycle. Patients 
receiving irinotecan will be monitored for diarrhea and given fluids and electrolytes at the 
investigator’s discretion. 
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. General safety assessments 
will include review of medical history, physical examinations, ophthalmologic examinations, and 
specific laboratory studies, including but not limited to serum chemistry and blood counts (see 
Appendix 1 for the Schedule of Assessments). In addition, patients will be closely monitored for 
the development of any signs or symptoms of autoimmune conditions and infection. 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomized 
to the tislelizumab arm, if treatment assignment is known. 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 5.1.4). 
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing of informed consent) and for up to 30 days after the last dose of study drug(s) 
(including paclitaxel, docetaxel and irinotecan) or until the initiation of another anticancer 
therapy, whichever occurs first. At the end of treatment, ongoing AEs considered related to study 
treatment will be followed until the event has resolved to baseline or ≤ Grade 1, the event is 
assessed by the investigator as stable, the patient is lost to follow-up, the patient withdraws 
consent, or it has been determined that study treatment or participation is not the cause of the 
AE. 
Immune-related AEs will be recorded up to 90 days after the last dose of tislelizumab, regardless 
of whether the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by 
the investigator after treatment discontinuation until patient death, withdrawal of consent, or loss 
to follow-up, whichever occurs first. 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection. Patients will receive standard of care 
medications for any adverse event according to the judgement of the investigator. 


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Reporting requirements for SAEs are discussed in Section 8.4.2. In addition, the medical monitor 
or Safety Physician will review and evaluate observed AEs on a regular basis. 
Patients who discontinue treatment for any reason will be asked to return to the clinic for a 
Safety Follow-up Visit within 30 days (± 7 days) after the last dose of study treatment or before 
the initiation of a new anticancer therapy, whichever occurs first. 
8.2. 
Adverse Events 
8.2.1. 
Definition and Reporting Guidelines 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
result), 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 redacted on the 
copies of the medical records prior to submission to the sponsor. 
8.2.2. 
Assessing Severity 
The investigator will assess the severity for each AE and SAE reported during the study. All AEs 
and SAEs are to be assessed and graded based upon NCI-CTCAE v4.03. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)  
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL  


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 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure 
of intensity (for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], 
severe [Grade 3], or life-threatening [Grade 4]), whereas seriousness is classified by 
the criteria based on the regulatory definitions. Seriousness serves as the guide for 
defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities as described in Section 8.4.2.3. 
8.2.3. 
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 


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8.2.4. 
Assessing 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 only limited 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE prior to transmission of the SAE report to 
the sponsor, since the causality assessment is one of the criteria used when determining 
regulatory reporting requirements. The investigator may subsequently change his/her opinion of 
causality considering follow-up information and may amend the SAE report accordingly.  
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on all information available at the time of reporting. 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)  
8.2.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, CBC, coagulation, or urinalysis) or other 
abnormal assessments (eg, ECGs or vital signs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs. This includes clinically significant abnormal 
laboratory findings or other abnormal assessments that are present at baseline and significantly 
worsen during the study. The definition of clinically significant is left to the judgement of the 


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investigator. In general, these are the laboratory test abnormalities assessments or other abnormal 
assessments that: 
 are associated with clinical signs or symptoms, or  
 require active medical intervention, or  
 lead to dose interruption or discontinuation, or 
 require close observation, more frequent follow-up assessments, or  
 further diagnostic investigation.   
8.2.6. 
Follow up of Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the condition of the patient. 
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. Once resolved, the appropriate AE or SAE will be updated. 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 will be recorded on the originally completed SAE report, with all 
changes signed and dated by the investigator. The updated SAE report should be re-sent to the 
sponsor within the time frames outlined in Section 8.4.2.1. 
8.3. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
8.4. 
Timing, Frequency, and Method of Capturing Adverse Events 
8.4.1. 
Reporting All Adverse Events 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 


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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 (including paclitaxel, docetaxel 
and irinotecan) or initiation of a new anticancer therapy, whichever occurs first. Immune-related 
AEs (serious or non-serious) should be reported for 90 days after the last dose of tislelizumab 
regardless of initiation of a subsequent anticancer therapy. After this period, the investigator 
should report any SAEs that are believed to be related to tislelizumab treatment. 
8.4.2. 
Reporting Serious Adverse Events 
8.4.2.1. 
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 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 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
8.4.2.2. 
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 8.4.2.1. The SAE report 
will always be completed as thoroughly as possible with all available details of the SAE 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 8.2.4. 
The sponsor will provide a list of project contacts for SAE receipt. 
8.4.2.3. 
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 8.4.2.1. 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. Prompt notification of SAEs by the investigator to the appropriate project 
contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards 
the safety of other patients are met.  
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24 hours 
of first 
knowledge of the 
AE 
SAE report 
As expeditiously as 
possible 
SAE report 
Email or 
fax SAE 
form or 
Pregnancy 
form 


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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 8.3), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
This protocol is being filed under an Investigational New Drug (IND) protocol amendment with 
the US FDA. All IND safety reports submitted to the FDA will also be sent to all investigators 
conducting studies under this IND. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised IB) from the sponsor, the responsible person according to local requirements 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. 
8.4.3. 
Eliciting Adverse Event Information 
The investigator or designee will ask about AEs by asking the patient 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?”  
8.4.4. 
Recording 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.”. 
8.4.5. 
Recording 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 “unexplained death”. 
8.4.6. 
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 180 days 
after the last dose of paclitaxel/docetaxel/irinotecan, a pregnancy report form is required to be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. 


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Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
follow-up will be no longer than 8 weeks following the estimated delivery date. Any premature 
termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, 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.  
8.4.7. 
Recording Post-Study Adverse Events  
A post-study AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting 
period that is defined in Section 8.4.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will 
notify the sponsor.  
8.4.8. 
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 documents: 
 Tislelizumab Investigator’s Brochure 
 Local prescribing information for paclitaxel 
 Local prescribing information for docetaxel 
 Local prescribing information for irinotecan 
8.5. 
Independent Data Monitoring Committee 
Regular safety monitoring (at least every 6 months) and efficacy monitoring will be performed 
by an Independent Data Monitoring Committee (IDMC). The first IDMC safety review will 
occur after at least 50 patients have been randomized to study treatment (ie, approximately 
25 patients per treatment arm) and have been on treatment for at least one treatment cycle. The 
IDMC may recommend modifications to the study procedures or conduct based on available 
data. 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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8.6. 
Dose Delays or Modifications  
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule every 3 weeks from Cycle 1 Day 1. 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 
chart and recorded in the eCRF. 
8.6.1. 
Dose Delay or Modification for Tislelizumab 
There will be no dose reduction of tislelizumab in this study. Dose delays or interruption of 
< 12 weeks will be permitted. The investigators should make every effort to maintain dose 
intensity in patients.  
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to tislelizumab and requires that a dose be withheld. If the administration delay is 
≤ 10 days, the delayed dose will be administered. If the delay is > 10 days, the delayed dose will 
be omitted in this cycle. As long as the AE resolves within 14 days, the next cycle will be 
administered as planned If the delay of tislelizumab is > 12 weeks, it will be stopped 
permanently. 
In case a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with medical monitor. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
event, the visit should be scheduled on the nearest feasible date (refer to the visit window in 
Appendix 1), with subsequent dosing continued on the 21-day intervals accordingly.  
Management guidelines for irAEs and infusion-related reactions in patients treated with 
tislelizumab are presented in Section 8.8.2, Section 8.8.3, and Appendix 10 respectively. 
8.6.2. 
Dose Delay, Interruption or Modification for Paclitaxel, Docetaxel and 
Irinotecan 
Study drug related toxicities must be resolved to baseline or Grade 0-1 prior to administering the 
next dose, with the exception of alopecia or Grade 2 fatigue. A maximum of 2 dose reductions 
for each chemotherapeutic agent are permitted. If additional reductions are required, that 
chemotherapeutic agent must be discontinued. Once the dose has been decreased, it should 
remain reduced for all subsequent administrations or further reduced if necessary. There will be 
no dose escalations in this study. Chemotherapy treatment may be delayed up to 21 days, if the 
reason for the delay is toxicity/adverse event. All subsequent chemotherapy doses must be 
rescheduled according to the last chemotherapy dose administration date. If any chemotherapy 
agent is held for more than 6 weeks from the anticipated treatment date, or the dose level -2 is 
not tolerated, chemotherapy should be permanently discontinued.  


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Dose Modifications for Paclitaxel 
 
Dose Levels for Paclitaxel given every 3 weeks 
Dose Level 
Dose (mg/m2) 
1 
175 
135 
-1 
135 
90 
-2 
90 
75 
 
Dose Levels for Weekly Paclitaxel 
Dose Level 
Dose (mg/m2) 
1 
80 -100 
-1 
65 - 80 (~20% decrease from Dose Level 1) 
-2 
50 - 60 (~25% decrease from Dose Level -1) 
 
Paclitaxel dose modification for decreased neutrophils 
 
Absolute Neutrophil Count (cells/mm3) 
Paclitaxel Dose 
≥ 1500 (Grade 1) 
Dose Level 1 
1000 - 1499 (Grade 2) 
 Hold paclitaxel until recovery to Grade 1 and restart 
paclitaxel at Dose Level -1.  
 If no recovery within 3 weeks of planned next cycle, 
consider appropriateness for growth factor support or 
discontinue paclitaxel. 
500 - 999 (Grade 3) 
 Hold paclitaxel until recovery to Grade 1 and restart 
paclitaxel at Dose Level -2.  
 Initiate growth factor support 
 If no recovery within 3 weeks of planned next cycle 
despite growth factor support, discontinue paclitaxel. 
< 500 (Grade 4) 
 Initiate growth factor support 
 If ANC < 500 for > 7 days despite growth factor support, 
discontinue paclitaxel 
If a patient experiences febrile neutropenia or ≥ Grade 2 infection at any time, granulocyte 
colony stimulating factor (G-CSF) should be added initially and in advance of any dose 
reduction for the next cycle of paclitaxel. In the event of a second episode of febrile neutropenia 
or ≥ Grade 2 infection, paclitaxel should be dose reduced to the next lower level. For a third 
episode of febrile neutropenia or ≥ Grade 2 infection, paclitaxel should be discontinued. Any 
dose reductions for neutropenic fever are permanent. 


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Paclitaxel dose modification for decreased platelet counts 
 
Platelet Count (cells/mm3) 
Paclitaxel Dose 
> 100,000 
Dose Level 1 
75,000 - 100,000 (Grade 1) 
 Hold until recovery to a platelet count > 100,000 cells/mm3 
 Restart paclitaxel at Dose level 1 
50,000 - 74,999 (Grade 2) 
 Hold until recovery to a platelet count > 100,000 cells/mm3 
 Restart paclitaxel at Dose Level -1 
< 50,000 (Grade 3)  
 Hold until recovery to a platelet count > 100,000 cells/mm3 
 Restart paclitaxel at dose level -2 
< 25,000 (Grade 4) with clinically 
significant bleeding 
 Discontinue paclitaxel 
For any grade toxicity, if the platelet count does not recover by the next planned treatment cycle, 
paclitaxel must be discontinued. 
Paclitaxel dose modification for neuropathy 
 
Neuropathy Grade 
Recommended Paclitaxel Dose 
Grade 1 
Dose Level 1 
Grade 2 lasting > 7 days or  
Grade 3 lasting < 7 days 
 Hold until neuropathy recovery to Grade 1 
 Restart paclitaxel at Dose Level -1 
Grade 3 lasting > 7 days or Grade 4  
 Discontinue paclitaxel 
All dose reductions for neuropathy are permanent. 
Paclitaxel dose modification for hepatic impairment 
 
Degree of Hepatic impairment 
Recommended Paclitaxel Dose 
Transaminase levels 
 
Bilirubin Levels 
< 2.5 x ULN 
And 
≤ 1.25 x ULN 
 Continue dosing at Dose Level 1 
> 2.5 - 5 x ULN 
And 
1.26 - 2.0 x ULN 
 Hold until recovery to Grade 1 
 Restart paclitaxel at Dose Level -1 
> 5 - < 10 x ULN 
And 
2.01 - 5 x ULN 
 Hold until recovery to Grade 1 
 Restart paclitaxel at Dose Level -2 
≥ 10 x ULN 
OR 
> 5.0 x ULN 
 Discontinue Paclitaxel 
If the liver function test abnormalities do not recover by the next planned cycle, paclitaxel must 
be discontinued. All dose reductions for liver function abnormalities are permanent. 
Allergic Reaction/Hypersensitivity 
For moderate symptoms, paclitaxel infusion must be stopped and diphenhydramine 25 to 50 mg, 
dexamethasone 10 mg, or other appropriate therapy as per institutional guidelines must be 


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administered. Paclitaxel infusion may be gradually resumed after recovery of symptoms. If 
symptoms recur with reinstitution of the paclitaxel in fusion, the infusion must be stopped. 
Patients who experience severe or life-threatening symptoms of hypersensitivity despite standard 
pretreatment medications must discontinue paclitaxel permanently. 
Paclitaxel dose modification for other toxicities 
For other non-hepatic or non-hematologic toxicities such as Grade 3 nausea, vomiting, diarrhea 
or stomatitis that occur despite supportive care, paclitaxel will be held at the first occurrence and 
subsequently dose reduced to the next level once the toxicity has recovered to Grade 0 to 1 in 
severity.  
If paclitaxel is given on a weekly basis, dose reductions should be implemented according to the 
usual standard of care following to regional or country-specific guidelines and the guidelines 
described above. If considered in the best interest of the patient and consistent with local 
practice, investigators may decide to use supportive measures or treatment and/or secondary 
prophylaxis instead of dose reductions for the next cycle.  


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Dose Modifications for Docetaxel 
 
Dose Levels for Docetaxel 
Dose Level 
Dose (mg/m2), given Day 1, given every 21 days 
1 
75 
-1 
60 (20% decrease from Dose Level 1) 
-2 
45 (25% decrease from Dose Level -1) 
 
Dose Levels for Docetaxel in Japan 
Dose Level 
Dose (mg/m2), given Day 1, given every 21 days 
1 
70 
-1 
60 (15% decrease from Dose Level 1) 
-2 
50 (17% decrease from Dose Level -1) 
 
The following table provides guidance regarding docetaxel dose adjustments for specific adverse 
events. 
Docetaxel Dose 
Adverse event 
70 – 75 mg/m2 
Starting Dose 
Administer only if neutrophil count is > 1500 cell/mm3 
60 mg/m2 
 Febrile neutropenia or neutrophils < 500 cells/mm3 for more than 1 week (after fully 
recovering to a neutrophil count ≥ 1500 cells/mm3 
 Platelet count < 100,000 cells/mm3 (after recovering to a platelet count of ≥ 100,000 
cells/mm3 
 Severe or cumulative cutaneous reactions 
45 mg/m2 
 Second episode febrile neutropenia or neutrophils < 500 cells/mm3 for more than 1 
week (after fully recovering to a neutrophil count  
≥ 1500 cells/mm3) 
Permanently 
Discontinue 
Docetaxel 
After any of the following toxicities: 
 Severe hypersensitivity reactions 
 Peripheral neuropathy > Grade 3 
 Severe or cumulative cutaneous reactions that continue at a dose of 45 mg/m2 without 
recovery 
 Febrile neutropenia or neutrophils < 500 cells/mm3 without recovery 
 Platelet count < 100,000 cells/mm3 without recovery 
 Total bilirubin > ULN without recovery 
 Serum transaminase (AST, ALT) levels > 1.5 x ULN concurrent with serum alkaline 
phosphatase levels > 2.5 x ULN without recovery 
Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal. 
 


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Dose Modifications for Irinotecan 
 
Dose Levels for Irinotecan 
Dose Level 
Dose (mg/m2), given Days 1 and 8, given every 21 days 
1 
125 
-1 
100 (20% decrease from Dose Level 1) 
-2 
75 (25% decrease from Dose Level -1) 
 
Irinotecan Dose given every 21 days 
Adverse Event 
125 mg/m2 
Starting Dose 
Administer only if neutrophil count is > 1500 cell/mm3 
100 mg/m2 (Dose Level -1) 
Reduction from Dose Level 1 for any of the following toxicities 
 Grade 3 neutropenia (neutrophils 500 cells/mm3 – 
999 cells/mm3) 
 Grade 3 diarrhea (7-9 stools/day over pretreatment status) - 
hold dose until resolved to ≤ Grade 2 then restart at Dose 
Level -1 
 Other Grade 2 or 3 non-hematologic toxicities except alopecia, 
anorexia, asthenia 
75 mg/m2 (Dose Level -2) 
After any of the following toxicities: 
 Neutropenic fever - Omit dose until resolved, restart at Dose 
Level -2 
 Grade 4 neutropenia (neutrophils < 500 cells/mm3) - hold dose 
until neutrophil count is ≤ Grade 2 then restart at Dose Level -
2 
 Grade 4 diarrhea (≥ 10 stools/day over pretreatment status) - 
hold dose until recovery to ≤ Grade 2 then restart at Dose 
Level -2 
 Other Grade 4 nonhematologic toxicities except alopecia, 
anorexia, asthenia - omit dose until resolved to ≤ Grade 2 then 
restart at Dose Level -2  
The above tables for dose reduction match standard clinical practice and label guidelines for each 
agent, and the treating physician should use their clinical judgement when determining if the 
chemotherapy should be held or dose reduced.  If considered in the best interest of the patient 
and consistent with local practice, investigators may use supportive measures or treatment and/or 
secondary prophylaxis instead of dose reductions for the next treatment cycle. 
If any chemotherapy agent is held for more than 6 weeks from the anticipated treatment date, or 
the dose level - 2 is not tolerated, chemotherapy should be permanently discontinued. 


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8.7. 
Criteria for Permanent Discontinuing Chemotherapy Regimens 
Except where specified below, chemotherapy regimen should be discontinued for any of the 
following criteria. If any of these criteria are met, the chemotherapy will be permanently 
discontinued. 
 Any Grade 4 peripheral neuropathy 
 Grade 4 drug-related thrombocytopenia associated with clinically significant bleeding 
 Any Grade 4 drug-related adverse events or laboratory abnormality except as noted in 
Section 8.6.2. 
 Grade 4 neutropenia > 7 days despite growth factor support 
 Grade 4 electrolyte imbalances/abnormalities that are associated with clinical 
sequelae and are not correctable with supplementation/appropriate management 
within 72 hours of their onset 
 Any drug-related liver function test abnormality value that meets one of the following 
criteria requires discontinuation: 
 AST or ALT > 5-10 x upper limit of normal (ULN) for > 2 weeks or 
 AST or ALT > 10 x ULN or 
 Total bilirubin > 5 x ULN  
 Any drug-related AE which 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) felt to be causing the reaction. The drug not considered 
to be related to the hypersensitivity reaction or infusion reaction may be continued 
 Any Grade 4 AE which the investigator considers related to study drug and 
inappropriate to be managed by dose reduction(s) requires discontinuation of drug(s). 
The drug not considered to be related to the event may be continued 
 If any toxicity does not resolve within 42 days, the targeted treatment will be 
discontinued unless the treating physicians determines that the patient is clinically 
stable, the toxicity has stabilized, and the benefit of continuing the treatment 
compared to the risk of the toxicity is favorable  
 For any adverse event, laboratory abnormality, or intercurrent illness not listed above, 
the investigator should use their medical judgment to determine whether any 
individual chemotherapy agents should be discontinued, in accordance with subject’s 
well-being and local standards 


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8.8. 
Management of AE of Special Interest 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 1 hour afterwards in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a minimum of a 30-minute monitoring period is 
required in an area with resuscitation equipment and emergency agents.  
The management for infusion-related reactions, severe hypersensitivity reactions and irAEs 
according to the NCI-CTCAE criteria are outlined below.   
8.8.1. 
Assessing and Recording Immune-Related Adverse Events 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related should be classified as irAEs and identified as such in the 
eCRF AE page, until day 90, after treatment discontinuation.  
If the events listed below (Table 5) or similar events occur, appropriate diagnostic tests, which 
may include but is not limited to serologic, immunologic, and histologic (biopsy) data, should be 
ordered to exclude alternative causes such as infection, metabolic, toxin, disease progression or 
other neoplastic causes, and other drugs. If alternative explanations have been excluded, the AE 
required the use of systemic steroids, other immunosuppressants, or endocrine therapy and is 
consistent with an immune mediated mechanism of action, the irAE field in the eCRF should be 
checked. The purpose of this action is to assess the cumulative incidence and severity of irAEs in 
the study and to detect any correlation with efficacy. Any serious irAEs should be reported 
according to the seriousness criteria above in Section 8.4.2. For the investigator’s guidance, a list 
of potential irAEs appears below in Table 5. All conditions similar to those listed should be 
evaluated to determine whether they are irAEs, based on a similar diagnostic process to those 
reactions that are presented in more detail in Appendix 10.  
Recommendation for diagnostic evaluation and management of irAEs is based on a recent 
ESMO guideline (Haanen JBAG, 2017) and common immune-related toxicities are detailed in 
Appendix 10. For any adverse events not included in Appendix 10, please refer to the recent 
ESMO guideline (Haanen JBAG, 2017) for further guidance on diagnostic evaluation and 
management of immune-related toxicities.    


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Table 5: 
Immune-Related Adverse Events Associated with Anti-PD-1 Drugs 
Body System Affected 
Events 
Skin (mild-common): 
pruritus or maculo-papular 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  
Ocular: 
episcleritis; conjunctivitis; iritis/uveitis; retinal detachment 
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. 
Note: Refer to Weber JS 2015 
Dose modification and management for irAEs are detailed in Appendix 10. 
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. 
8.8.2. 
Managing Immune-Related Adverse Events 
Immune-related adverse events may develop during the course of the study, including following 
last dose of tislelizumab. Corticosteroids are usually prescribed at medium to high doses 
(0.5 to 1 mg/kg of prednisone) and should be continued until symptoms resolve, become mild, or 
return to baseline levels, whereupon the doses given can be tapered over at least 1 month 
(Boutros C, 2016; Champiat S, 2016). See Appendix 10 for irAE evaluation and management. 
8.8.3. 
Managing Infusion-Related Reactions due to Tislelizumab 
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.   


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Treatment modification guidelines for suspected infusion-related reactions due to tislelizumab 
are summarized in Table 6. 
Table 6: 
Treatment Modification Guidelines for Symptoms of Infusion-Related 
Reactions Due to Tislelizumab 
NCI-CTCAE Grade  
Guideline for Modification of Tislelizumab Treatment 
Grade 1 or 2  
Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated.  
Decrease tislelizumab infusion rate by 50% and closely monitor 
any worsening.  
Manage medically as needed.  
Subsequent infusions should be given after premedication and at 
the reduced infusion rate. 
Grade 2  
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for < 24 hours.  
Decrease tislelizumab infusion rate by 50% of previous rate once 
infusion-related reactions have resolved or decreased to at least 
Grade 1 in severity and closely monitor any worsening. 
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: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events; NSAID, nonsteroidal anti-inflammatory drug. 
8.8.4. 
Medical Management Guidelines for Infusion-Related Reactions (All Grades) 
 Immediate access to resuscitation equipment (including epinephrine, corticosteroids, 
IV antihistamines, bronchodilators, and oxygen) must be available to treat infusion-
related reactions 
 Patients should be instructed to seek emergency care if they experience 
lightheadedness, shortness of breath, wheezing, or swelling after they have left the 
treatment center 
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. 


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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 anti-histamine (eg, 
diphenhydramine or equivalent), anti-pyretic (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.  
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, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
8.8.5. 
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 (eg, 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 (eg, paracetamol) may be given to patients at the discretion of 
the investigator. 
8.8.6. 
Renal Function Abnormalities 
Patients with moderate renal dysfunction (estimated glomerular filtration rate 
≥ 30 mL/min/1.73 m2 and < 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration equation) may be enrolled into the study. The following algorithm is proposed for 
the use of steroid treatment in the management of irAEs: 
 If the serum creatinine is normal at baseline, please see Section 8.8.1 and refer to 
Appendix 10 for diagnosis and management of patients with abnormal renal 
laboratory values.  
 If the serum creatinine is Grade 1 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with 


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tislelizumab, refer to Appendix 10 for diagnosis and management of patients with 
abnormal renal laboratory values. Check the estimated GFR using Appendix 11 and 
the eGFR calculator link. In the setting of a Grade 2 serum creatinine increase only, 
study treatment can continue unless the serum creatinine increases by at least 50% 
from the baseline value OR the eGFR falls below 20 mL/min.  
  If the serum creatinine is Grade 2 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with 
tislelizumab, refer to Appendix 10 for diagnosis and management of patients with 
abnormal renal laboratory values. In the setting of a Grade 3 serum creatinine 
increase only, study treatment will be held until serum creatinine improves to baseline 
and treatment may resume only after discussion with the medical monitor. 


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9. 
STATISTICAL METHODS AND ANALYSIS PLAN 
The statistical analyses will be performed by the sponsor or designee after the data collection for 
the primary efficacy and safety analyses are completed and the database is locked and released. 
Data will be listed and summarized per sponsor agreed reporting standards, where applicable. 
Details of the statistical analyses will be included in a separate Statistical Analysis Plan (SAP). 
9.1. 
Analysis Sets 
Intention-to-Treat (ITT) analysis set includes all randomized patients. It will be the primary 
analysis set for the efficacy analysis.  
Safety analysis set includes all patients who received at least one dose of study treatment. It will 
be the primary analysis set for safety analysis. 
Per-Protocol (PP) analysis set includes patients who have received ≥ 1 dose of study medications 
and had no major protocol deviations that impact efficacy evaluation. Major protocol deviations 
will be determined and documented before the database lock for the primary analysis 
The PD-L1 positive analysis set includes patients whose tumor and immune cell score (TIC 
score) met the pre-defined cut-off (specified in the statistical analysis plan) using VENTANA 
PD‑L1 (SP263) CDx Assay. TIC score is the total percentage of the tumor area covered by tumor 
cells with PD-L1 membrane staining and tumor‑associated immune cells with PD-L1 staining at 
any intensity. 
The PK analysis set includes all patients who received at least 1 dose of tislelizumab per the 
protocol, for whom any post-dose PK data are available. 
The ADA analysis set includes all patients who have non-missing baseline ADA and at least one 
post-baseline ADA result. 
9.2. 
Patient Disposition 
The number of patients randomized, treated, discontinued from study drug and/or study and 
those with major protocol deviations will be counted and summarized. 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. 
9.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the ITT analysis set and 
the PD-L1 positive analysis set using descriptive statistics. Continuous variables include age, 
weight, vital signs, time since initial cancer diagnosis, and time since advanced/metastatic 
disease diagnosis; categorical variables include, gender, ECOG status, geographical region of 
enrollment, country, race, age (<45 years old, ≥45 to ≤65 years old and >65 years old), TNM 
Classification of Malignant Tumors staging (smoking status [never, previous and current], 
alcohol consumption [never, previous and current], primary tumor location [cervical, upper, 


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middle, lower] and previous treatment [chemotherapy, radiation therapy, surgery]), anatomic 
locations of metastases, and number of metastatic lesions (≤ 1 site vs ≥ 2 sites). 
9.4. 
Prior and Concomitant Therapies 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes. Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior and 
concomitant medications will be summarized and listed by drug and drug class in the Clinical 
Study Report (CSR) for this protocol. Prior medications will be defined as medications that 
stopped before the 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 (Safety Follow-up visit). In addition, telephone contacts with 
patients should be conducted to assess irAEs and concomitant medications (if appropriate, ie, 
associated with an irAE or is a new anticancer therapy) at 60 and 90 days (± 14 days) after the 
last dose of study drugs regardless of whether or not the patient starts a new anticancer therapy. 
A listing of prior and concomitant medications will be included in the CSR for this study. 
9.5. 
Efficacy Analyses 
The primary endpoint of OS in the ITT analysis set will be tested once at a one-sided alpha of 
0.025. If the null hypothesis for OS in the ITT analysis set is rejected, the key secondary 
endpoint will be tested sequentially for OS in the PD-L1 positive analysis set. The inferential test 
for OS in the PD-L1 positive analysis set will be stopped at the non-significant endpoint of OS in 
the ITT analysis set. The familywise type I error will be strongly controlled at one-sided level 
0.025. More details will be given in the statistical analysis plan. 
9.5.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is OS in the ITT analysis set as defined in the primary endpoint 
section. In the absence of death, patients will be censored either at the date that the patient was 
last known to be alive or the date of data cut-off, whichever comes earlier. 
OS will be compared between tislelizumab and ICC arms in a stratified log-rank test using a 
significance level of one-sided 0.025. 
The null hypothesis to be tested is: 
H0: OS in tislelizumab = OS in ICC against the alternative: 
H1: OS in tislelizumab ≠ OS in ICC 
This will be the primary analysis once the targeted event number of approximately 400 is 
reached. The p-value from one-sided log-rank test will be calculated, stratified by selected 
stratification factors of ECOG performance status (0 vs 1) and ICC option (paclitaxel vs 
docetaxel vs irinotecan). Sample size calculation is included in Section 9.9. 
The median OS and the cumulative probability of OS at every 3 months, if estimable, will be 
calculated for each treatment arm and presented with two-sided 95% CIs. Kaplan-Meier survival 
probabilities for each arm will be plotted over time. 


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The treatment effect will be estimated by fitting a Cox regression model with treatment arm as a 
factor and with ICC and ECOG performance status as strata. From this model, the hazard ratio 
(HR) of OS will be estimated and presented with a two-sided 95% CI. 
These analyses will be performed in the ITT analysis set as the primary analysis. Outcomes in 
the Per Protocol analysis set will be evaluated as a sensitivity analysis. 
9.5.2. 
Secondary Efficacy Analyses 
Key Secondary Efficacy Endpoint-OS in PD-L1 positive analysis set: 
The OS in the PD-L1 positive analysis set will be analyzed similarly as described in the primary 
analysis for OS in the ITT analysis set. 
Other Secondary Efficacy Endpoints: 
Cochran-Mantel-Haenszel (CMH) test adjusting for selected stratification factors (ECOG and 
ICC option) in the ITT analysis set and the PD-L1 positive analysis set will be provided for ORR 
per RECIST v1.1. The two-sided 95% CIs for the odds ratio in ORR will be calculated, as well 
as Clopper-Pearson 95% CIs of ORR for each treatment arm. 
PFS based on assessment by investigator per RECIST v1.1 will be estimated using the 
Kaplan-Meier (KM) method in the ITT analysis set and the PD-L1 positive analysis set. PFS 
censoring rule will follow United States (US) Food and Drug Administration (FDA) Guidance 
for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and Biologics (2007). Data 
for patients without disease progression or death at the time of analysis will be censored at the 
time of the last tumor assessment. Data for patients who are lost to follow-up prior to 
documented disease progression will be censored at the last tumor assessment date when the 
patient is known to be progression-free. Data for patients who start to receive new anti-cancer 
therapy will be censored at the last tumor assessment date prior to the introduction of new 
therapy.  
A log-rank test stratified by selected stratification factors (ECOG and ICC option) will be used to 
test the PFS differences between two treatment arms. The stratified Cox regression will be used 
to estimate the hazard ratio of PFS. A 95% confidence interval (CI) of HR in PFS will be 
constructed. Median PFS and PFS every 3 months for each treatment arm, if estimable, will be 
presented. 
Duration of response based on assessment by investigator will be analyzed similarly as PFS in 
the responders. 
EORTC QLQ-C30 and EORTC QLQ-OES18 will be summarized using functional 
scale/symptom scale/single item. Observed values and changes from baseline for functional 
scale/symptom scale/single item will be summarized using descriptive statistics. Time to 
clinically meaningful worsening in HRQoL domains will be estimated using Kaplan-Meier 
method. Log-rank test will be employed for testing treatment difference.  
EQ-5D-5L will be compared between tislelizumab and ICC arms. Descriptive statistics will be 
used to show the changes from baseline in each arm. These HRQoL assessment will be analyzed 
in both the ITT analysis set and the PD-L1 positive analysis set. 


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9.5.3. 
Exploratory Efficacy Analyses 
Best overall response (BOR) is defined as the best response per RECIST v1.1 recorded from 
randomization till data cut or start of new anti-cancer treatment. Patients with no post-baseline 
response assessment (for any reason) will be considered non-responders for BOR. The 
proportion and its corresponding Clopper-Pearson 95% CI for each of the response categories 
(CR, PR, SD and PD) will be presented by treatment arm. 
DCR will be analyzed similarly as ORR in the ITT analysis set and the PD-L1 positive analysis 
set. 
PD-L1 expression and, gene expression profiling, tumor mutation burden, MSI, and 
tumor-infiltrated immune cells may be examined in the ITT analysis set. Efficacy analyses, 
including but not limited to OS, PFS, and ORR, may be explored according to biomarker status. 
Other potential predictive markers may also be assessed. 
Methodology for exploratory analyses will be described in the statistical analysis plan. 
9.6. 
Safety Analyses 
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE 
v4.03. Laboratory values (eg, hematology, clinical chemistry, coagulation and urinalysis), vital 
signs, ECGs, and physician examinations will also be evaluated in defining the safety profile of 
each treatment arm. Descriptive statistics will be used to analyze all safety data in the Safety 
analysis set.  
9.6.1. 
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), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.6.2. 
Adverse Events 
The AE verbatim descriptions (investigator’s description from the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to MedDRA (Version 20.0 or higher) lower level term 
closest to the verbatim term. The linked MedDRA System Organ Class (SOC) and Preferred 
Term (PT) are also classified. 
In this protocol, a treatment-emergent adverse event (TEAE) is defined as an AE that had an 
onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of 
study drug up to 30 days following study drug discontinuation or initiation of a new anticancer 
therapy. TEAEs also include all irAEs and drug-related serious AEs recorded up to 90 days after 
the last dose of study drug regardless of whether or not the patient starts a new anticancer 


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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 PT. A patient will be counted only once by the highest severity grade per 
NCI-CTCAEv.4.03 within an SOC and PT, even if the patient experienced more than 1 TEAE 
within a specific SOC and PT. The number (percentage) of patients with TEAEs will also be 
summarized by relationship to the study drug.  
Serious adverse events, deaths, TEAE with grade 3 or above, irAE, related TEAE and TEAEs 
that led to treatment discontinuation, dose reduction, dose interruption or dose delay will be 
summarized. 
9.6.3. 
Clinical Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry) values will be evaluated as appropriate. 
Abnormal laboratory values will be flagged and identified as those outside (above or below) the 
normal range. Reference (normal) ranges for laboratory parameters will be included in the 
Clinical Study Report (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-CTCAEv.4.03 will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low ranges (eg, glucose, potassium, sodium) will be 
summarized separately. 
9.6.4. 
Vital Signs Analyses 
Descriptive statistics for vital sign parameters (eg, blood pressure, temperature) and changes 
from baseline will be summarized.  
9.6.5. 
Ophthalmologic Examination 
Ophthalmologic examination results will be listed by patient. 
9.7. 
Pharmacokinetic Analyses 
Pharmacokinetic samples will be collected in this study as outlined in Appendix 1, and only from 
patients randomized to receive tislelizumab and in sites that are able to adequately perform 
sampling, handling and processing procedures outlined in the Laboratory Manual.  
Tislelizumab serum concentration data, including but not limited to Ctrough, will be tabulated and 
summarized for each cycle at which pharmacokinetics are collected. Descriptive statistics will 
include means, medians, ranges, and standard deviations, as appropriate.  
Additional PK analyses such as population PK analysis and exposure-response (efficacy or 
safety endpoints) analysis may be conducted as appropriated and the results of such additional 
analysis may be reported separately from the CSR. 


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9.8. 
Immunogenicity Analyses  
Samples to assess anti-tislelizumab antibodies will be collected only in patients randomized to 
receive tislelizumab and in sites that are able to adequately perform sampling, handling and 
processing procedures outlined in the Laboratory Manual. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
9.9. 
Determination of Sample Size  
The sample size calculation is based on the primary efficacy analysis of OS comparison between 
tislelizumab and ICC arms in the ITT analysis set. Assuming an OS-HR (Arm Tislelizumab/Arm 
ICC) of 0.75 and a dropout rate of 5% per year, approximately 500 patients will be enrolled and 
randomized in a 1:1 ratio to Arm Tislelizumab and ICC over a 26-month period to accumulate 
approximately 400 deaths, which is estimated to occur approximately 30.2 months after the first 
patient is enrolled when median OS in the tislelizumab and ICC arms are 8 months and 
6 months, respectively. Assuming OS-HR is 0.75, based on recently published results of anti-
PD-1 therapies in second line treatment of ESCC (Kojima et al 2019; Kato et al 2019; Huang et 
al 2019), the study will have a power of 82% with a one-sided alpha of 0.025. 
9.10. 
Interim Analysis 
No interim analysis is planned for this study. 


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10. 
DATA HANDLING AND QUALITY ASSURANCE  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures (SOPs), working practice documents, and applicable regulations and 
guidelines. Site audits may be conducted periodically by the sponsor’s or contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
10.1. 
Data Collection  
Data required by the protocol will be entered into the eCRFs in an EDC system that is compliant 
with all regulatory requirements. All study-related data collected or received by the investigator 
or study team shall be promptly entered into the eCRFs. In no event should the entry of the study 
data into the eCRF be later than what is stipulated in the site contract after the data is collected or 
received by the investigator or study team without prior communication with and approval by 
sponsor. 
Data collection in the eCRF must follow the instructions described in the eCRF Completion 
Guidelines (eCCGs). The investigator has ultimate responsibility for the collection and reporting 
of all clinical data entered in the eCRF. The investigator or designee must sign the completed 
casebooks 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.  
10.2. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at the sponsor’s facility 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 course of the study, a study monitor (ie, 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. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs 
for completeness, clarity and cross checking with source documents is required to monitor the 
progress of the study. Direct access to source data is also required for inspections and audits, and 
will be carried out giving due consideration to data protection and medical confidentiality. 
Adverse events and concomitant diseases/medical history will be coded using MedDRA version 
20.0 or higher. Concomitant medications will be coded using the World Health Organization 
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10.3. 
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. 
10.4. 
Data Integrity Protection Plan and In-house Blinding 
Due to the open-label design of the study, access to the unblinded patient level clinical data in 
the EDC system will only be assigned to predefined study personnel. Functions/persons with 
access to the EDC system shall be prohibited from using the EDC system to generate 
unnecessary listings/summaries that may introduce unwanted bias, or share such outputs or the 
unblinded data from the EDC system with other functions/persons who do not have access to the 
EDC. Although the study is open label, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. More details 
will be described in a Data Integrity Protection Plan (DIPP). 
10.5. 
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) investigator’s study file, and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF 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 CRFs) would include (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, electrocardiogram, electroencephalogram, radio imaging, pathology 
and special assessment reports, consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable back up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 


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The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of 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. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the CRO managing the biological samples, for the shorter of: a period of up to 10 years or 
as allowed by your IRB/IEC. 
10.6. 
Publication and Data Sharing Policy 
A clinical study report will be prepared and provided to the regulatory agency(ies). BeiGene will 
ensure that the report meets the standards set out in the International Council for Harmonization 
(ICH) Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an 
abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the study. The data generated in this clinical study are the exclusive 
property of the sponsor and are confidential. For multicenter studies, the first publication or 
disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors). 
After conclusion of the study and without prior written approval from BeiGene, investigators in 
this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
 The results of the study in their entirety have been publicly disclosed by or with the 
consent of BeiGene in an abstract, manuscript, or presentation form; or 
 The study has been completed at all study sites for at least 2 years. 
No such communication, presentation, or publication will include BeiGene’s confidential 
information.  


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Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsor prior to submission. This allows the sponsors to protect 
proprietary information, provide comments based on information from other studies that may not 
yet be available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. 


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11. 
ETHICAL CONSIDERATIONS 
11.1. 
Compliance with Laws and Regulations 
This study will be conducted in full conformance with the International Council for 
Harmonization (ICH) E6 guideline for GCP and the principles of the Declaration of Helsinki or 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the ICH E2A 
guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting).  
11.2. 
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.  
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 ICFs must be provided to the sponsor for health authority 
submission purposes.  
Patients must be re-consented 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.  
11.3. 
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. Copies of the IEC/IRB correspondence and 
approval of the amended ICF/other information and the approved amended ICF/other 
information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. The investigator is also responsible for promptly 
informing the IRB/IEC of any protocol amendments (Section 12.5). In addition to the 


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requirements for reporting all adverse events to the sponsor, the investigator must comply with 
the requirements for reporting SAEs to the local health authority and IRB/IEC. The investigator 
may receive written IND safety reports or other safety-related communications from the sponsor.  
The investigator is 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.  
11.4. 
Confidentiality 
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. The principal investigator will 
maintain confidentiality 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. In the event of a breach of the confidentiality of a patient’s personal and medical 
information, the principal investigator and sponsor, as appropriate, shall fulfill all remediation 
steps and reporting obligations under applicable data privacy laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated by this study must be available for inspection upon request by representatives of 
the FDA, China Food and Drug Administration (CFDA), 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 sponsor, including but not limited to the Investigator’s Brochure, this protocol, 
CRFs, the IND, and any other study information, remain 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 sponsor. The investigator further agrees to 
take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study is executed, and that contract includes 
confidentiality provisions inconsistent with this section, that contract’s provisions shall apply to 
the extent they are inconsistent with this section. 
11.5. 
Financial Disclosure 
The investigator will provide the sponsor with sufficient and accurate financial information, in 
accordance, with local regulations to allow the sponsor to submit complete and accurate financial 


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certification or disclosure statements to the appropriate health authorities. Investigators are 
responsible for providing information about their financial interests during the course of the 
study and for 1 year after completion of the study (ie, last patient, last visit). 


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12. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
12.1. 
Study Documentation 
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.  
12.1.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation to verify the data recorded in the CRFs for consistency. 
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
12.1.2. 
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. 
12.2. 
Case Report Forms 
For each patient randomized/assigned to treatment, an eCRF must be completed and signed by 
the principal investigator or subinvestigator within a reasonable time period after data collection. 
If a patient withdraws from the study, the reason must be noted in the appropriate eCRF. If a 
patient is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome. 
The eCRF exists within an EDC system with controlled access managed by BeiGene or its 
authorized representative for this study. Study staff will be appropriately trained in the use of 
eCRFs and applications of electronic signatures before being given access to the EDC system. 
Original data and any changes of data will be recorded using the EDC system, with all changes 
tracked by the system and recorded in an electronic audit trail. The investigator attests that the 
information contained in the eCRF is true by providing an electronic signature within the EDC 
system. After final database lock, the investigator will receive a copy of the patient data from 
that site (eg, paper, CD, or other appropriate media) for archiving the data at the study site. 


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12.3. 
Protocol Deviations 
The investigator is to document and explain any deviations from the IRB/Ethics committee 
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, and shall report all protocol deviations to sponsor.  
12.4. 
Study Site Inspections 
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.  
12.5. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. Protocol amendments will be 
submitted to the IRB/IEC and to regulatory authorities in accordance with local regulatory 
requirements.  
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an immediate 
hazard to patients or changes that involve logistical or administrative aspects only (eg, change in 
medical monitor or contact information). 


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13. 
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Ando N (Ed.). (2015). Esophageal Squamous Cell Carcinoma. Springer. 
Arnold M, et al. (2015). Global incidence of esophageal cancer by histological subtype in 2012. 
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Beers SA, Glennie MJ, White AL. Influence of immunoglobulin isotype on therapeutic antibody 
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Boutros C, et al. (2016). Safety profiles of antiCTLA-4 and antiPD-1 antibodies alone and in 
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Fukushima R, et al. (2014). A Retrospective Analysis of Irinotecan for Heavily Pretreated 
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14. 
APPENDICES 
APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Assessment Window (Days) 
Screening1 
All Treatment Cycles2  
End of Treatment3 
(0-7 days) 
Safety Follow-
up4 
(30 ± 7 days 
after last dose) 
Survival 
Follow-up5 
(Every 
month) 
Day -28 to 
Day -1 
Cycles 1-2  
Cycle 3 and 
Subsequent 
Cycles  
Day 1 
(± 3) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 1 
(± 3) 
Informed consent1 
x 
  
 
 
 
 
  
  
Inclusion/Exclusion criteria 
x 
  
 
 
 
 
  
  
Randomization 
x 
 
 
 
 
 
 
 
Demographic/Medical 
history/Prior medications  
x 
  
 
 
 
 
  
  
Cancer Diagnosis and 
Treatment History6 
x 
 
 
 
 
 
 
 
Concomitant medications7 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events8 
x 
x 
x 
x 
x 
x 
x 
  
Physical examination9 
x 
x 
 
 
x 
x 
x 
  
ECOG performance status10 
x10 
x10 
 
 
x10 
x 
x 
  
Vital signs/Weight11 
x 
x 
x 
x 
x 
x 
x 
  
12-lead ECG12 
x 
As clinically indicated  
x 
 
  
HBV and HCV serology13 
x 
As clinically indicated 
 
  
 
Hematology14 
x 
x14 
x14 
x14 
x14 
x14 
x14 
  
Serum chemistry14 
x 
x14 
x14 
x14 
x14 
x14 
x14 
  
Total CK and CK-MB14 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation parameters14 
x 
As clinically indicated 
x 
x 
  


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Assessment Window (Days) 
Screening1 
All Treatment Cycles2  
End of Treatment3 
(0-7 days) 
Safety Follow-
up4 
(30 ± 7 days 
after last dose) 
Survival 
Follow-up5 
(Every 
month) 
Day -28 to 
Day -1 
Cycles 1-2  
Cycle 3 and 
Subsequent 
Cycles  
Day 1 
(± 3) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 1 
(± 3) 
Urinalysis14 
x 
As clinically indicated 
x 
x 
  
Pregnancy test15 
 x 
x15 
 
 
x15 
x 
x 
  
Thyroid function16 
x 
x16 
 
 
x16 
 
x 
  
Pharmacokinetics17 
  
x 17 
 
 
x 17 
 
x17 
  
Anti-tislelizumab antibodies18 
 
x18 
 
 
x18 
 
x18 
 
Tumor assessment19 
x (within 28 
days) 
Every 6 weeks for 6 months, then every 9 
weeks27 
x 
 
  
Tislelizumab administration20 
  
x 
 
 
x 
 
  
  
Chemotherapy administration21 
 
x 
 
 
x 
 
 
 
Archive/Fresh Tumor tissue 
collection22 
x 
  
 
 
 
x (optional) 
  
  
Optional blood sample for 
biomarker analysis23 
 
x 
 
 
HRQoL Assessments24 
x 
x  
 
 
Cycles 3-6 
only 
x 
x 
 
Survival status  
  
  
 
 
 
 
 
x 
Pulmonary function tests25 
x 
 
 
 
 
 
 
 
Optical coherence tomography 
(or equivalent diagnostic test) 
and visual acuity tests26 
x    
Every 15 weeks ± 7 days 
x28 
x28 
 
Abbreviations: x, to be performed; ECOG, Eastern Cooperative Oncology Group; ECHO, echocardiography; ECG, electrocardiogram; FEV1, forced expiratory 
volume in the first second of expiration; HBV, hepatitis B virus; HCV, hepatitis C virus; HRQoL, Health Related Quality of Life; MRI, magnetic resonance 
imaging. 
1  
Written informed consent is required prior to performing any study-specific tests or procedures. Results of standard-of-care laboratory tests and physical 
examinations performed prior to obtaining informed consent and within 7 days prior to randomization may be used for screening assessments rather than 
repeating such tests. Baseline radiologic examinations for tumor status may be performed within 28 days of randomization. Fresh tumor biopsy is 
permitted, if no archival tumor tissue is available. 


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2  
Cycle 1 treatment must be given within 3 business days of randomization. After Cycle 1 there is a 3-day window for all study treatment given on a 21-
day cycle unless otherwise noted. There is a 2-day window for treatments given on a weekly schedule. Efficacy assessments will be performed 
approximately every 6 weeks for 6 months, then every 9 weeks regardless of the duration of a chemotherapy cycle. 
3  
The End-of-Treatment (EOT) Visit is conducted when the investigator determines that tislelizumab or ICC will no longer be used, at which time all of 
the assessments listed for the EOT Visit will be performed. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the EOT Visit, tests need not be repeated. Tumor assessment is not required at the EOT Visit provided that fewer than 6 weeks have passed since 
the last assessment.   
4  
The mandatory Safety Follow-Up Visit is required to be conducted 30 days (± 7 days) after the last dose of study therapy, or before initiation of a new 
anti-cancer treatment. At the end of treatment, ongoing AEs considered related to study treatment will be followed until the event has resolved to 
baseline or ≤ Grade 1, the event is assessed by the investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the AE. The EOT Visit may be combined with the Safety Follow-up Visit, provided 
that the EOT occurred 30 days (± 7 days) after the last study treatment; the assessments for both visits should be performed. 
5  
Survival follow-up information will be collected via telephone calls, email or other communication; patient medical records; and/or clinic visits 
approximately 1 month (4 weeks ± 7 days) after the Safety Follow-up Visit and approximately monthly thereafter until death, loss to follow-up, 
withdrawal of consent, or study termination by sponsor. All patients will also be followed for new anti-cancer therapy information unless the patient 
requests to be withdrawn from follow-up. 
6  
Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Radiographic imaging 
performed prior to study entry may be collected for review by the investigator, as clinically appropriate.  
7  
Concomitant medications include any prescription medications, over-the-counter medications, herbal supplements, and IV medications and fluids. All 
concomitant medications received within 30 days before the first dose of study drug and 30 days after the last infusion of study medication should be 
recorded. At subsequent visits, changes to current medications or medications used since the last documentation of medications will be recorded. Only 
new anti-cancer treatment will be collected at Survival Follow-up Visits. 
8  
AEs and laboratory safety measurements will be graded per NCI-CTCAE version 4.03. All AEs, whether gradable by CTCAE or not, 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 or the initiation of a new anticancer therapy, whichever occurs first. Immune-related AEs should be reported for 90 days 
after the last dose of tislelizumab regardless of initiation of subsequent anticancer therapy. After this period, the investigator should report any SAEs 
that are believed to be related to tislelizumab treatment (Section 8.4.1). 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 (Section 8.2.6). 
9  
A complete physical examination should include an evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems. At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations 
are required to be performed. Height will only be measured and recorded at Screening Visit. Investigators should solicit patients regarding changes in 
vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab treatment. For any change in vision, referral to an 
appropriate specialist will be made for further management guidance.    
10  ECOG performance status are required to be obtained within 7 days prior to randomization. 
11  Vital signs to include temperature, pulse, blood pressure, and weight; pulse and BP should be recorded while the patient is in a seated position after 
resting for 10 minutes. For all infusions of tislelizumab, the patient’s vital signs should be recorded before the infusion, and between 30 to 45 minutes 
after the infusion. Vital signs must be collected during the infusion if clinically indicated. For the subjects randomized to Paclitaxel, patients will be 
monitored for anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension. Monitor diarrhea and give fluid and 
electrolytes as needed on all patients receiving irinotecan.  


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12  Electrocardiogram (ECG) recordings will be obtained during screening, End of Treatment, and as clinically indicated at other timepoints. Patients 
should be resting and in a sitting or supine position for at least 10 minutes prior to ECG collection. A repeat ECG should be performed to confirm 
findings, if any. 
13  Testing will be performed at screening and as clinically indicated, including HBsAg, HBcAb, and HCV antibody. Patients who are HBsAg positive at 
screening must not be enrolled until further definite testing with HBV DNA titers < 500 IU/mL (or 2500 copies/mL).  
14  Local or central laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will 
be collected as specified in Section 7.10. Laboratory tests are required to be obtained within 14 days of randomization. If laboratory tests are not 
performed within 7 days prior to the administration of study drug(s) on Cycle 1 Day 1, these tests should be repeated and reviewed before study drug(s) 
administration. Hematology and serum chemistry (including liver function tests) will be performed weekly for the first 2 cycles and then at the 
beginning of each subsequent cycle. After Cycle 1, results are to be reviewed within 3 business days before study drug administration. It is 
recommended to perform weekly peripheral blood cell counts on all patients receiving paclitaxel, docetaxel, and irinotecan. All patients will have 
creatine kinase (CK) and creatine kinase-cardiac muscle isoenzyme (CK-MB) testing at screening and at all scheduled visits during the first 3 treatment 
cycles, all pre-dose assessments from Cycle 4 onwards, and at the EOT and Safety Follow-up Visits. In the event that CK-MB fractionation cannot be 
evaluated in the local laboratory, troponin I and/or troponin T should be assessed instead; the same test should be administered throughout the study. 
Urinalysis and coagulation parameters are to be assessed during the treatment period only if clinically indicated. Refer to Section 8.2.5 for additional 
information regarding clinical assessment and management of clinical laboratory abnormalities. 
15  Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days prior to randomization, EOT Visit and at Safety Follow-up. Urine pregnancy test will be performed at each visit prior to study 
treatment; a serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
16  Thyroid function tests will be performed within 7 days prior to randomization with analysis of free T3, free T4 and TSH. They will be tested every 
3 cycles thereafter (eg, Cycles 4, 7 and 10, etc.) from randomization and at the mandatory Safety Follow-Up Visit in tislelizumab arm. Thyroid function 
testing performed during the study and at the Safety Follow-up Visit will only be for patients on the tislelizumab arm. 
17  Only for patients randomized to tislelizumab. Only in sites that can adequately perform sampling, handling and processing procedures outlined in the 
Laboratory Manual. Procedures for collection of tislelizumab PK samples are described in the Laboratory Manual. Predose (within 60 min before start 
infusion) samples are required to be collected at Day 1 of Cycle 1, 2, 5, 9 and 17; post-dose (within 30 minutes after completing tislelizumab infusion) 
samples are required to be collected at Day 1 of Cycles 1 and 5. An additional PK sample is required to be collected at the Safety Follow-Up Visit. If a 
patient present with any immune-related adverse event, additional blood PK samples may be taken to determine the plasma concentration of BGB- 
A317. These tests are required when it is allowed by local regulations/IRBs/ECs. 
18  Only for patients randomized to tislelizumab. 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 when it is allowed by local regulations/IRBs/ECs. 
19  Examinations performed as standard of care prior to obtaining informed consent at the same study site within 28 days prior to randomization may be 
used rather than repeating tests. CT/MRI of the head at baseline is required for patients who are suspected to have central nervous system (CNS) 
metastases. All measurable and evaluable lesions are required to be assessed and documented at the screening visit. The same radiographic procedure 
must be used throughout the study for each patient. Patients will undergo tumor assessments approximately every 6 weeks (± 7 days) for 6 months, then 
every 9 weeks (± 7 days) from last assessment afterwards. Patients who discontinue from treatment for reasons other than disease progression or death 
will continue scheduled tumor assessments until the start of a new anti-cancer therapy, disease progression, death, lost to follow-up, withdrawal of 
consent, or until the study completion, whichever occurs first. Investigators may perform additional scans or more frequent assessments if clinically 
indicated. If previous tumor imaging was obtained within 6 weeks prior to the date of discontinuation, then additional tumor imaging at treatment 
discontinuation is not required. Imaging timing should follow calendar days and should not be adjusted for delays in treatment. Patients who continue 


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tislelizumab treatment beyond radiographic disease progression will be monitored with a follow-up scan at least 4 weeks later or at the next regularly 
scheduled timepoint (not to exceed 6 weeks) before discontinuation of study treatment.  
20  The initial infusion of tislelizumab will be delivered over 60 min; if well-tolerated, second infusion and each subsequent infusion may be administered 
over 30 min which is the shortest period permissible for infusion. As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 
2, patients must be monitored for at least 1 hour afterwards in an area with resuscitation equipment and emergency agents. From cycle 3 onward, a 
minimum of a 30-minute monitoring period is required in an area with resuscitation equipment and emergency agents. 
21  Study treatment must begin within 3 business days of randomization for Cycle 1 Day 1. Patients may receive premedications prior to the initiation of 
chemotherapy according to the routine standard of care. The treatment window for paclitaxel given on a weekly schedule is ± 2 days. The dosing 
frequency in this appendix will not be applicable for patients receiving weekly paclitaxel as a chemotherapy regimen, and they should follow the dosing 
regimen described in Table 2 of Section 3.3.2 or Table 3 of Section 5.1.4, or other local guidelines, as applicable. 
22  Representative tumor specimens in paraffin blocks (preferred) or approximately 10 unstained slides are required to be submitted for biomarker analysis 
if available. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is highly recommended. 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 at baseline. Written patient consent is required for 
fresh tumor biopsies.  
23  Optional blood samples (approximately 10 mL each timepoint) will be taken at the time of first tumor response (tumor assessment is CR/PR) and/or 
confirmed disease progression for all randomized patients, to explore the association of blood-based biomarkers with response, resistance, and prognosis 
to tislelizumab or chemotherapy. Written patient consent is required for blood sample collections. 
24  All HRQoL assessments are to be performed prior to study treatment initiation, Cycles 1-6 Day 1 or at the EOT Visit (whichever occurs first), and at the 
Safety Follow-Up Visit. A visit window of ± 7 days will apply to an HRQoL visit assessment. HRQoL instruments are to be given to the patient prior to 
being seen by a health care professional. NOTE: HRQoL assessments are to be conducted both at screening and C1D1 visit; if screening visit is < 7 days 
from C1D1 visit, the HRQoL assessment does not need to be repeated. 
25  Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant respiratory symptoms unrelated to underlying 
cancer will have pulmonary function testing which may include but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period, to assist the determination of suitability for enrollment on the study. Uncertain cases should be discussed with the medical monitor. 
26  Eye examination, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of 
care prior to obtaining written informed consent and within 28 days of randomization may be used rather than repeating tests. Eye examination, visual 
acuity test, and optical coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit. Patients on the tislelizumab arm 
will undergo repeated assessments approximately every 15 weeks (± 7 days) during study treatment and a final assessment < 30 days (± 7 days) after the 
last dose of study treatment. Investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each 
scheduled study visit during tislelizumab treatment. For any change in vision, referral to an appropriate specialist will be made for further management 
guidance. 
27  To avoid bias, tumor assessments should occur independently of treatment and the timing of the tumor assessments should be based on the date of 
randomization.  
28  For patients on the tislelizumab arm, ophthalmologic assessments including eye examination, visual acuity test, and OCT (or equivalent diagnostic test) 
should only be performed once at either the EOT or during safety follow up, within 30 days (± 7 days) of study treatment end.  
 


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APPENDIX 2. 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, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (Version 
1.1). Eur J Cancer. 2009; 45:228-247. 
DEFINITIONS 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
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 (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 
 10 mm caliper measurement by clinical examination (when superficial). 
 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
 Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
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 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
 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. Study 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 x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 


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sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 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 studies 
where recurrence following complete response or surgical resection is an endpoint. 
 Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. Because tumor 
markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis. Specific guidelines for both 
CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen (PSA) 
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 studies in 
ovarian cancer. 
 Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease to 
differentiate between response (or stable disease) and progressive disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
 Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or 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 


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may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of < 10 mm. Case report recorded in a separate 
section where, to qualify for CR, each node must achieve a short axis <10 mm. For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions. 
 Target lesions that become “too small to measure”. While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the eCRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (NOTE: It is 
less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value 
will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm. 
 Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
 CR: Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
 PD: Unequivocal progression (as detailed below) of existing non-target lesions. 
(NOTE: the appearance of one or more new lesions is also considered progression.) 
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 


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 When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease 
in the face of 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 studies when it is not a criterion of study entry to have measurable disease. 
The same general concept apply 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 complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up study 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 study 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. 


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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up: This 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 best overall response 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 best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in studies where confirmation of complete or partial response IS NOT required: 
Best response in these studies is defined as the best response across all timepoints (for example, 
a patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response 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 timepoint response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to 
follow-up after the first SD assessment would be considered unevaluable. 


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Target Lesions 
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” on the eCRF. 
In studies where confirmation of response is required, repeated ‘NE’ timepoint assessments may 
complicate best response determination. The analysis plan for the study must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most studies it is reasonable to consider a patient with timepoint 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 study therapy. 
Conditions that define “early progression, early death, and unevaluable response” are study 
specific and should be clearly described in each protocol (depending on treatment duration, 
treatment periodicity). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 


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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 non-randomized studies 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 studies. However, in all other circumstances, ie, in 
randomized studies (phase 2 or 3) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 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 complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular study, the protocol should specify the minimal time interval 
required between two measurements for determination of stable disease. 
NOTE: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between studies are to be made. 


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APPENDIX 3. ECOG PERFORMANCE STATUS-GRADING SYSTEM 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 


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APPENDIX 4. 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. Patients with a history 
of one or more of the conditions listed in the table below are excluded from participating in the 
study, with some possible exceptions, as follows: 
 An exception may be made for patients with a medical history of such entities as 
atopic disease or childhood arthralgias, for which the clinical suspicion of 
autoimmune disease is low.  
 Patients with a history of autoimmune-related hypothyroidism who are on a stable 
dose of thyroid replacement hormone may be eligible for this study. 
 Patients with a history of transient autoimmune manifestations of an acute infectious 
disease that resolved upon treatment of the infectious agent (eg, acute Lyme arthritis) 
are not excluded.  
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 
Diabetes mellitus Type 1 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture’s syndrome 
Granulomatosis with polyangiitis 
 Graves’ disease 
 Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 


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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 
Sjögren’s syndrome 
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
 


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APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL” AND 
“WOMEN OF 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 
NOTE: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
NOTE: A sterile male is one for whom azoospermia, in a semen sample examination, 
has been demonstrated as definitive evidence of infertility. Males with ‘low sperm 
counts’ (consistent with ‘sub-fertility) are not to be considered sterile for purposes of 
this study. 
 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, post-ovulation 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 another highly effective form of birth control listed above. 
Definitions of “Women of Childbearing Potential" and “Women of Non-Childbearing Potential” 
are applicable to both study participants and sexual partners of male participants. 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  


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Conversely, “women of non-childbearing potential” are defined as female patients meeting any 
of the following criteria: 
 Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
 Post-menopausal, defined as: 
 > 55 years of age with no spontaneous menses for > 12 months OR 
 < 55 years of age with no spontaneous menses for > 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL 
Study participants receiving chemotherapy have a potential risk of irreversible infertility. 
Patients should be advised to speak to their physician for further information about their locally 
available options for fertility preservation. 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and pregnancy 
testing in clinical studies. 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 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity (eg, no 
shortness of breath when walking, climbing stairs, et cetera). 
II 
Mild symptoms (eg, mild shortness of breath and/or angina).  
Slight limitations during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, eg, 
walking short distances (20-100 meters). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound. 


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APPENDIX 7. EORTC-QLQ-C30 QUESTIONNAIRE 
 
 


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APPENDIX 8. EORTC QLQ-OES18 QUESTIONNAIRE 
 


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APPENDIX 9. EQ-5D-5L QUESTIONNAIRE 
 


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APPENDIX 10. IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE 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. However, stopping rules for study drug must be 
followed as described below. 
Criteria used to diagnose irAEs 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 irAE diagnosis:  
 What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
 How did the patient respond to withdrawal of tislelizumab? 
 Did the event recur when tislelizumab was reintroduced? 
 Was there a clinical response to corticosteroids? 
 Is the event an autoimmune endocrinopathy? 
 Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field, 
associated with the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of  
Possible Immune-related Adverse Events 
Immune-related 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-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all 
CNS symptoms; review alcohol history and other medications. Conduct a 
diabetic screen, and assess blood B12/folate, HIV status, TFTs, and 
consider autoimmune serology. Consider the need for brain/spine 
MRI/MRA and nerve conduction study for peripheral neuropathy. Consult 
with a neurologist if there are abnormal findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive 
testing, including the following: FBC, UEC, LFTs, CRP, TFTs, stool 
microscopy and culture, viral PCR, Clostridium difficile toxin, 
cryptosporidia (drug-resistant organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a 
patient experiences bleeding, pain or distension, consider colonoscopy with 
biopsy and surgical intervention, as appropriate.  
Ocular Disorders 
If patients experience 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 or 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 rheumatology 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to 
rheumatology for further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, 
CRP, troponin and consider a muscle biopsy 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC,  urea electrolytes and creatinine. 
 


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Treatment of Immune-related Adverse Events 
 Immune-related AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, 
with patients is required 
 Immune-related 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 
irAEs, 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 
 Tislelizumab must be permanently discontinued for any onset of Grade 4 or recurrent 
Grade 3 immune-related adverse events 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
Thyroid Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if 
hypothyroid, until TSH/T4 
levels return to normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist. 
In cases with systemic 
symptoms: withhold study 
treatment, treat with a beta 
blocker and consider oral 
prednisolone 0.5 mg/kg/day 
for thyroid pain. Taper 
corticosteroids over 2-4 weeks. 
Monitor thyroid function 
regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an 
endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day 
(for the elderly or those with 
co-morbidities, the suggested 
starting dose is 0.5 µg/kg/day). 
Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker 
and may require carbimazole 
until thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
 
For recurrent Grade 3: 
Discontinue study 
treatment.   
 
For Grade 4: 
Discontinue study 
treatment. 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an 
endocrinologist for hormone 
replacement. Add oral 
prednisolone 0.5-1 mg/kg/day 
for patients with pituitary 
inflammation. Taper 
corticosteroids over at least 
1 month. If there is no 
improvement in 48 hours, treat 
as Grade 3-4. Taper 
corticosteroids over at least 1 
month. 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3-4 
Moderate-severe symptoms 
Refer patient to an 
endocrinologist for assessment 
and treatment. Initiate pulse IV 
methylprednisolone 1 mg/kg 
for patients with 
headache/visual disturbance 
due to pituitary inflammation. 
Convert to oral prednisolone 
and taper over at least 1 month. 
Maintain hormone replacement 
according to endocrinology 
advice. Maintain hormone 
replacement according to 
endocrinology advice. 
For Grade 3: 
Discontinue study 
treatment.   
 
For Grade 4: 
Discontinue study 
treatment. 
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. 
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. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
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 1 month. 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 1 
month.  
Consider azathioprine, MMF, 
cyclosporine if no response 
within 72-96 hours. 
Discontinue study 
treatment. 
Colitis/ 
Diarrhea 
1 
Mild symptoms: < 3 liquid 
stool 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 1 month. 
Consider prophylaxis for 
adverse steroid effects, eg, 
blood glucose monitoring, 
vitamin D/calcium supplement. 
If no improvement in 72 hours 
or symptoms worsen, consider 
infliximab 5 mg/kg if no 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
For recurrent Grade 3: 
Discontinue study 
treatment 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
4 
Life-threatening symptoms 
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 2-4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1 or 2) 
after discussion with the 
study medical monitor. 
 
For recurrent Grade 3: 
Discontinue study 
treatment 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment), including 
Stevens-Johnson Syndrome 
(all grades), and toxic 
epidermal necrolysis 
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. 
 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated 
above upper limit of normal 
but < 2.5 x ULN 
and patient has symptoms, 
consider oral steroids and 
treat as Grade 2 
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 x ULN or worse 
initiate oral prednisolone 
0.5-1 mg/kg and taper over at 
least 4 weeks 
Hold study treatment 
until improved to grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate 
oral prednisolone 1 mg/kg. 
Consider bolus IV 
(methyl)prednisolone and 
1-2 mg/kg/day maintenance 
for severe activity restriction 
or dysphagia. If symptoms do 
not improve add 
immunosuppressant therapy. 
Taper oral steroids over at 
least 4 weeks 
Discontinue if any 
evidence of myocardial 
involvement 
 
For recurrent Grade 3: 
Discontinue study 
treatment. 
 
For Grade 4: 
Discontinue study 
treatment. 
Myocarditis 
1 
Asymptomatic but 
significantly increased CK-
MB (an elevation of CK-
MB would be any value 
above upper limit of 
normal) 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 refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac 
symptoms or any increase in 
Follow the same study 
drug management for 
Grade 1. 
3 
Severe symptoms with 
mild exertion 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
4  
Life-threatening  
cardiac serum markers to the 
coronary care unit. 
Initiate oral prednisolone or IV 
(methyl) prednisolone at 1-2 
mg/kg/day. Manage symptoms 
of cardiac failure according to 
local guidelines. 
If no immediate response 
change to pulsed doses of 
(methyl)prednisolone 1g/day 
and add MMF, infliximab or 
anti-thymocyte globulin 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3 x 
ULN 
Check LFTs within 1 week and 
before the next dose to verify 
that there has been no 
worsening. 
Based on clinical 
judgement, continue 
study treatment or hold. 
If study drug is held, 
recheck LFTs in 
48-72 hours and restart 
study drug if LFTs did 
not worsen.  
2 
ALT or AST 3-5 x ULN 
Recheck LFTs every 48-72 
hours:   
For persistent ALT/AST 
elevation: consider oral 
prednisolone 0.5-1 mg/kg/day 
for 3 days then taper over 2-4 
weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and 
taper over 2-4 weeks; 
re-escalate dose if LFTs 
worsen, depending on clinical 
judgement.  
Hold study treatment, 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤ 10 mg. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
ALT or AST 5-20 x ULN 
ALT/AST < 400 IU/L and 
normal bilirubin/INR/albumin: 
Initiate oral prednisolone 
1 mg/kg and taper over 2-4 
weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: 
Initiate IV 
(methyl)prednisolone 
2 mg/kg/day and recheck LFTs 
every day. When LFTs 
improve to Grade 2 or lower, 
convert to oral prednisolone 
and taper over at least 1 month. 
Recheck LFTs according to 
severity grade above. 
Hold study treatment 
until improved to 
baseline grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
 
If ALT or 
AST > 8xULN or rise 
in total 
bilirubin > 5xULN: 
Discontinue study 
treatment 
 
For recurrent Grade 3: 
Discontinue study 
treatment 
4 
ALT or AST > 20X ULN 
Initiate IV methylprednisolone 
2 mg/kg/day and recheck LFTs 
every day. Convert to oral 
prednisolone and taper over at 
least 6 weeks. Recheck LFTs 
according to severity grade 
above. 
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 1.5 x baseline 
or > ULN to 1.5 x ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage 
as per criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5-3 x 
baseline or > 1.5-3 x 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. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
Creatinine > 3 x baseline 
or > 3-6 x ULN 
Hospitalize patient for 
monitoring and fluid balance; 
repeat creatinine every 24 
hours; refer to a nephrologist 
and discuss need for biopsy. If 
worsening, initiate IV 
(methyl)prednisolone 
1-2 mg/kg. Taper 
corticosteroids over at least 1 
month. 
Hold study treatment 
until the cause is 
investigated.  
If study drug suspected: 
Discontinue study 
treatment. 
For recurrent Grade 3: 
Discontinue study 
treatment 
4 
Creatinine > 6 x 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. 
Checks 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. 
 
For recurrent Grade 3: 
Discontinue study 
treatment 
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. 
Discontinue study 
treatment 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
Ocular Toxicity 
1 
Asymptomatic eye 
examination/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. 
Discontinue study 
treatment. 
 
For recurrent Grade 3: 
Discontinue study 
treatment 
4 
Blindness (at least 20/200) 
in the affected eyes 
Initiate IV 
(methyl)prednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks 
Discontinue study 
treatment 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes 
Continue study 
treatment  
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management. Initiate IV 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone when 
amylase/lipase improved to 
Grade 2, and taper over at least 
4 weeks 
Discontinue study 
treatment.  
 
For recurrent Grade 3: 
Discontinue study 
treatment 
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 to 
worsen, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
Severe pain with 
inflammation or permanent 
joint damage, daily living 
activity limited 
Refer patient urgently to a 
rheumatologist for assessment 
and management. Initiate oral 
prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
For recurrent Grade 3: 
Discontinue study 
treatment 
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 guideline, treat 
with analgesics, topical 
treatments and oral hygiene 
care. Ensure adequate 
hydration. If symptoms worsen 
or there is sepsis or bleeding, 
manage as Grade 3. 
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 to 1. 
For recurrent Grade 3: 
Discontinue study 
treatment 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for 
emergency care. Consider IV 
corticosteroids if not 
contraindicated by infection 
Discontinue study 
treatment 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, chronic heart failure; CK, creatine kinase; CK-MB, creatine kinase-cardiac muscle 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 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation1 and the Modification of Diet in Renal Disease (MDRD) Study equation. The National 
Kidney Disease Education Program (NKDEP) calculators rely on creatinine determinations 
which are isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be using 
creatinine methods calibrated to be IDMS traceable. Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL. This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1) α x max (Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area 
The online calculator for CKD-EPI can be found here: 
https://www.niddk.nih.gov/health-information/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators 


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APPENDIX 12. DETERMINING LINE OF THERAPY IN ESCC 1 
 
 
Notes: 
1  
This is a general guide to determine the line of therapy and cannot cover all possibilities; if you have 
questions, please consult the medical monitor 
2  
The First Line or Front-Line systemic treatment is defined as “platinum-based regimen”. Single drug 
regimen or non-platinum regimen which is used alone or used for radiotherapy sensitization (the dose is 
lower than the NCCN treatment guidance recommended standard systematic treatment dose) should not be 
considered as one line of therapy. 
Combination must include chemotherapy and may also include surgery and radiotherapy.  
3  
Treatment free interval (TFI) is defined as duration from the last day (given day/infusion day) of prior 
treatment to the date of progression. 
4  
Patients with stage IV disease at first diagnosis are eligible for this study when their cancer has progressed 
after the 1st line of systemic treatment, regardless of the length of the TFI. 
5  
Patients must meet all inclusion and exclusion criteria to be enrolled into this study. 


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APPENDIX 13. SAFETY RUN-IN SUBSTUDY INVESTIGATING SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND 
PRELIMINARY ANTITUMOR ACTIVITY OF ANTI-PD-1 
MONOCLONAL ANTIBODY TISLELIZUMAB IN 
JAPANESE PATIENTS WITH ADVANCED 
UNRESECTABLE/METASTATIC ESOPHAGEAL 
SQUAMOUS CELL CARCINOMA 


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SYNOPSIS FOR SUBSTUDY 
Name of Sponsor: BeiGene, Ltd. 
Investigational Product: Tislelizumab (BGB-A317)  
Title of Study: Safety Run-in Substudy Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activity of Anti-PD-1 Monoclonal Antibody Tislelizumab 
(BGB-A317) in Japanese Patients with Advanced Unresectable/Metastatic Esophageal 
Squamous Cell Carcinoma  
Protocol Identifier: BGB-A317-302 Substudy 
Number of Patients: A minimum of 6 and up to a maximum of 10 patients will be enrolled to 
assess pharmacokinetics (PK) and dose-limiting toxicity (DLT). (Up to 20 patients will be 
enrolled if more than one dose level is explored.) 
Study Centers: To be determined 
Study Objectives: 
Primary: 
 To assess the safety and tolerability of tislelizumab in Japanese patients with advanced 
unresectable esophageal squamous cell carcinoma (ESCC) 
 To confirm the pivotal Phase 3 dose of tislelizumab in Japanese patients 
 To characterize the pharmacokinetics of tislelizumab in Japanese patients 
Secondary: 
 To assess the preliminary antitumor activity of tislelizumab 
 To assess host immunogenicity to tislelizumab 
Exploratory: 
 To explore correlations between drug exposure and response 


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Study Endpoints: 
Primary: 
 Tislelizumab safety and tolerability: The safety of tislelizumab will be assessed throughout 
the study by monitoring adverse events (AEs) and serious adverse events (SAEs) per National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 
(v)4.03, relevant physical examination, electrocardiograms (ECGs) and laboratory assessments 
as needed 
 The pivotal Phase 3 dose for tislelizumab will be confirmed based on safety, tolerability, 
pharmacokinetics, and other available data 
 PK evaluations: Individual tislelizumab concentrations and PK parameters will be 
tabulated by visit/cycle and/or dose cohort 
Secondary: 
 
Efficacy evaluations: Overall response rate (ORR), progression-free survival (PFS), and 
duration of response (DOR) will be determined based on assessment by investigator per 
Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1. Overall survival 
(OS) will be evaluated. 
 Anti-BGB-A317 antibody: Assessments of immunogenicity of tislelizumab to determine 
the incidence of anti-drug antibodies (ADAs) 
Exploratory: 
 
Assessments of the correlations between drug exposure and response (efficacy, safety 
endpoints) 


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Study Assessments: 
Dose-limiting toxicities (DLTs) will be assessed among evaluable patients after 21 days on 
study. An evaluable patient is defined as the patient who has received at least 80% of the dose 
and completed all safety assessments required during the first 21 days, or any patient who has 
experienced a DLT within 21 days. The first six patients will be hospitalized for the first week 
of Cycle 1. 
Tumor response will be evaluated by the investigator per RECIST v1.1 approximately every 
6 weeks for the first 6 months and every 9 weeks thereafter. If a patient discontinues study 
treatment due to any reason other than disease progression or death, tumor assessments will 
continue as scheduled until disease progression, death, loss to follow-up, or withdrawal of 
consent, whichever occurs first. 
Patients will be evaluated for any AEs and serious adverse events (SAEs) occurring up to 
30 days after the last dose of study drug (all severity grades, per NCI-CTCAE v4.03) or 
initiation of a new anticancer therapy, whichever occurs first, and immune-related AEs (irAEs) 
occurring up to 90 days after the last dose of study drug regardless of initiation of a subsequent 
anticancer therapy. All drug-related SAEs will be recorded by the investigator after treatment 
discontinuation until patient death, withdrawal of consent, or loss to follow-up, whichever 
occurs first. All study drug-related SAEs will be followed until they resolve to baseline or 
≤ Grade 1, the investigator assesses the AE as stable and unlikely to improve, or the patient is 
lost to follow-up, whichever occurs first. 
Safety and efficacy monitoring will be performed by an Independent Data Monitoring 
Committee (IDMC) as per the main protocol (Section 8.5). The IDMC will additionally 
evaluate and confirm the Phase 3 dose based on the safety and tolerability of tislelizumab, and 
decide whether to add unscheduled dose levels for the study. The IDMC may recommend 
modifications to the study, including termination due to safety and/or efficacy concerns. 
Dose Level 
Based on the safety results of the Phase 1 studies of tislelizumab (Studies 
BGB-A317_Study_001 and BGB-A317-102), this study will initially assess the safety and PK 
characteristics of fixed dose 200 mg once every three weeks (Q3W) in Japanese patients with 
advanced unresectable/metastatic ESCC. Other dose levels may be further explored based on 
the tolerability in these patients. 
Among the 6 patients in the 200 mg Q3W cohort, if 2 or more patients experience DLT in 
Cycle 1, that starting dose will be considered as exceeding the maximum tolerated dose 
(MTD), and a lower dose (eg, 150 mg Q3W), will be subsequently assessed in 3 to 6 patients. 
If the 200-mg Q3W regimen passes the DLT assessment, the cohort at that dose level can be 
expanded to approximately 10 patients to further assess the safety, tolerability, 
pharmacokinetics and preliminary pharmacodynamic characteristics of tislelizumab. Up to 
20 patients may be enrolled if a lower dose level is evaluated (such as 150 mg Q3W). 
Dose-limiting Toxicity 
All AEs will be graded according to the NCI-CTCAE v4.03. The occurrence of any of the 
following toxicities during Cycle 1 will be considered DLT, if judged by the investigator as 
related to study drug administration: 
Hematologic Dose-limiting Toxicities: 
1. Grade 4 neutropenia lasting > 7 days 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1000/mm3 with a single 
temperature of 38.3°C or a sustained temperature of 38°C for > 1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding 


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5. Grade 4 thrombocytopenia 
6. Grade 4 anemia (life-threatening) 
Non-hematologic Dose-limiting Toxicities: 
1. Grade 4 or above toxicity 
2. Grade 3 toxicity lasting > 7 days despite optimal supportive care 
 
NOTE: The following AEs will not be considered as DLTs: 
 Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
 
Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumors) 
 Grade 3 rash 
 
Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical sequelae 
(eg, LDH) 
In addition, clinically important or persistent toxicities that are not included above may also be 
considered a DLT following review by IDMC. 
Patients who received less than two-thirds (67%) of the assigned dose of tislelizumab (eg, 
because the infusion had to be discontinued due to an infusion reaction) and did not experience 
a DLT will not be taken into account in the assessment of the overall DLT rate for that 
particular dose level. 
Key Eligibility Criteria: 
The population under study is adult Japanese patients (≥ 20 years of age on the day the patient 
voluntarily agrees to participate in the study) with histologically confirmed diagnosis of ESCC 
with tumor progression during or after first-line treatment for advanced 
unresectable/metastatic disease. All patients are also required to have at least one evaluable 
lesion per RECIST v1.1 within 28 days prior to Cycle 1 Day 1, an Eastern Cooperative 
Oncology Group Performance Status score of 0 or 1. 
Test Product, Dose, and Mode of Administration: 
Tislelizumab will be administered at a dose of 200 mg intravenously (IV) Q3W. The proposed 
dose level can be further adjusted according to the safety and tolerability observed in the dose 
verification stage, and lower dose levels may be added if necessary. 


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Statistical Methods: 
Descriptive statistics will be used to summarize the demographic, disease characteristic, 
efficacy and safety data. No statistical hypotheses are planned in this exploratory study. 
All patients who have received tislelizumab will be included in the Safety analysis set. All 
patients with valid tislelizumab PK sampling after treatment will be included in the PK 
analysis set. For other parameters, all evaluable data will be included in the summaries. 
Efficacy Analysis: 
The efficacy per RECIST v1.1 (ie, ORR, PFS and DOR) will be summarized to explore the 
preliminary anti-cancer activities in Japanese patients. 
The ORR is defined as the proportion of patients who had confirmed complete response (CR) 
or partial response (PR) assessed by the investigator using RECIST v1.1. 
The DOR is defined as the time from the first determination of a confirmed objective response 
by investigator per RECIST v1.1 until the first documentation of progression or death, 
whichever comes first. 
The PFS is defined as the time from the date of first dose of study drug to the date of first 
documentation of disease progression assessed by investigator using RECIST v1.1 or death, 
whichever occurs first. 
The ORR and its 95% confidence interval will be summarized in the Safety analysis set. Both 
PFS and DOR will be estimated using the Kaplan-Meier method. Waterfall plot of maximum 
tumor shrinkage per patient will be presented. 
Safety Analysis: 
Safety will be determined by the reporting of AEs and by laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and ECG 
findings will also be used in determining safety. The severity of AEs will be graded per 
NCI-CTCAE v4.03. The incidence of DLT events and treatment-emergent adverse events 
(TEAEs) will be reported as the number (percentage) of patients with TEAEs by System 
Organ Class and Preferred Term. Descriptive summary statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables) and changes from baseline will be determined for laboratory parameters and vital 
signs. 
Statistical methods will be described in detail in the Statistical Analysis Plan. 


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1. 
INTRODUCTION 
Before initiating this Phase 3 study in Japan, a substudy investigating the safety, tolerability, 
pharmacokinetics (PK), and preliminary efficacy is planned. This study is a dose-validation 
clinical study of the monoclonal antibody BGB-A317 in Japanese patients with advanced 
unresectable/metastatic esophageal squamous cell carcinoma (ESCC), aiming to explore safety, 
tolerability, and pharmacokinetics. This study is carried out based on Phase 1 studies evaluating 
tislelizumab (BGB-A317_Study_001 and BGB-A317-102). Per the preliminary results of the 
Phase 1A Study BGB-A317_001, 0.5, 2, 5, and 10 mg/kg once every two weeks (Q2W) are all 
tolerable doses. In addition, 2 and 5 mg/kg Q3W (once every 3 weeks) and 200 mg Q3W have 
also been confirmed as tolerable. A 200 mg Q3W fixed dose was selected as the pivotal dose for 
Phase 3 studies. In the Phase 1 clinical study in China, six patients were administered the 200 mg 
Q3W fixed dose and PK analysis indicated that this is equivalent to 2.4 to 3.8 mg/kg, based on 
body weight. The comparison results of dose normalized Cmax and area under the concentration-
time curve from Day 0 to Day 14 (AUC0-14d) showed that the PK is consistent in Chinese and 
Caucasian patients. The available safety and PK data suggest that the proposed dose of 200 mg 
Q3W tislelizumab is expected to be a safe dose to investigate in Japanese patients. 
The background on ESCC and on the monoclonal antibody, BGB-A317 is provided in the main 
study in Section 1 , Introduction. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
 To assess the safety and tolerability of tislelizumab as second-line in treatment 
Japanese patients with advanced unresectable/metastatic ESCC 
 To confirm the pivotal Phase 3 dose of tislelizumab in Japanese patients 
 To characterize the pharmacokinetics of tislelizumab in Japanese patients 
2.1.2. 
Secondary Objectives: 
 To assess the preliminary antitumor activity of tislelizumab 
 To assess host immunogenicity to tislelizumab 
2.1.3. 
Exploratory Objectives 
 To explore correlations between drug exposure and response 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
 Tislelizumab safety and tolerability: The safety of tislelizumab will be assessed 
throughout the study by monitoring AEs and serious adverse events (SAEs) per 


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National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE Version [v]4.03), relevant physical examination, electrocardiograms 
(ECGs) and laboratory assessments as needed 
 The pivotal Phase 3 dose for tislelizumab will be determined based on safety and 
tolerability, and other available data (which may include PK and/or preliminary 
efficacy) 
 PK evaluations: Individual tislelizumab concentrations and PK parameters will be 
tabulated by visit/cycle and/or dose cohort 
2.2.2. 
Secondary Endpoints 
 Efficacy evaluations: Overall response rate (ORR), progression-free survival (PFS), 
and duration of response (DOR) will be determined based on assessment by 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST) Version 
(v)1.1. Overall survival (OS) will also be evaluated. 
 Anti-tislelizumab antibody: Assessments of immunogenicity of tislelizumab to 
determine the incidence of anti-drug antibodies (ADAs) 
2.2.3. 
Exploratory Endpoints 
 Assessments of the correlations between drug exposure and response (efficacy, safety 
endpoints) 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is an open-label, multicenter, non-randomized Phase 1 clinical study in Japanese patients 
with advanced unresectable/metastatic ESCC who have received prior treatment. Screening can 
last up to 28 days and treatment can last until the investigator considers the patient is no longer 
benefiting from tislelizumab, toxicity, or voluntary withdrawal of study treatment. A minimum 
of 6 patients and a maximum of 10 patients will be enrolled to assess dose-limiting toxicities 
(DLTs) and to adequately address the PK profile of tislelizumab in Japanese patients. Up to 
20 patients may be enrolled if more than one dose level is explored. A Safety Follow-up phase 
will last 30 days (± 7 days) after the last dose of tislelizumab or before the initiation of a new 
anti-cancer treatment, whichever occurs first for any AEs, and up to 90 days following last dose 
of tislelizumab for irAEs, regardless of initiation of subsequent anticancer treatment. Survival 
follow-up information will be collected approximately 1 month (4 weeks ± 7 days) after the 
Safety Follow-up Visit and approximately monthly thereafter until death, loss to follow-up, 
withdrawal of consent, or study termination by sponsor. The first 6 patients will remain 
hospitalized during the first week of the first cycle of treatment. 
3.2. 
Schedule of Study Assessments 
A schedule of efficacy and safety assessments is presented in Table 7. 
 


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Table 7: 
Japan Substudy Schedule of Assessments 
Assessment Window (Days) 
Screening1 
All Treatment Cycles2 
End of 
Treatment3 
(0-7 days) 
Safety 
Follow-up3 
(30 ± 7 
days after 
last dose) 
Survival 
Follow-up4 
(Every 
month) 
Day -28 to -1 
Cycles 1-2 
Cycle 3 
and 
Subsequent 
Cycles 
Day 1 
(± 3) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 1 
(± 3) 
Informed consent1 
x 
  
 
 
 
 
  
  
Inclusion/Exclusion criteria 
x 
  
 
 
 
 
  
  
Demographic/Medical 
history/Prior medications  
x 
  
 
 
 
 
  
  
Cancer Diagnosis and Treatment 
History5 
x 
 
 
 
 
 
 
 
Concomitant medications6 
x 
x 
x 
x 
x 
x 
x 
  
Adverse events7 
x 
x 
x 
x 
x 
x 
x 
  
Physical examination8, 9 
x 
x 
 
 
x 
x 
x 
  
ECOG performance status9 
x 
x 
 
 
x 
x 
x 
  
Vital signs10 
x 
x 
 
 
x 
x 
x 
  
12-lead ECG11 
x 
As clinically indicated  
x 
 
  
HBV and HCV serology12 
x 
As clinically indicated 
 
  
 
Hematology13 
x 
x 
x 
x 
x 
x 
x 
  
Serum chemistry13 
x 
x 
x 
x 
x 
x 
x 
  
Total CK and CK-MB13 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation parameters13 
x 
As clinically indicated 
x 
x 
  
Urinalysis13 
x 
As clinically indicated 
x  
x 
  
Pregnancy test14 
x 
x 
 
 
x 
x 
x 
  
Thyroid function15 
x 
Every 3rd cycle 
 
x 
  
Pharmacokinetics16 
  
x 
x 
x 
x 
 
x 
  
Anti-drug antibodies16 
 
x 
 
 
x 
 
x 
 
Tumor assessment17 
x 
Every 6 weeks for 6 months, then every 9 weeks 
x 
 
 
Tislelizumab administration18 
  
x 
 
 
 
 
  
  
Archive/Fresh Tumor tissue 
x 
 
 
 
 
  
  
  


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Assessment Window (Days) 
Screening1 
All Treatment Cycles2 
End of 
Treatment3 
(0-7 days) 
Safety 
Follow-up3 
(30 ± 7 
days after 
last dose) 
Survival 
Follow-up4 
(Every 
month) 
Day -28 to -1 
Cycles 1-2 
Cycle 3 
and 
Subsequent 
Cycles 
Day 1 
(± 3) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 1 
(± 3) 
collection19 
HRQoL Assesments20 
x 
x 
 
 
Cycles 3-6 
only 
x 
x 
 
Survival status  
  
  
 
 
 
 
 
x 
Pulmonary function tests21 
x 
 
 
 
 
 
 
 
Optical coherence tomography 
(or equivalent diagnostic test) and 
visual acuity tests22 
x 
Every 15 weeks ± 7 days 
x23 
x23 
 
Abbreviations: x, to be performed; ECOG, Eastern Cooperative Oncology Group; ECHO, echocardiography; ECG, electrocardiogram; HBV, hepatitis B virus; 
HCV, hepatitis C virus; MRI, magnetic resonance imaging; HRQoL, Health-Related Quality of Life. 
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 Cycle 1 Day 1 may be used for screening assessments rather than repeating 
such tests. Fresh tumor biopsy is permitted if no archival tumor tissue is available. 
2  After Cycle 1, there is a three-day window for all study treatment unless otherwise noted. Efficacy assessments will be performed approximately every 
6 weeks for 6 months, then every 9 weeks. 
3  The End-of-Treatment (EOT) Visit is conducted when the investigator determines that tislelizumab will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the EOT Visit, tests need not be repeated. Tumor assessment is not required at the EOT 
Visit provided that fewer than 6 weeks have passed since the last assessment.  
The mandatory Safety Follow-Up visit is required to be conducted 30 days (± 7 days) after the last dose of study therapy, or before initiation of a new 
treatment. At the end of treatment, ongoing AEs considered related to study treatment will be followed until the event has resolved to baseline or 
≤ Grade 1, the event is assessed by the investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it has been determined that 
study treatment or participation is not the cause of the AE. 
4  Survival follow-up information will be collected after discontinuation of the study treatment via email or other communication, patient medical records, 
and/or clinic visits approximately 1 month (4 weeks ± 7 days) after the Safety Follow-up Visit and approximately monthly thereafter until death, loss to 
follow-up, withdrawal of consent, or study termination by sponsor. All patients will also be followed for new anti-cancer therapy information unless the 
patient requests to be withdrawn from follow-up. 
5  Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Radiographic imaging 
performed prior to study entry may be collected for review by the investigator.  
6  Concomitant medications include any prescription medications, over-the-counter medications, herbal supplements, and IV medications and fluids. All 
concomitant medications received within 30 days before the first dose of tislelizumab and 30 days after the last infusion of tislelizumab should be 
recorded. At subsequent visits, changes to current medications or medications used since the last documentation of medications will be recorded. 


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7  AEs and laboratory safety measurements will be graded per NCI-CTCAE version v4.03. All AEs, whether gradable by CTCAE or not, will also be 
evaluated for seriousness. After informed consent has been signed but prior to the administration of the study drug, only SAEs should be reported. After 
the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship to study drug, are to be reported until either 30 days after the last 
dose of study treatment or the initiation of a new anticancer therapy, whichever occurs first. All immune-related AEs should be reported for 90 days after 
the last dose of tislelizumab, regardless of initiation of a new anticancer therapy. After this period, the investigator should report any SAEs that are 
believed to be related to tislelizumab treatment (Section 8.4.1). 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 (Section 8.2.6).  
8  A complete physical examination should include an evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems. At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations 
are required to be performed. Investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each 
scheduled study visit during tislelizumab treatment. For any change in vision, referral to an appropriate specialist will be made for further management 
guidance.     
9  If screening ECOG performance status, physical examination and local laboratory assessments are obtained within seven days of Cycle 1 Day 1, these 
assessments do not have to be repeated at Cycle 1 Day 1. 
10  Vital signs to include temperature, pulse, blood pressure, height and weight. Height will only be measured and recorded at Screening Visit. Pulse and BP 
should be recorded while the patient is in a seated position after resting for 10 minutes. For all infusions of tislelizumab, the patient’s vital signs should be 
recorded before the infusion, and between 30 to 45 minutes after the infusion. Vital signs must be collected during the infusion if clinically indicated.  
11  Electrocardiogram (ECG) recordings will be obtained during screening, End of Treatment, and as clinically indicated at other timepoints. Patients should 
be resting and in a sitting or supine position for at least 10 minutes prior to ECG collection. 
12  Testing will be performed by the local laboratory at screening and as clinically indicated. Include HBsAg, HBcAb, and HCV antibody. Patients who are 
HBsAg positive at screening must not be enrolled until further definite testing with HBV DNA titers < 500 IU/mL (or 2500 copies/mL). 
13  Local or central laboratory assessments on serum chemistry (including liver function tests), hematology, coagulation, and urinalysis will be conducted 
within 7 days prior to Cycle 1 Day 1, of which certain elements will be collected as specified in Section 7.10 of the main protocol. If laboratory tests at 
screening are not performed within 7 days prior to the administration of study drug on Cycle 1 Day 1, these tests should be repeated and reviewed before 
study drug administration. Serum chemistry (including liver function tests) and hematology will be performed weekly for the first 2 cycles and then at the 
beginning of each subsequent cycle. After Cycle 1, results are to be reviewed within 3 business days before study drug administration. All patients will 
have creatine kinase (CK) and creatine kinase-cardiac muscle isoenzyme (CK-MB) testing at screening and all scheduled visits during the first 3 treatment 
cycles, all pre-dose assessments from Cycle 4 onwards, and at the EOT and Safety Follow-up Visits. In the event that CK-MB fractionation cannot be 
evaluated in the local laboratory, troponin I and/or troponin T should be assessed instead; the same test should be administered throughout the study. 
Urinalysis and coagulation parameters are to be assessed during the treatment period only if clinically indicated. Refer to Section 8.2.5 of the main 
protocol for additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
14  Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within seven days prior to Cycle 1 Day 1. Urine pregnancy tests will be performed at each visit prior to dosing while on treatment, and at Safety 
Follow-up. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
15  Analysis of T3, T4 and TSH will be performed by the local study site laboratory. Thyroid function tests will be performed within 7 days prior to Cycle 1 
Day 1 and every three cycles thereafter (eg, Cycles 4, 7 and 10, etc.), and at the mandatory Safety Follow-Up Visit.  
16  Procedures for collection of tislelizumab PK and ADA samples are described in the Laboratory Manual. Refer to Table 8 for details on timing of PK and 
ADA sample collection; additional PK and ADA samples are required to be collected at the Safety Follow-Up Visit. If a patient presents with any 
immune-related adverse event, additional blood PK samples may be taken to determine the plasma concentration of tislelizumab. These tests are required 
when it is allowed by local regulations/IRBs/ECs. 


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17  Examinations performed as standard of care prior to obtaining informed consent and within 28 days prior to Cycle 1 Day 1 may be used rather than 
repeating tests. CT/MRI of the head at baseline is required for patients who are suspected to have CNS metastases. All measurable and evaluable lesions 
are required to be assessed and documented at the screening visit. 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 6 months, then every 9 weeks (± 7 days) afterwards. Patients who discontinue from treatment for reasons other than disease progression or 
death will continue scheduled tumor assessments until disease progression, withdrawal of consent, death or start of a new anti-cancer therapy. 
Investigators may perform additional scans or more frequent assessments if clinically indicated. Imaging timing should follow calendar days and should 
not be adjusted for delays in cycle starts. Patients who continue tislelizumab treatment beyond radiographic disease progression will be monitored with a 
follow-up scan at least 4 weeks later or at the next regularly scheduled timepoint (not exceed 6 weeks) before discontinuation of study treatment.  
18  The initial infusion of tislelizumab will be delivered over 60 min; if well-tolerated, second infusion and each subsequent infusion may be administered 
over 30 min which is the shortest period permissible for infusion. 
19  Representative tumor specimens in paraffin blocks (preferred) or at least 10 unstained slides is required to be submitted for biomarker analysis if available. 
In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is highly recommended. 
20  All HRQoL assessments are to be performed prior to study treatment initiation, Cycles 1- 6 Day 1 or at the EOT Visit (whichever occurs first), and at the 
Safety Follow-up Visit. A visit window of ± 7 days will apply to a HRQoL visit assessment. HRQoL instruments are to be given to the patient prior to 
being seen by a health care professional. NOTE: HRQoL assessments are to be conducted both at screening and C1D1 visit; if screening visit is < 7 days 
from C1D1 visit, the HRQoL assessment does not need to be repeated. 
21  Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant respiratory symptoms unrelated to underlying 
cancer will have pulmonary function testing which may include but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period, to assist the determination of suitability for enrollment on the study. Uncertain cases should be discussed with the medical monitor. 
22  Eye examination, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care 
prior to obtaining written informed consent and within 28 days of Cycle 1 Day 1 may be used rather than repeating tests. Eye examination, visual acuity 
test, and optical coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeated assessments 
approximately every 15 weeks (± 7 days) during study treatment and a final assessment < 30 days (± 7 days) after the last dose of study treatment. 
23  The ophthalmologic assessments including eye examination, visual acuity test, and OCT (or equivalent diagnostic test) should only be performed once at 
either the EOT or during safety follow up within 30 days (± 7 days) of study treatment end. 
 


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Table 8: 
Schedule of Japan Substudy Pharmacokinetic Sampling and 
Anti-Tislelizumab Antibody Sampling 
Japan Substudy 
Days 
Timing in 
relation to 
dose  
Timepoints 
PK for Patients in 
the Fixed Dose 
Exploration 
Cohorts 
Anti-
Tslelizumab 
Antibody 
Samples 
Treatment 
Period 
 
Cycle 1  
1 
Predose 
-60 min to 0 h 
x 
x 
  
Postdose 
End infusion to 
30 min1 
x 
— 
2 
-- 
24 h2 
x 
— 
4  
-- 
72 h2 
x 
— 
8 ± 2 
-- 
any time in the 
window 
x 
— 
15 ± 2 
-- 
any time in the 
window 
x 
— 
Cycle 2 and 3  
1 ± 2 
Predose 
-60 min to 0 h 
x 
x 
Postdose 
End infusion to 
30 min1 
x 
— 
Cycle 5  
1 ± 2 
Predose 
-60 min to 0 h 
x 
x 
  
Postdose 
End infusion to 
30 min1 
x 
— 
2 
-- 
24 h2 
x 
— 
4  
-- 
72 h2 
x 
— 
8 ± 2 
-- 
any time in the 
window 
x 
— 
15 ± 2 
-- 
any time in the 
window 
x 
— 
Cycle 6 
1 ± 2 
Predose 
-60 min to 0 h 
x 
— 
Cycles 7, 9, 13, 
17, 25, 33, and 
every 8 cycles 
thereafter3 
1 ± 2 
Predose 
-60 min to 0 h 
x 
x 
Postdose 
End infusion to 
30 min1 
x 
— 
Safety 
Follow-up  
(30 days ± 7 
days after last 
dose) 
30 ± 7 
-- 
any time in the 
window 
x4 
x 
Please NOTE: Actual drug dosing and PK sampling times have to be documented by the sites and will be 
captured in the database.  
Abbreviations: h, hour(s); irAE, immune-related adverse event; min, minutes; PK, pharmacokinetic(s). 
1  Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered 
via a central venous catheter, sample collection for PK should be from a different site. 
2  Window: ±2 h. 
3  Cycle 7, Cycle 9 and subsequently every 4 cycles through Cycle 17, and then every 8 cycles thereafter.  
4  PK assays should be performed at the mandatory Safety Follow-up Visit (if there is an irAE, an additional PK 
sample may be taken per the Schedule of Assessments). These tests are required when it is allowed by local 
regulations/IRBs/ECs. 


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3.3. 
Duration of Study 
Total duration of study participation will vary by patient. Each study phase is further discussed in 
the main protocol in Section 3.3.1 though Section 3.3.5. 
3.4. 
Dose-Limiting Toxicities 
Dose-limiting toxicities (DLTs) will be assessed among evaluable patients after 21 days on 
study. An evaluable patient is defined as the patient who has received at least 80% of the dose 
and completed all safety assessments required during the first 21 days, or any patient who has 
experienced a DLT within 21 days. 
Among the six patients in the 200 mg Q3W cohort, if two or more patients experience DLT 
within 21 days, that dose will be considered as exceeding the maximum tolerated dose (MTD), 
and a lower dose (eg, 150 mg Q3W) will be subsequently assessed in three to six patients. The 
first six patients will remain hospitalized for the first week of Cycle 1; after the first week they 
will be monitored with weekly complete blood count (CBC) and serum chemistry through the 
end of the 21-day DLT assessment period. After the DLT assessment period, hematology and 
serum chemistry (including liver function tests) will be performed weekly for Cycle 2 and Cycle 
3 and then at the beginning of each subsequent cycle for Cycle 4 and beyond. 
If the 200 mg Q3W dose passes the DLT assessment, the cohort at that dose level can be 
expanded to approximately 10 patients to further assess the safety, tolerability, PK and 
preliminary pharmacodynamic characteristics of tislelizumab. Up to 20 patients may be enrolled 
if more than dose level is evaluated. To continuously monitor safety, if the cohort has been 
expanded to 10 patients and ≥ 33% of them have experienced DLT within 21 days, enrollment 
will be suspended, and an Independent Data Monitoring Committee (IDMC) meeting will be 
immediately held to discuss and determine whether that dose is safe. 
3.5. 
 
Study Rationale 
Before initiating a large Phase 3 study in Japan, this substudy in Japanese patients will provide 
additional safety information allowing the enrollment of patients into the larger Phase 3 study in 
Japan. Please see the main protocol, Section 3.4.1 and Section 3.4.2 for rationale on the 
evaluation of tislelizumab in ESCC and selection of dose. 


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4. 
MATERIALS AND METHODS 
4.1. 
Selection of Study Population 
4.1.1. 
Inclusion Criteria 
To be eligible to participate in this study, a patient must meet all of the following criteria: 
1. Age (at the time of signing informed consent): 20 years and older. 
2. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments. 
3. Histologically confirmed diagnosis of esophageal squamous cell carcinoma (ESCC) 
4. Tumor progression during or after first-line systemic treatment for advanced 
unresectable/metastatic ESCC (Appendix 12). 
NOTE: patients with disease progression that occurs during treatment or within 
≤ 6 months (180 days) of cessation of neoadjuvant/adjuvant treatment (chemotherapy or 
chemoradiotherapy) are eligible provided all other eligibility criteria are met. 
NOTE: A line of treatment begins with the administration of the first agent in a regimen 
and ends with disease progression. A line of therapy is preserved when chemotherapy is 
switched due to toxicities. 
5. At least one measurable/evaluable lesion by RECIST v1.1 as determined by local site 
investigator/radiology assessment within 28 days prior to Cycle 1 Day 1. 
NOTE: Lesions that have been previously irradiated may be considered evaluable 
provided there is evidence of disease progression following the completion of radiation 
and initiation of study treatment. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to 
Cycle 1 Day 1. 
7. Laboratory data meeting the criteria below within seven days prior to Cycle 1 Day 1. 
Laboratory data will not be valid if the patient has received growth factors or blood 
transfusion for prophylactic use within 7 days before the laboratory testing: 
 Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 
 Platelet count ≥ 100,000 cells/mm3 
 Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L  
 Estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 11).  
 Serum total bilirubin ≤ 1.5 x ULN (or < 3 x ULN in patients with Gilbert’s 
syndrome). 
 Prothrombin time/international normalized ratio (PT/INR) ≤ 1.5 x ULN unless the 
patient is receiving anti-coagulant therapy  


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 Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (or ≤ 
5.0 x ULN in patients with liver metastases).  
8. HBV or HCV infection and meets the following criteria as applicable to the infection 
type:  
For patients with inactive/asymptomatic carrier, chronic, or active HBV must have:  
HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at screening.  
NOTE: Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV 
DNA should be managed per treatment guidelines. Patients receiving antivirals at 
screening should have been treated for > 2 weeks and HBV < 500 IU/mL prior to 
enrollment and should continue treatment for 6 months after study drug treatment 
discontinuation. 
For patients with HCV:  
Patients with detectable HCV RNA and who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study. 
9. Females of childbearing potential must have a negative serum pregnancy test during 
screening and must be willing to have additional pregnancy tests during the study. 
Females of childbearing potential must be willing to use highly effective methods of birth 
control for the duration of the study, and for at least 120 days after the last dose of 
tislelizumab. 
10. Non-sterile males who have female sexual partner(s) of childbearing potential 
(Appendix 5) must use a highly effective method of birth control for the duration of the 
study, and for at least 120 days after the last dose of tislelizumab. 
a. A sterile male is defined as one for whom known azoospermia, in a semen sample 
examination, has been previously demonstrated as definitive evidence of infertility.  
b. Males with known ‘low sperm counts’ (consistent with ‘sub-fertility) are not to be 
considered sterile for purposes of this study. 
4.1.2. 
Exclusion Criteria 
To be eligible to participate in this study, a patient cannot meet any of the following exclusion criteria: 
1. Palliative radiation treatment for ESCC within 14 days of study treatment initiation 
Cycle 1 Day 1 (C1D1).  
2. History of gastrointestinal perforation and/or fistula or aorto-esophageal fistula within 
6 months prior to Cycle 1 Day 1. 
3. Tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or 
respiratory tract) at an increased risk of fistula in the study treatment assessed by 
investigator 
4. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within two weeks of intervention). 


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5. Current or past history of severe hypersensitivity reactions to other monoclonal 
antibodies. 
6. Received prior therapies targeting PD-1 or PD-L1. 
7. Has 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) exceptions are to be determined by 
investigator in consultation with the medical monitor 
8. Prior malignancy active within the previous 2 years before the first dose of study drug 
(exceptions include the tumor under investigation in this study, and surgically excised 
non-melanoma skin cancer, curatively treated carcinoma in situ of the cervix, localized 
prostate cancer treated with curative intent, curatively treated low-stage bladder cancer, 
ductal carcinoma in situ treated surgically with curative intent, or a malignancy 
diagnosed >2 years ago, with no current evidence of disease and no therapy ≤2 years 
before the first dose of study drug).   
9. Active brain or leptomeningeal metastasis. Patients with equivocal findings or with 
confirmed brain metastases are eligible for enrollment provided that they are 
asymptomatic and radiologically stable without the need for corticosteroid treatment for 
at least 4 weeks prior to the first dose of study drug(s). CT/MRI of the head at baseline is 
required for patients who are suspected to have central nervous system (CNS) metastases.  
10. Has active autoimmune disease or history of autoimmune diseases at high risk for 
relapse.  
NOTE: Patients with following diseases may be enrolled if they meet all other eligibility 
criteria: controlled type I diabetes, hypothyroidism managed with hormone replacement 
therapy only, controlled celiac disease, skin diseases not requiring systemic treatment 
(such as vitiligo, psoriasis or alopecia), or diseases not expected to recur in the absence of 
external triggering factors. 
11. Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalents) or other immunosuppressive medications within 14 days prior 
to Cycle 1 Day 1.  
 Patients who have a history of organ transplant, including stem cell allograft are not 
permitted to enroll 
 Adrenal replacement steroid dose ≤10 mg daily prednisone equivalents are permitted 
in the absence of active autoimmune disease 
 Patients are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  
 A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
12. Undergone surgery requiring general anesthesia or epidural anesthesia within 28 days 
prior to Cycle 1 Day 1.  


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13. Undergone surgery involving local anesthesia within 14 days prior to Cycle 1 Day 1. 
Exceptions to this exclusion criteria include:  
a. Placement of a central venous access device that requires up to a 3-day surveillance 
period. 
b. A biopsy procedure performed under local anesthesia during the screening period that 
require a 7-day post procedure surveillance period. 
14. Received any radiopharmaceuticals (except for examination or diagnostic use of 
radiopharmaceuticals) within 42 days prior to Cycle 1 Day 1. 
15. Has received: 
a. Within 28 days or 5 half-lives (whichever is shorter but at least 14 days) of the first 
study drug administration: any chemotherapy, immunotherapy (eg, interleukin, 
interferon, thymoxin) or any investigational therapies 
b. Within 14 days of the first study drug administration: any Chinese herbal medicine or 
Chinese patent medicines used to control cancer or boost immunity 
16. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that could interfere 
with the subject’s safety, obtaining informed consent, or compliance with study 
procedures  
17. Receipt of a live vaccine within 4 weeks prior to Cycle 1 Day 1.  
NOTE: Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live viruses and are not allowed. 
18. Known history of, or any evidence of interstitial lung disease, non-infectious 
pneumonitis, pulmonary fibrosis diagnosed based on imaging or clinical findings, or 
uncontrolled systemic diseases, including diabetes, hypertension, acute lung diseases, etc 
NOTE: Patients with radiation pneumonitis may be enrolled if the radiation pneumonitis 
has been confirmed as stable (beyond acute phase) and is unlikely to recur. Patients with 
severe but stable radiation-induced pneumonitis may be required to undergo routine 
pulmonary function studies  
19. Has severe chronic or active infection (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal or antiviral therapy, within 14 days prior to Cycle 1 
Day 1. 
NOTE: Patients who require systemic antiviral therapy for HBV are excepted 
20. Known history of Human Immunodeficiency Virus (HIV). 
21. Known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study.  
22. Has any of the following cardiovascular risk factors: 
 Ongoing cardiac chest pain, defined as moderate pain that limits instrumental 
activities of daily living 
 Symptomatic pulmonary embolism within 28 days before study drug administration 


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 Any history of acute myocardial infarction within 6 months before study drug 
administration 
 Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 6) within six months before study drug administration 
 Any event of ventricular arrhythmia > Grade 2 in severity within 6 months before 
study drug administration 
 Any history of cerebrovascular accident or transient ischemic attack within 6 months 
before study drug administration  
23. Known, active alcohol or drug abuse or dependence. 
24. Pregnant or breastfeeding woman. 
5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, Handling, and Storage 
Please refer to the Section 5.1 of the main protocol for information on the formulation, 
packaging, handling and storage of tislelizumab. 
5.2. 
Dosage, Administration, and Compliance 
Patients will be treated with 200 mg intravenous (IV) tislelizumab Q3W until intolerable 
toxicity, withdrawal of informed consent, or until the patient is no longer benefiting from study 
therapy in the opinion of the investigator. All patients will be monitored continuously for AEs. 
Treatment modifications (eg, dose delay, reduction, interruption, or discontinuation) will be 
based on specific laboratory assessments and AE criteria, as described in Section 8.6 of the main 
protocol. 
5.3. 
Handling of Overdose 
Please refer to Section 5.3 of the main protocol for detailed information. 
5.4. 
Investigational Medicinal Product Accountability 
Please refer to Section 5.4 of the main protocol for detailed information. 
5.5. 
Disposal and Destruction 
Please refer to Section 5.5 of the main protocol for detailed information. 
6. 
PRIOR AND CONCOMITANT THERAPY 
Please refer to Section 6 of the main protocol for detailed information. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures will be similar to those in the main protocol, Section 7 
(Section 7.1 through Section 7.17), with the exception that patients will not be randomized for 
the substudy and there is no second treatment arm. In addition, PK assessments have been 
increased in this substudy for thorough characterization of PK after a single dose and at steady 
state in Japanese patients and are provided in further detail in Section 9.7 of this substudy 
protocol. Patients will be closely monitored for safety and tolerability throughout the study and 
the first six patients will be hospitalized during Cycle 1 of treatment. All assessments must be 
performed and documented in the medical record and electronic case report form (eCRF) for 
each patient. 
Tumor response will be assessed by investigators based on RECIST v1.1. For immune therapies 
such as tislelizumab, pseudo-progression may occur due to immune-cell infiltration and other 
mechanisms leading to an apparent increase of existing tumor masses or appearance of new 
tumor lesions. Thus, for progressive disease (PD) suspected by the investigator as pseudo-
progression, the following criteria must be met to treat patients continuously until PD is 
confirmed by repeated imaging performed no more than six to eight weeks beyond the initial 
diagnosis of radiographic PD: 
 Absence of clinical symptoms and signs of disease progression (including worsening 
laboratory values) 
 ECOG PS ≤ 1 
 Absence of rapid progression of disease or progression at a critical anatomical site 
(eg, progression of a spinal lesion with impending cord compression) or that 
necessitates urgent alternative medical intervention 
If, in the judgement of the investigator, the patient is anticipated to benefit from continued 
treatment, the patient must re-sign an informed consent, agreeing to continue treatment beyond 
radiographical disease progression. If patients agree to continue treatment beyond radiographical 
progression, a follow-up radiographic evaluation will be performed no later than 6 weeks after 
the initial scan that diagnosed progressive disease, as outlined in Section 7.4 of the main 
protocol.  
If, in the judgement of the investigator, rapid early progression is evident (“hyperprogression”), 
tislelizumab should be discontinued.  


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8. 
SAFETY MONITORING AND REPORTING 
Safety monitoring and reporting procedures will follow those in the main protocol (Section 8). 
Another addition to this substudy is the definition of DLTs. All toxicities or AEs will be graded 
per NCI-CTCAE v4.03. The occurrence of any of the following toxicities within 21 days after 
the first dose of tislelizumab, if judged by the investigator as related to tislelizumab, will be 
considered a DLT. The first six patients will remain hospitalized for the first week of Cycle 1; 
after the first week, they will be monitored with weekly CBC and serum chemistry through the 
end of the 22-day DLT assessment period. After the DLT assessment period, the patients will be 
further assessed on a weekly basis for up to 3 cycles. 
Hematologic: 
1. Grade 4 neutropenia lasting > 7 days 
2. Grade 3 febrile neutropenia (defined as absolute neutrophil count [ANC] < 1000/mm3 
with a single temperature of 38.3oC or a sustained temperature of 38oC for > 1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding 
5. Grade 4 thrombocytopenia 
6. Grade 4 anemia (life-threatening) 
Non-hematologic: 
1. Grade 4 or above toxicity 
2. Grade 3 toxicity lasting > 7 days despite optimal supportive care 
NOTE: The following AEs will not be considered as DLTs: 
 Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
 Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumors) 
 Grade 3 rash 
 Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical 
sequelae (eg, LDH) 
In addition, clinically important or persistent toxicities that are not included above may also be 
considered a DLT following review by IDMC. 
Patients who received <two-thirds (67%) of the assigned dose of tislelizumab (eg, because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a DLT will 
not be taken into account in the assessment of the overall DLT rate for the particular dose level. 
Independent Data Monitoring Committee 
An IDMC (described in Section 8.5 of the main protocol) will evaluate and confirm the Phase 3 
dose based on the safety and tolerability of tislelizumab, and decide whether or not to add 
unscheduled dose levels for study. To confirm the pivotal Phase 3 dose, an IDMC meeting will 
be held within 6 weeks after the sixth patient is treated. If ≥ 33% of patients have experienced a 


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DLT within 21 days after the first dose of tislelizumab, enrollment will be suspended, and the 
IDMC will determine whether such a dose is safe or if a lower dose level should be tested. If < 
33% have experienced DLT, the cohort will be expanded to 10 patients in total to provide more 
safety experience on treatment. 
Safety review will then subsequently be followed as per the main protocol. The IDMC may 
recommend modifications to the study, including termination due to safety and/or efficacy 
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9. 
STATISTICAL METHODS AND ANALYSIS PLAN 
As described in the main protocol, Section 9, the statistical analyses will be performed by the 
sponsor or designee after the data collection for the primary efficacy and safety analyses are 
completed and the database is locked and released. Data will be listed and summarized using 
SAS® Version 9.3 or higher (SAS Institute, Inc., Cary, North Carolina) per sponsor agreed 
reporting standards, where applicable. Details of the statistical analyses will be included in a 
separate Statistical Analysis Plan. 
9.1. 
Analysis Sets 
 DLT Evaluable Analysis Set: Includes all patients who have received at least 80% of 
the dose and completed all safety assessments required in Cycle 1, or any patient who 
has experienced DLT in Cycle 1 
 PK Analysis Set: Includes all patients who receive at least one dose of tislelizumab 
per the protocol, for whom any post-dose PK data are available. To get an adequate 
sample size to characterize PK, patients will be replaced if necessary 
 Safety Analysis Set: Includes all patients who received at least one dose of study drug 
and is the primary analysis set used for all safety analyses 
9.2. 
Patient Disposition 
Please refer to Section 9.2 of the main protocol for detailed information. 
9.3. 
Demographic and Other Baseline Characteristics 
Please refer to Section 9.3 of the main protocol for detailed information. 
9.4. 
Prior and Concomitant Therapies 
Please refer to Section 9.4 of the main protocol for detailed information. 
9.5. 
Analyses 
Descriptive statistics will be used to summarize the demographic, disease characteristic, efficacy 
and safety data. No statistical hypotheses are planned in this exploratory study. 
All patients who have received tislelizumab will be included in the Safety analysis set. All 
patients with valid tislelizumab PK sampling after treatment will be included in the PK analysis 
set. For other parameters, all evaluable data will be included in the summaries. 
9.5.1. 
Primary Analyses 
Tislelizumab safety and tolerability: The safety of tislelizumab will be assessed throughout the 
study by monitoring AEs and serious SAEs per NCI-CTCAE v4.03, relevant physical 
examination, ECGs and laboratory assessments as needed. 
The recommended dose for the Phase 3 for tislelizumab will be determined based on safety, 
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9.5.2. 
Secondary Analyses 
Efficacy evaluations per RECIST v1.1 (ie, ORR, PFS and DOR) will be summarized to explore 
the preliminary anti-cancer activity in Japanese patients. 
The ORR is defined as the proportion of patients who had confirmed complete response (CR) or 
partial response (PR) assessed by the investigator using RECIST v1.1. 
The DOR is defined as the time from the first determination of a confirmed objective response 
by investigator per RECIST v1.1 until the first documentation of progression or death, whichever 
comes first. 
The PFS is defined as the time from the date of first dose of study drug to the date of first 
documentation of disease progression assessed by investigator using RECIST v1.1 or death, 
whichever occurs first. 
The ORR and its 95% confidence interval will be summarized in the Safety analysis set. Both 
PFS and DOR will be estimated using the Kaplan-Meier method. Waterfall plot of maximum 
tumor shrinkage per patient will be presented. 
Immunogenic responses to tislelizumab will be assessed by monitoring the incidence of ADAs. 
9.5.3. 
Exploratory Analyses 
Assessments of the correlations between drug exposure and response (efficacy and safety 
endpoints) will be made. Results of such exploratory analysis may be reported separately from 
the clinical study report (CSR). 
9.6. 
Safety Analyses 
As described in the main protocol (Section 9.6), safety will be assessed by monitoring and 
recording of all AEs graded per NCI-CTCAE v4.03. Laboratory values (eg, hematology, clinical 
chemistry), vital signs, ECGs, and physical examinations will also be used in determining safety. 
Descriptive statistics will be used to analyze all safety data in the Safety analysis set. Substudy 
Protocol Section 8 includes DLT definitions as well as specific information on the role of the 
IDMC in the assessment of DLTs and the confirmation of the Phase 3 dose. 
9.7. 
Pharmacokinetic Analyses 
Pharmacokinetic samples will be collected in this study as outlined in Table 8. The PK analysis 
will include, but is not limited to, area under the concentration-time curve from Day 0 to Day 21 
(AUC0-21d), Cmax and Tmax, Ctrough, t1/2, CL and Vd. Mean serum tislelizumab concentration data 
and PK parameters will be tabulated and summarized by visit/cycle at which these data are 
available. Concentrations of tislelizumab will be summarized descriptively. Descriptive statistics 
will include means, medians, ranges, and standard deviations, as appropriate. Additional PK 
analyses may be conducted as appropriate. 
Details concerning handling of PK serum samples, including labeling and shipping instructions 
will be provided in the Laboratory Manual. Samples will be shipped to the central laboratory 
where all samples will be analyzed for serum tislelizumab concentrations using a validated 


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method. The actual time each sample was collected will be captured to the nearest minute in the 
eCRF and recorded in the database. 
9.8. 
Immunogenicity Analyses 
As described in the main protocol (Section 9.8), the immunogenicity results will be summarized 
using descriptive statistics by the number and percentage of patients who develop detectable 
anti-drug antibodies (ADAs). The incidences of positive ADAs and neutralizing ADAs will be 
reported for evaluable patients. The effect of immunogenicity on PK, efficacy, and safety may be 
evaluated if data allow. 
10. 
DATA HANDLING AND QUALITY ASSURANCE 
Please refer to Section 10 of the main protocol for detailed information. 
11. 
ETHICAL CONSIDERATIONS 
Please refer to Section 11 of the main protocol for detailed information. 
12. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
Please refer to Section 12 of the main protocol for detailed information. 

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-A317-302 
Study Protocol 
Title: 
A Randomized, Controlled, Open-label, Global Phase 3 Study 
Comparing the Efficacy of the anti-PD-1 Antibody Tislelizumab (BGB-
A317) versus Chemotherapy as Second Line Treatment in Patients with 
Advanced 
Unresectable/Metastatic 
Esophageal 
Squamous 
Cell 
Carcinoma 
Date: 
Dec 22, 2020 
Version: 
3.0 
 




 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
2.1 
Study Design 
7 
2.2 
Study Assessments 
9 
3 
STUDY OBJECTIVES 
9 
3.1 
Primary Objectives 
9 
3.2 
Secondary Objectives 
10 
3.2.1 Key Secondary Objective: 
10 
3.2.2 Other Secondary Objectives: 
10 
3.3 
Exploratory Objectives 
10 
4 
STUDY ENDPOINTS 
10 
4.1 
Primary Endpoints 
10 
4.2 
Secondary Endpoints 
10 
4.2.1 
Key Secondary Endpoint: 
10 
4.2.2 
Other Secondary Endpoints: 
10 
4.3 
Exploratory Endpoints 
11 
5 
SAMPLE SIZE CONSIDERATIONS 
11 
6 
STATISTICAL METHODS 
12 
6.1 
Analysis Sets 
12 
6.2 
Data Analysis General Considerations 
12 
6.2.1 
Definitions and Computations 
12 
6.2.2 
Handling of Missing Data 
13 
6.2.3 
Adjustments for Covariates 
14 
6.2.4 
Multiplicity Adjustment 
14 
6.2.5 
Data Integrity 
14 
6.3 
Subject Characteristics 
14 
6.3.1 
Subject Disposition 
14 
6.3.2 
Protocol Deviations 
14 
6.3.3 
Demographics and Other Baseline Disease Characteristics 
15 
6.3.4 
Disease History and Baseline Disease Symptoms 
15 
6.3.5 
Prior Anti-Cancer Systemic Therapy, Radio Therapy and 
Surgeries 
16 
6.3.5.1 
Prior Anti-Cancer Systemic Therapy 
16 
6.3.5.2 
Prior Anti-Cancer Radio Therapy 
16 
6.3.5.3 
Prior Anti-Cancer Surgeries 
16 
6.3.6 
Prior and Concomitant Medication and Therapy 
16 
6.3.7 
Subsequent Anti-Cancer Therapy 
17 
6.3.8 
Medical History 
17 
6.4 
Efficacy Analysis 
17 
6.4.1 
Primary Efficacy Endpoints 
17 
6.4.1.1 
Sensitivity Analysis 
18 


 
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6.4.2 
Secondary Efficacy Endpoints 
19 
6.4.2.1 
Overall Survival 
19 
6.4.2.2 
Objective Response Rate 
19 
6.4.2.3 
Progression-Free Survival 
19 
6.4.2.4 
Duration of Response 
22 
6.4.2.5 
Health-Related Quality of Life (HRQoL) 
22 
6.4.3 
Exploratory Efficacy Endpoints 
26 
6.4.4 
Subgroup Analyses 
26 
6.5 
Safety Analyses 
27 
6.5.1 
Extent of Exposure 
27 
6.5.2 
Adverse Events 
28 
6.5.2.1 
Treatment Emergent Adverse Event 
28 
6.5.2.2 
Immune-related Adverse Event 
30 
6.5.2.3 
Infusion-related Adverse Event 
30 
6.5.3 
Death 
30 
6.5.4 
Laboratory Values 
31 
6.5.5 
Vital Signs 
32 
6.5.6 
Ophthalmology Examination 
32 
6.5.7 
Electrocardiograms (ECG) 
32 
6.5.8 
ECOG 
32 
 
ECOG performance status will be summarized by treatment arm and by 
visit. 
32 
6.6 
Pharmacokinetic Analyses 
32 
6.7 
Immunogenicity 
32 
6.8 
Other Analysis 
33 
8 
CHANGES IN THE PLANNED ANALYSIS 
33 
9 
REFERENCES 
34 
10 
APPENDIX 
35 
10.1 
Impute partial dates for concomitant medication 
35 
10.2 
Impute partial dates for adverse events 
35 
10.3 
Impute partial dates for subsequent anti-cancer therapy 
36 
10.4 
Impute partial dates for prior anti-cancer therapy 
36 
10.5 
Immune-mediated Adverse Event Category List 
37 
10.6 
Sensitivity analyses for subsequent therapy 
38 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Antidrug antibody 
AE 
Adverse event 
BGB-A317 
Tislelizumab, a humanized monoclonal antibody directed at PD-1 
BOR 
Best overall response 
Cmax 
Maximum observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete response 
CT 
Computed tomography 
Ctrough 
Trough serum concentration 
DCR 
Disease control rate 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
CRF 
Case report form 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
EORTC QLQ-OES18 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Oesophagus Cancer Module 
EQ-5D-5L 
European Quality of Life 5-Dimensions (EQ-5D-5L Version) 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HRQoL 
Health Related Quality of Life 
ICC 
Investigator chosen chemotherapy 
imAE 
Immune-related adverse event 
IRT 
Interactive response technology 
ITT 
Intention-to-Treat 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
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MSI  
Microsatellite instability  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PD-L1 
Programmed cell death protein ligand-1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol Population 
PR 
Partial response 
PT  
Preferred term 
Q2W 
Once every two weeks 
Q3W 
Once every three weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 
 
 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used in data analysis and results reporting for A317-302: A randomized, 
controlled, open-label, global Phase 3 study comparing the efficacy of the anti-PD-1 antibody 
tislelizumab (BGB-A317) versus chemotherapy as second line treatment in patients with 
advanced unresectable/metastatic esophageal squamous cell carcinoma. This SAP is based on 
BGB-A317-302 Protocol Amendment 4.0 dated as March 20th, 2020. The focus of this SAP is 
the planned final analysis specified in the study protocol.  The study was masked to statistician 
and the statistical analysis plan is finalized before unmasking. 
The analysis details for pharmacokinetic (PK), pharmacodynamics, pharmacogenomics and 
biomarker analyses are not described within this SAP. Separate analysis plans will be completed 
for these analyses and will be attached to the clinical study report. 
2 
STUDY OVERVIEW 
2.1 
STUDY DESIGN 
This is a randomized, controlled, open-label, global Phase 3 study comparing overall survival 
following treatment with the anti-PD-1 monoclonal antibody tislelizumab to ICC given as a 
second line treatment in patients with advanced unresectable/metastatic ESCC that has 
progressed during or after first line therapy. 
Before initiating this Phase 3 study in Japan, a sub-study investigating the safety, tolerability, PK 
and preliminary efficacy in Japanese patients is planned (see Appendix 13 of the Protocol 
Amendment 4 for details).  The separate analysis plan will be planed for Japan sub-study.  
After providing written informed consent, completing all screening assessments, and being 
confirmed as eligible for study participation, approximately 500 patients will be randomized 1:1 
to receive either tislelizumab monotherapy or investigator chosen chemotherapy 
(paclitaxel/docetaxel/irinotecan). The choice of chemotherapy must be determined prior to 
randomization. 
At randomization, patient enrollment will be stratified by the following 3 factors: 
 
Region (Asia [excluding Japan] vs Japan vs United States [US]/European Union 
[EU]) 
 
Eastern Cooperative Oncology Group performance status (0 vs 1) 
 
ICC option (paclitaxel vs docetaxel vs irinotecan) 
After randomization, patients will then begin open-label treatment with one of the following 
regimens.  
Arm A:  Tislelizumab 200 mg intravenously (IV), Day 1, given every 21 days  
Arm B:  One of the following three single-agent chemotherapies as determined by the 
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Abbreviations: ECOG, Eastern Cooperative Oncology Group; ESCC, Esophageal squamous cell carcinoma; 
ICC, investigator chosen chemotherapy; ITT, Intention-to-treat; OS, Overall survival; ORR, Overall response rate; 
PD-L1, Programmed cell death protein ligand-1; PFS, Progression-free survival; DOR, Duration of response; 
HRQoL, Health Related Quality of Life; DCR, Disease control rate; ADA, Anti-drug antibody. 
a. The initial infusion (Cycle 1, Day 1) will be administered over a period of 60 minutes. If this infusion is well 
tolerated, subsequent infusions may be administered over 30 minutes. After tislelizumab infusion, patients will 
be further monitored for at least 1 hour during Cycles 1 and 2. From Cycle 3 onward, a post-infusion monitoring 
period of at least 30 minutes will be required. 
b. At the discretion of the Investigator, patients randomized to receive tislelizumab may be treated beyond 
progression under protocol defined conditions. See Section 7.17.1 of the Protocol Amendment 4. 
2.2 
STUDY ASSESSMENTS 
Progression free survival and tumor response will be assessed by the Investigator using 
RECIST v1.1 criteria (Eisenhauer EA, 2009).  Tumor imaging (CT with or without contrast or 
MRI) must be performed within 28 days prior to randomization. On-study tumor assessments 
will occur approximately every 6 weeks (±7 days) for 6 months, then every 9 weeks (±7 days) 
until disease progression. If a patient discontinues study treatment due to the reasons other than 
disease progression or death, tumor assessments will continue to be performed as scheduled 
until the start of a new anti-cancer therapy, disease progression, loss to follow up, withdrawal 
of consent, death, or until study termination, whichever occurs first.  
Health related quality of life (HRQoL) will be collected via patient reported outcomes (PRO) 
instruments using the EORTC QLQ-C30, EORTC QLQ-OES18 and the EQ-5D-5L at baseline, 
Cycles 1-6 Day 1 or at the End of Treatment Visit (whichever occurs first), and at the Safety 
Follow-up Visit. Patients will be evaluated for any AEs and serious adverse events (SAEs) 
occurring up to 30 days after the last dose of study drug (all severity grades, per NCI-CTCAE 
v.4.03) or initiation of new anticancer therapy, whichever occurs first, and immune-related 
AEs (immune-mediated adverse events) occurring up to 90 days after the last dose of study 
drug regardless of initiation of a subsequent anticancer therapy. All drug-related SAEs will be 
recorded by the investigator after treatment discontinuation until patient death or loss to 
follow-up, whichever occurs first. All study drug related SAEs will be followed until they 
resolve to baseline or 
 Grade 1, the Investigator assesses the AE as stable and unlikely to 
improve, or the patient is lost to follow-up, whichever occurs first.  
Safety monitoring will be performed by an Independent Data Monitoring Committee (IDMC). 
The IDMC may recommend modifications to the study, including termination due to safety. 
The functions and membership of the IDMC will be described in an IDMC Charter. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
To compare the overall survival (OS) in Intent-to-treat patients following treatment with 
tislelizumab vs. investigator chosen chemotherapy (ICC) when given as second line treatment in 
patients with advanced unresectable/metastatic Esophageal Squamous Cell Carcinoma (ESCC). 


 
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3.2 
SECONDARY OBJECTIVES  
3.2.1 Key Secondary Objective: 
 To compare the OS in the PD-L1 positive population following treatment with 
tislelizumab versus investigator chosen chemotherapy (ICC). 
3.2.2 Other Secondary Objectives: 
 The following will be compared between the tislelizumab and the chemotherapy 
treatments based on assessment by investigator per RECIST v 1.1 criteria: 
 Overall response rate (ORR)  
 Progression-free survival (PFS) 
 Duration of response (DOR) 
 To compare HRQoL endpoints between the tislelizumab and the chemotherapy treatment 
arms as assessed by patient reported outcome (PRO) measures: European EORTC QLQ-
C30 index (EORTC QLQ-C30), the European esophageal cancer specific module QES 18 
(EORTC QLQ-OES18), and the generic health state instrument Euroqol 5D (EQ-5D-5L). 
 To compare the safety and tolerability between tislelizumab and the chemotherapy 
treatments 
3.3 
EXPLORATORY OBJECTIVES 
 To characterize the disease control rate (DCR) with tislelizumab compared to 
chemotherapy 
 To characterize the pharmacokinetics (PK) of tislelizumab  
 To determine host immunogenicity to tislelizumab  
 To explore potential predictive biomarkers (including but not limited to PD-L1 
expression, gene expression profiling, tumor mutation burden, microsatellite instability 
(MSI), and tumor-infiltrated immune cells) and resistance mechanism immune cells 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
 Overall survival (OS) in the ITT analysis set  defined as the time from the date of 
randomization to the date of death due to any cause for all intent-to-treat patients. 
4.2 
SECONDARY ENDPOINTS 
4.2.1 Key Secondary Endpoint: 
 OS in the PD-L1 positive analysis set  defined as the time from the date of 
randomization until the date of death due to any cause for all PD-L1 positive patients. 
4.2.2 Other Secondary Endpoints: 
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response (PR) assessed by the Investigators per RECIST v1.1 
 PFS - defined as the time from the date of randomization to the date of first 
documentation of disease progression assessed by the Investigators per RECIST v1.1 or 
death, whichever occurs first 
 DOR- measured from the time measurement criteria are first met for CR/PR (whichever 
is first recorded) until the first documentation of progression assessed by the Investigators 
per RECIST v1.1 or death, whichever comes first. 
 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 
index, GHS, and the functional and symptoms scales, the EORTC QLQ esophageal 
cancer module OES18 index score and the symptoms scale scores, and the generic health 
state instrument Euroqol 5D (EQ-5D-5L) 
 The incidence and severity of adverse events according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 
4.3 
EXPLORATORY ENDPOINTS 
 Disease control rate (DCR)- defined as the proportion of patients who have CR, PR and 
stable disease (SD) assessed by the Investigators per RECIST v1.1 
 Pharmacokinetic endpoints: summary of serum concentration of tislelizumab to include 
but not limited to trough serum concentration (Ctrough) 
 Assessments of immunogenicity of tislelizumab to determine the incidence of anti-drug 
antibodies (ADA) 
 Predictive biomarkers (including but not limited to PD-L1 expression, gene expression 
profiling, tumor mutation burden, MSI, and tumor-infiltrated immune cells) and 
resistance mechanism 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the primary efficacy analysis of OS comparison between 
tislelizumab and ICC arms in the ITT analysis set. Power of 82% and one-sided alpha of 0.025 
are used in the sample size calculation. Assuming an OS-HR (Arm tislelizumab/Arm ICC) is 
0.75 and a dropout rate of 5% per year, approximately 500 patients will be enrolled and 
randomized in a 1:1 ratio to Arms tislelizumab and ICC over 26-month period in order to 
accumulate approximately 400 deaths when median OS in the tislelizumab and ICC arms are 8 
months and 6 months, respectively. The assumed OS-HR 0.75 is based on recently published 
results of anti PD-1 therapies in second line treatment of ESCC (Kojima et al 2019, Kato et al 
2019, Huang et al 2019). . 


 
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6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
 Intent-to-Treat (ITT) analysis set  Includes all randomized patients. Patients will be 
analyzed according to their randomized treatment arm. This will be the primary 
analysis set for all efficacy analyses. Patients who were dead before the randomization 
but were inadvertently randomized into the study will be excluded from the ITT 
analysis set.  
 The PD-L1 positive analysis set includes patients whose visually-estimated combined 
positive (vCPS) score  10% using VENTANA PD
L1 (SP263) CDx Assay. 
Visually-estimated combined positive is the total percentage of the tumor area covered 
by tumor cells with PD-L1 membrane staining and tumor associated immune cells 
with PD-L1 staining at any intensity. 
 Per-Protocol (PP) analysis set  Includes all randomized patients who received at least 
1 dose of their assigned study drug and had no critical protocol deviations which are a 
significantly impact efficacy or safety evaluation. Critical protocol deviations are pre-
specified in the protocol deviation specification. All cases of prospectively defined 
protocol deviations are identified prior to clinical database lock. 
 Safety analysis set  Includes all randomized patients who received at least one dose 
of study drug. This will be the primary analysis set for all safety analyses. Patients will 
be analyzed by actual treatment received.   
 The PK analysis set includes all patients who received at least one dose of tislelizumab 
per the protocol, for whom any post-dose PK data are available. 
 The ADA analysis set includes all patients who received at least one dose of 
tislelizumab, have non-missing baseline ADA and at least one post-baseline ADA 
result. 
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 Definitions and Computations 
Study day: For efficacy analysis, study day will be calculated in reference to the date of 
randomization date. For safety analysis, study day will be calculated in reference to the first dose 
date.  For assessments conducted on or after the date of randomization/first dose date, study day 
will be calculated as (assessment date  randomization/first dose date + 1). For assessments 
conducted before randomization/first dose date, study day is calculated as (assessment date  
randomization/first dose date). There is no study day 0.  
Baseline: For analysis in ITT analysis set and PD-L1 positive analysis set, a baseline value is 
defined as the last non-missing value collected on or before the randomization date.  For analysis 
in safety analysis set, a baseline is defined as the last non-missing value collected on or before 
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Study Follow-up Duration (SFD): Study follow-up duration is defined as the duration from the 
randomization date to the study discontinuation date (e.g. death, consent withdrawal, lost to 
follow-up) or to cutoff date a patient is still ongoing.   
All calculations and analyses will be conducted using SAS version 9.2 or higher. 
Conventions 
Unless otherwise specified, all tabular outputs are summarized by tislelizumab, ICC options and 
total. The following conventions will be applied to all analyses: 
o 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
o 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 decimal. 
o Age will be calculated as the integer part of (date of informed consent  date of birth + 
1)/365.25 
o P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
 
-
 
 
o Time-to-event or duration of event endpoints based on tumor assessment will be based on 
the actual date of the radiograph was obtained rather than the associated visit date. 
o Missing efficacy or safety data will not be imputed unless otherwise specified. 
o For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
o For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator, unless otherwise specified. 
o For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median and range (minimum and maximum). 
o The unit of time duration is month unless otherwise specified.  
6.2.2 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP.  Missing 
dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures.  
Specific rules for handling of missing or partially missing dates for adverse events, 
prior/concomitant medications/procedures, and subsequent anti-cancer therapy are provided in 
Appendix 10.1, 10.2, 10.3, and 10.4  
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included.  


 
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6.2.3 Adjustments for Covariates 
The value of the stratification factors used at randomization (IWRS) ECOG performance status 
(0 vs 1) and ICC option (paclitaxel vs docetaxel vs irinotecan) will be used in stratified log-rank 
test and stratified Cox proportional hazard model for primary endpoint OS (ITT), key secondary 
endpoints OS(PD-L1 positive), and other secondary endpoints. The stratification factor region 
(Asia excluding Japan, Japan, US/EU) will not be adjusted in the model. However, subgroup 
analysis by region will be performed to assess the efficacy consistency by region 
6.2.4 Multiplicity Adjustment 
The primary endpoint of OS in the ITT analysis set will be tested once at a one-sided alpha of 
0.025. If the null hypothesis for OS in ITT analysis set is rejected, the key secondary endpoint 
OS in PD-L1 positive analysis set will be tested.   
6.2.5 Data Integrity 
Before final statistical analysis begins, the integrity of the data should be reviewed to assure fit-
for-purpose.  The data set for analysis should be an accurate and complete representation of the 
subjects' relevant outcomes from the clinical database.  All data should be complete and 
reviewed up to a pre-specified cutoff date.  Consistency checks and appropriate source data 
verification should be complete.  
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The number (percentage) of patients who signed informed consent, randomization, screen 
failures, and screened previously will be summarized. The number (percentage) of screen failure 
reason will also be summarized. 
The number (percentage) of subjects randomized, treated, discontinued from treatment and 
discontinued from the study will be summarized. The primary reason for end of treatment (study 
drug discontinuation) and end of study will be summarized by categories in the eCRF. Study 
follow-up duration will be summarized descriptively.  
Patient disposition and reasons for discontinuation will also be summarized by region (Asia and 
Europe/North America) for ITT analysis set.  
6.3.2 Protocol Deviations 
Protocol deviation criteria will be established together with its category/term of important or not 
important. Subjects with important protocol deviations will be identified and documented before 
the database lock.  Important protocol deviations will be summarized for all patients in the ITT 
analysis set.  
Critical protocol deviation that significantly impacts efficacy or safety evaluation will be 
reviewed prior to data base lock according to the criteria defined in protocol deviation 
specification. The patient with those critical important protocol deviations will be excluded from 
per protocol analysis set. 


 
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Patient data listings of protocol deviation will be provided. A separate list of patients with critical 
protocol deviation will also be provided. 
Important and non-important protocol deviations related to COVID-19 will be summarized. 
6.3.3 Demographics and Other Baseline Disease Characteristics 
Following demographics and other baseline characteristics collected will be summarized by 
using ITT analysis set and PD-L1 baseline status: 
 Age (years) and age group (< 65 years,  >= 65 years) 
 Gender (Male, Female) 
 Race 
 Ethnicity 
 Baseline ECOG  
 Baseline height (cm) 
 Baseline weight (kg) 
 BMI (kg/m2) 
 PD-L1 status (vCPS score  10%, < 10 %, Missing) 
 Smoking status (never, former, and current) 
 Alcohol consumption (never, former, and current) 
Demographics and other baseline characteristics will also be summarized by region (Asia and 
Europe/North America) for ITT analysis set. 
The stratification factors (Region, ICC option, ECOG) collected in IWRS and CRF will also be 
summarized using ITT analysis set.  
6.3.4 Disease History and Baseline Disease Symptoms 
Following disease history and characteristics at study entry will be summarized using ITT 
analysis set and by PD-L1 baseline status: 
 Number of Patients with Metastatic Diagnosis at Study Entry 
 Time from Metastatic Diagnosis to Study Entry (month) 
 Prior Systemic Therapy 
 Primary Site of Esophageal Cancer 
 Histologic Grade 
 Target lesions sum of diameters by investigator 
 Target lesion and non-target lesion location at Study Entry 


 
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Histology Grade Cancer associated symptoms at baseline will be coded by MedDra version 22.0 
and summarized by system organ class, preferred term, and NCI CTCAE 4.03 grade using ITT 
analysis set. 
Disease history and characteristics at study entry will also be summarized by region (Asia and 
Europe/North America) for ITT analysis set. 
Patient data listings of disease history and cancer associated symptoms at baseline will be 
provided. 
6.3.5 Prior Anti-Cancer Systemic Therapy, Radio Therapy and Surgeries 
6.3.5.1 Prior Anti-Cancer Systemic Therapy 
The number (percentage) of patient with at least one prior anti-cancer systemic therapy, maximal 
number of regimen of prior anti-cancer systemic therapies (0, 1, 2, >=3) and treatment setting 
(adjuvant/neoadjuvant, locally advanced, metastatic), duration of last prior anti-cancer systemic 
therapy (months) , and time from end of last anti-cancer systemic therapy to study entry (months) 
will be summarized by using ITT analysis set.   
The prior anti-cancer systemic will also be summarized by Anatomical Therapeutic Chemical 
(ATC) class and preferred term based on treatment setting (Adjuvant, Neoadjuvant, Locally 
advanced, and Metastatic). In addition, the last prior anti-cancer systemic therapy before study 
entry will be summarized by ATC class and preferred term. 
The prior anti-cancer systemic will also be summarized by region (Asia and Europe/North 
America) for ITT analysis set. 
6.3.5.2 Prior Anti-Cancer Radio Therapy 
The number (percentage) of patient with at least one prior anti-cancer radio therapy, treatment 
intent, treatment setting, time from last radio therapy to study entry (months), and treatment site 
(irradiated) will be summarized by using ITT analysis set.  
6.3.5.3 Prior Anti-Cancer Surgeries 
The number (percentage) of patient with at least one prior anti-cancer surgery, curative intent, 
will be summarized by using ITT analysis set.  
Patient data listings of prior anti-cancer systematic therapy, radio therapy and surgeries will be 
provided.  
6.3.6 Prior and Concomitant Medication and Therapy 
Prior and concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior 
and concomitant medications will be summarized and listed by Anatomical Therapeutic 
Chemical (ATC) class and WHO drug preferred term for the safety analysis set. 
Prior medications is defined as medications that stopped before the first dose of study drug. 


 
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Concomitant medications is 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 
In addition, 
concomitant medication also includes medications associated with an immune-mediated adverse 
event recorded up to 90 days after last dose of study drug.  Patients who received concomitant 
systemic corticosteroid will also be summarized. 
Patient data listings of prior and concomitant medication will be provided 
6.3.7 Subsequent Anti-Cancer Therapy 
Subsequent anti-cancer therapy is defined as the anti-cancer therapy started after the last dose 
date of study drug. A summary of number and pecentage of patients who received subsequent 
systematic anticancer therapy/immunotherapy by arm will be provided based on ITT and PD-L1 
positive analysis sets.  
Patient data listings of subsequent anti-cancer therapy will be provided. 
6.3.8 Medical History 
Medical History will be coded using MedDRA (version 22.0 or later). The number (percentage) 
of subjects reporting a history of any medical condition, as recorded on the CRF, will be 
summarized by system organ class and preferred term for the ITT population.  
Patient data listings of medical history will be provided. 
6.4 
EFFICACY ANALYSIS 
The primary and key secondary endpoints of OS in the ITT and PD-L1 positive analysis sets will 
be tested sequentially at a one-sided alpha of 0.025. No statistical inference is planned for the 
other efficacy and safety analyses; the p-values from these analyses will be calculated for 
descriptive purpose only.  
6.4.1 Primary Efficacy Endpoints 
The primary efficacy endpoint overall survival (OS) measured from the date of randomization to 
date of death from any cause. In absence of death on or before data cut-off, OS will be censored 
either at the date that the patient was last known to be alive or the date of data cut-off, whichever 
comes earlier (Table 1). 
                  Overall Survival (months) = (OS End Date  Date of Randomization + 1)/30.4275, 
where OS End Date is defined below. 
Table 1: Censoring Rules for Overall Survival 
Situation 
OS End Date 
Censored
Death before/on cut-off  
Date of death* 
No 
Death after cut-off 
Date of data cut-off 
Yes 
Subject still on treatment at data cut-off 
Date of data cut-off  
Yes 


 
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Other 
Date last known to be alive **
Yes 
* Every effort should be made to ensure complete death dates. In the rare case, if day of 
death date is missing, death date is imputed as maximum of last available date showing 
patients alive +1 and first day of year/month of death date. 
** The last know alive date is minimum of last available date showing patients alive and 
cutoff date. In general, any data after clinical cutoff date cannot be considered. The only 
exception is the data on the survival follow up CRF page after planned survival sweep with 
100% clean and verified survival follow up data. After survival sweep, data collected from 
survival follow up page should be kept in the database even after clinical cutoff date. Any 
data that are used in last known alive date derivation need to be verified. 
 
he null hypothesis to be tested is: 
                                  H0: OS in tislelizumab arm = OS in ICC arm  
against the alternative hypothesis: 
                                  H1: OS in tislelizumab arm 
 
The primary analysis of overall survival will be analyzed in ITT once the targeted number of 
deaths (approximately 400) is reached.  The p-value from one-sided log-rank test will be 
calculated, stratified by selected stratification factors at randomization: ECOG performance 
status (0 vs 1) and ICC option (paclitaxel vs docetaxel vs irinotecan). Median of OS with 95% 
confidence interval, if estimable, will be constructed with a generalized Brookmeyer and 
Crowley method.  The cumulative probabilty of OS at 6 and 12 months, if estimable will be 
caculated and presented with two-
   
The treatment effect will be estimated by fitting a Cox regression model to the OS times 
including treatment arm as a factor and stratified by ICC and ECOG performance status.  From 
this model, the hazard ratio (HR) of OS will be estimated and presented with a two-sided 95% 
confidence interval. 
Kaplan-Meier survival curve for each arm will also be provided.  
6.4.1.1 Sensitivity Analysis 
The following sensitivity analyses are planned: 
 The analysis in primary efficacy will be repeated based on PP analysis set, PD-L1 
positive analysis set, modified ITT analysis set. Modified Intent-to-Treat analysis set is 
defined as ITT analysis set excluding patients who are randomized but did not receive 
any dose of assigned study treatment. 
 An unstratified analysis of OS will repeated in ITT analysis set. The treatment effect 
will be estimated by fitting a Cox regression model to OS times only including 
treatment arm as a factor. 
 The treatment effect will be estimated by fitting a Cox regression model to the OS times 


 
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including treatment arm as a factor and stratified by ICC and ECOG performance status 
based on Case Report Form strata.  
 The additonal PD-L1 categories are potentially planned  applying  different vCPS score 
cut-off. 
If necessary, restricted mean survival time (RMST, Uno H, Claggett B, Tian L, Inoue E, et al. 
2014), Max-combo (Satrajit R, Keaven A, Jiabu Y, Pralay M, 2019) will be performed to 
account for the possible non-proportional hazard effects.  
In this study, patients can receive subsequnet systematic anticancer therapies (Immune 
checkpoint inhibitor or chemotherapy or target therapy) after treatment discontinuation which 
will casue bias in primary OS analysis. More sensitiviy analysis (i.e.,Rank Preserving Structural 
Failure Time (RPSFT) may be explored and is provided in Appendix 10.6. 
6.4.2 Secondary Efficacy Endpoints 
6.4.2.1 Overall Survival 
The same statistical methods described above in the primary efficacy analysis will be applied for 
the key secondary efficacy endpoint (OS in the PD-L1 positive analysis set).  
6.4.2.2 Objective Response Rate 
The difference in ORR per RECIST v1.1 will be evaluated using Cochran-Mantel-Haenszel 
(CMH) test adjusting for ECOG performance status, and ICC option for the ITT analysis set and 
PD-L1 positive analysis set.  The common odds ratio for ORR adjusted for strata and its two-
sided 95% CIs will be calculated.  ORR and difference in ORR as well as Clopper-Pearson 95% 
CI will be calculated.  
Best overall response (BOR), defined as the best response recorded from randomization until data 
cut-off or the start of new anticancer treatment. Patients with no post-baseline response assessment 
(due to any reason) will be considered not assessable (NA) for BOR.  The proportion for each of 
the response categories (e.g. CR, PR, SD, PD, NE, and NA) will be presented by treatment arm. 
6.4.2.3 Progression-Free Survival 
Progression-Free survival is defined in section 4.2. Progression-free survival censoring rule for 
PFS primary and sensitivity analysis are described in Table 2, which follows United States (US) 
Food and Drug Administration (FDA) Guidance for Industry, Clinical Trial Endpoints for 
Approval of Cancer drugs and Biologics (2018).  
Table 2: The primary and secondary censoring rules for the derivation of PFS 
No. 
Situation 
Date of Progression or 
Censoring 
Primary 
Analysis 
Sensitivity 
Analysis 1 
Sensitivity 
Analysis 2 
1 
No baseline or any 
post-baseline tumor 
assessments and 
Randomization date 
Censored 
Censored 
Censored 


 
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without death within 
two tumor 
assessments 
specified in protocol
from reference start 
date  
2 
Progression 
documented 
between scheduled 
visits 
Date of first radiologic 
PD assessment  
Progressed 
Progressed 
Progressed*
** 
3 
No progression at 
the time of data cut-
off or withdrawal 
from study 
Date of last adequate 
radiologic assessment 
prior to or on date of data 
cut-off or withdrawal 
from study 
Censored 
Censored 
Censored 
4 
New anticancer 
treatment started 
Date of last adequate 
radiologic assessment 
prior to or on date of new 
anticancer treatment 
Censored 
- 
Censored 
5 
Death before first 
PD assessment 
Date of death 
Progressed 
Progressed 
Progressed*
** 
6 
Death between 
adequate assessment 
visits* 
Date of death 
Progressed 
Progressed 
Progressed*
** 
7 
Death or 
progression after 
more than one 
missed visit** 
Date of last adequate 
radiologic assessment 
before missed tumor 
assessments 
Censored 
Censored 
Progressed 
or died 
8 
No baseline or any 
post-baseline tumor 
assessments and 
died within two 
tumor assessments 
specified in protocol
weeks from 
randomization date 
Date of death 
Progressed 
Progressed 
Progressed*
** 
 
*Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD 
or PD as determined by the investigators. 
** More than one missed visit is defined if the duration between the last tumor 
assessment and death or PD is longer than D2. The D2 is defined as two times protocol 


 
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specified interval between tumor assessments (TAs) plus the protocol allowed window 
around the assessments.  Since tumor assessment is scheduled as once every 6 weeks for 
first 6 months and once every 9 weeks afterwards with one-week window, D2 is 12 
weeks + 1 week in the first 6 months and 18 weeks + 1 week afterwards.  
*** Progression date for PFS event will be the earliest date of events defined in 2,4,5,6,8.
The priority of the censoring rules in the primary analysis is as follows: 
1. If the patient had PD or death, the following sequence will be applied: 
a. If a patient did not have baseline tumor assessment (No. 1), the patient will be 
censored on the randomization date.  However, if the patient died within two 
consecutive tumor assessments specified in protocol after randomization and did not 
receive new anticancer treatment, the date of death will be the PFS event date (not 
censored).  
b. If a patient had new anticancer treatment before PD or death (No. 4), the patient will 
be censored on the date of the last adequate tumor assessment prior to or on the date 
of new anticancer treatment. 
c. If a patient missed more than one assessment before PD or death (No. 7), the patient 
will be censored on the date of the last tumor assessment before PD or death.  Not 
that if a patient is censored by both this criterion and the anticancer treatment criteria, 
the earliest censoring date will be used.  
d. Otherwise, if a patient has event (No. 2, No. 5, or No. 6), the earliest event date will 
be used.  
2. If a patient did not have PD or death, the censoring date will be the earliest censoring date 
if the patient met multiple censoring criteria (No. 1, No. 3, No. 4). 
3. In sensitivity analysis 1, the PFS event date will be derived ignoring new anti-cancer 
therapy. 
4. In sensitivity analysis 2, any PD or death after more than one missing tumor assessment 
will be considered as a PFS event. 
PFS primary analysis is based on ITT analysis set and PD-L1 positive analysis set. The 
sensitivity analysis is based on ITT analysis set only. The number and percentage of patients who 
were dead/progressed, censored with reason of censoring will be summarized for each arm.  The 
p-value from one-sided log-rank test will be calculated, stratified by selected stratification factors 
at randomization: ECOG performance status (0 vs 1) and ICC option (paclitaxel vs docetaxel vs 
irinotecan).  Median of PFS with 95% confidence interval, if estimable, will be constructed with 
a generalized Brookmeyer and Crowley method.  The cumulative probabilty of PFS at 3 and 6 
months, if estimable will be caculated and presented with two-sided 95% confidence interval by 
 
The treatment effect will be estimated by fitting a Cox regression model to the PFS times 
including treatment arm as a factor and stratified by ICC and ECOG performance status. From 
this model, the hazard ratio (HR) of PFS will be estimated and presented with a two-sided 95% 


 
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confidence interval. 
An unstratified analysis of PFS will repeated in ITT analysis set. The treatment effect will be 
estimated by fitting a Cox regression model to PFS times only including treatment arm as a 
factor. 
Kaplan-Meier survival curve for each arm will also be provided. 
Sensitivity Analysis for Progression-Free Survival 
In order to evaluate the robustness of the PFS per RECIST 1.1, two sensitivity analyses with a 
different set of censoring rules will be performed (Table 2). The first sensitivity analysis is the 
same as the primary analysis except that it uses the actual reported date of progression or death 
to define PFS regardless of the use of new anti-cancer therapy. The second sensitivity analysis is 
the same as the primary analysis except that is uses the actual reported date of progression or 
death to define PFS regardless of the progression or death occur after more than one missed 
tumor assessment visit.  
6.4.2.4 Duration of Response 
Duration of Response (DOR) is defined in Section 4.2 as progression/death event free time 
counted from the first objective response date to the first documented radiological PD date/or 
death date, whichever occur first.  All the censoring rules for PFS primary analysis (Table 2Table 
2). should be applied to DOR as well.  DOR analysis is based on ITT analysis set and PD-L1 
positive analysis set. 
The p-value from one-sided unstratified log-rank test will be calculated for descriptive purpose 
only. Hazard ratio will be based on a unstratified Cox regression model only including treatment 
as covariate. Median of DOR with 95% confidence interval, if estimable, will be constructed 
with a generalized Brookmeyer and Crowley method.  The cumulative probabilty of DOR at 3 
and 6 months, if estimable will be caculated and presented with two-sided 95% confidence 
  
Kaplan-Meier survival curve for each arm will also be provided. 
6.4.2.5 Health-Related Quality of Life (HRQoL) 
The EORTC-QLQ-C30 consists of thirty questions that are associated with one global health 
status/QoL (GHS) scale (Aaronson NK, et al., 1993; Fayers PM, et al., 2001), five functional 
scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and 
nausea and vomiting), and six single items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties). A high derived score for a functional scale represents a 
high/healthy level of functioning, a high derived score for global health status/QoL represents a 
high QoL, but a high derived score for a symptom scale/item represents a high level of 
symptomatology/problems. 
The EORTC-QLQ-OES18 (Wen Y, et al., 2015)  is the specific esophageal symptoms module of 
the QLQ-C30, and includes 18 questions: 6 single item subscales measuring saliva swallowing, 


 
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choking, dry mouth, taste, coughing, and talking. It also includes 12 items grouped into 4 
subscales: dysphagia (3 items), eating (4 items), reflux (2 items), and pain (3 items). 
The EQ-5D-5L comprises a descriptive module and an EQ Visual Analogue scale (EQ VAS). 
The EQ-5D-5L descriptive module comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ 
-
health you 
 Lower scores in descriptive 
dimension indicates better HRQoL and higher VAS score indicates better health state. 
EORTC Scoring Derivation 
The principle for scoring applies to all scales/scores: Raw scores are calculated as the average of 
the items that contribute to the scale.  A linear transformation to standardize the raw scores is 
utilized, so that the scores are ranged from 0 to 100.  Increases in scores for functional domains 
(e.g., physical, role, social, emotional, etc.) are improvements while increases in scores for 
symptoms (e.g., fatigue, vomiting and nausea, diarrhea, pain, etc.) are deteriorations. 
If at least half of the items for a scale are answered, then all the completed items are used to 
calculate the score.  Otherwise, the scale score is set to missing. 
Raw Score (RS) 
For all scores, the raw score (RS), is the mean of the component items: 
RS=(I1+I2
n)/n 
Derived Scale (DS) 
The derived scales are obtained from the raw scores as defined in the EORTC manual. The derived 
scales have a more intuitive interpretation: larger function scale or global health status / QoL are 
improvements while larger symptom scales (e.g., pain, nausea, etc.) are deteriorations. The 
derivation formulas are as follows. 
For functional scales: 
DS=[1 - (RS-1)/range]*100 
For symptom scales and global health status: 
DS=[(RS-1)/range]*100 
Refer Table 3 and Table 4 for EORTC -QLQ-C30 and EORTC-QLQ-OES18 scoring. 
OES18 index
DS of Dysphagia, DS of Eating, Reflux, Pain, Trouble swallowing 
saliva, Choked when swallowing, Dry mouth, Trouble with taste, Trouble with coughing, 
Trouble talking) ÷ 10 
C30 index
100-DS of Physical functioning, 100-DS of Role functioning, 100-DS of 
Emotional functioning, 100-DS of Cognitive functioning, 100-DS of Social functioning, 100-DS 
of global QOL, DS of Fatigue, Nausea, Vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, 
Constipation, Diarrhea, Financial Difficulty] ÷ 15 


 
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Table 3: Scoring of QLQ-C30 
 
Scale 
Number 
of items 
Item 
range 
Item Numbers 
Global health status/ QoL 
Global health status/QOL 
QL2 
2 
6 
29,30 
Functional Scales 
 
 
 
 
Physical functioning  
PF2 
5 
3 
1, 2, 3, 4, 5  
Role functioning  
RF2 
2 
3 
6, 7  
Emotional functioning  
EF 
4 
3 
21, 22, 23, 24  
Cognitive functioning  
CF 
2 
3 
20, 25  
Social functioning  
SF 
2 
3 
26, 27  
Symptom Scales 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Single Items 
 
 
 
 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhea 
DI 
1 
3 
17 
Financial Difficulties 
FI 
1 
3 
28 
Table 4: Scoring of QLQ-OES18 
 
Scale 
Number 
of items 
Item 
range 
Item 
Numbers 
Symptom Scales 
 
 
 
 
Dysphagia 
DY 
3 
3 
1,2,3* 
Eating 
EA 
4 
3 
6,7,8,9 
Reflux 
RE 
2 
3 
14,15 
Pain 
PA 
3 
3 
16,17,18 


 
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Single Items 
 
 
 
 
Trouble swallowing saliva 
SA 
1 
3 
4 
Choked when swallowing 
SW 
1 
3 
5 
Dry mouth 
DM 
1 
3 
10 
Trouble with taste 
TA 
1 
3 
11 
Trouble with coughing 
CO 
1 
3 
12 
Trouble talking 
TA 
1 
3 
13 
*: Reversing scoring items. 
All HRQoL measures will be summarized in ITT analysis set and PD-L1 positive analysis set.  
Completion rates for the EORTC-QLQ-C30, QLQ-OES18, and EQ-5D-5L will be summarized 
separately at each visit.  A questionnaire module is considered complete if at least one question 
is answered.  In addition, the adjusted completion rate which defined as number of patients 
complete all questions divided by the number of patients still on study at relevant visit will also 
be summarized. 
For the EORTC-QLQ-C30, EORTC-QLQ-OES18 at each visit, raw score for functional scales 
and symptom scales will be calculated based on questionnaire items. Raw scores for the 
functional scale/symptom scale/single items will be transformed into 0-100 scale via linear 
transformation. The index score and derived score (functional scales/symptom scales/single 
items and the global scale) of EORTC-QLQ-C30, EORTC-QLQ-OES18 will be summarized as 
well as change from baseline using descriptive statistics.  
For EQ-5D-5L, descriptive system will be summarized by visit and dimension in an ordinal scale 
using descriptive statistics. The EQ VAS and change from baseline will be summarized by visit 
in a continuous scale using descriptive statistics. 
Time to clinically meaningful worsening in a HRQoL domains (for functional scales and global 
health status/) is defined as the time from randomization to the first time the difference between 
the current der
A deterioration is not 
counted as an event if a subsequent improvement returned the overall worsening from baseline to 
less than 10 points. Patients without clinically meaningful worsening will be censored at the last 
time the HRQoL domain was assessed. Time to clinically meaningful worsening will be analyzed 
for comparing the difference between the two treatment arms using Cox model for selected 
domains, hazard ratio and its 95% confidence interval will be provided, and a forest plot for 
selected domains will be provided. Time to clinically worsening for a selected number of domains 
of major interest will be tested for comparing the difference between tislelizumab and ICC arms. 
The domains of major interest include: the global scale and physical function scale of QLQ-C30 
and four symptom scale (dysphagia, eating, reflux, pain) from QLQ-OES18. 
 


 
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KM estimates by treatment arm, the hazard ratio estimates and their 95% CI will be provided. 
Hazard ratio is based on a Cox regression model including treatment as covariate and stratified by 
ECOG status and ICC options. 
Country-specific subgroups may also be summarized per local regulatory requirements. 
6.4.3 Exploratory Efficacy Endpoints 
Disease control rate (DCR) defined as the proportion of patients who have CR, PR and SD 
assessed by the investigator per RECIST 1.1. DCR will be analyzed similarly to ORR analysis 
by using ITT analysis set and PD-L1 positive analysis set.  
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesion. The 
maximum tumor shrinkage based on target lesion used in the plots will be listed. The post-
baseline nadir will be summarized using descriptive statistics. These analyses will be performed 
based on ITT analysis set and PD-L1 positive analysis set. 
6.4.4 Subgroup Analyses 
The following exploratory subgroup analyses may be conducted on the primary efficacy endpoint 
for OS in ITT analysis set. 
 
ICC options 
 
Geographic region 
o Asia vs Europe/North America 
o Asia (excluding Japan) vs. Japan vs. Europe/North America 
 
ECOG Performance status (0/1) 
 
Age group (< 65 years, >= 65 years) 
 
Gender 
 
Smoking status (former/current smoker, non-smoker) 
 
Race (White,  , Other) 
 
Baseline PD-L1 expression category: 
o vCPS score >= 10%, vCPS score < 10%, missing 
Geographic region (Asia vs Europe/North America) and Race (White vs Other) will also be 
summarized for the OS in PD-L1 positive analysis set. 
KM estimates by treatment arm, the unstratified hazard ratio estimates and their 95% CI will be 
provided.  The treatment effect will be estimated by fitting a Cox regression model to OS times 
only including treatment arm as a factor. 
Country-specific subgroups may also be summarized per local regulatory requirements. For the 
secondary endpoints, PFS, ORR and DOR will be summarized by region (Asia vs Europe/North 
America) in ITT analysis set. 


 
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6.5 
SAFETY ANALYSES 
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (e.g., hematology, clinical chemistry, coagulation and urinalysis), vital signs, 
ECGs, and physician examinations will also be evaluated in defining the safety profile of each 
treatment arm. Descriptive statistics (e.g., n, mean, standard deviation, median, Q1, Q3, minimum, 
maximum for continuous variables; n [%] for categorical variables) will be used to analyze all 
safety data in the Safety analysis set. Safety analysis will be performed based on actual treatment 
received. 
Treatment arm for safety analyses is defined as follows. 
If a patient was randomized to the tislelizumab treatment arm, and received tislelizumab at least 
once, the treatment arm for this patient is tislelizumab; otherwise, the actual treatment arm for this 
patient is ICC, as determined by his/her first study drug received. 
If a patient was randomized to the ICC treatment arm, and received assigned ICC treatment at least 
once, then the treatment arm for this patient is ICC. Otherwise, the actual treatment arm is 
determined by his/her first ICC drug received. If the patient only received tislelizumab, then the 
treatment arm for this patient is tislelizumab.  
 
6.5.1 Extent of Exposure 
Extent of exposure will be summarized by treatment arm. For ICC arm, extent of exposure will be 
summarized by study drug. 
Extent of exposure will be summarized descriptively as the number of cycles received, duration of 
exposure (days), cumulative total dose received per patient, dose intensity and relative dose 
intensity. 
The number (percentage) of patients requiring infusion related dose omission, dose interruption, 
dose delay, and dose reduction (in the ICC arm only) due to AEs will be summarized for each 
study drug. Consecutive dose omission/skips will only be counted once. Frequency of the above 
dose adjustments will be summarized by category.  
 The number of cycles taken will be calculated as the sum of numbers of non-missing doses 
(dose>0) within each cycle for each study drug. 
 Cumulative total dose per subject will be computed as the sum of all of the doses received 
in each cycle for each study drug. The dose unit is mg for tislelizumab and mg/m2 for ICC 
arm. 
 Dose intensity is defined as total dose / duration of exposure (day) * cycle length in days. 
Relative dose intensity is defined as Dose intensity / planned dose intensity. The planned 
dose intensity is the total planned dose in a cycle. For a patient in the tislelizumab arm, the 
planned dose intensity is 200 mg Q3W.  For ICC, use the plan dose capture in the case 
report form. 
Treatment duration  


 
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For the tislelizumab arm, Treatment duration = date of the last dose  date of first dose + 
21.  
 
For patients taking Paclitaxel on a once weekly schedule,   
Treatment duration = date of the last dose  date of first dose + 7. 
 
For patients taking paclitaxel on a Q3W schedule,  
Treatment duration = date of the last dose  date of first dose + 21. 
 
For Japanese patients taking paclitaxel on Days 1, 8, 15, 22, 29, and 36, followed by one 
week of rest,  
Treatment duration = date of the last dose  date of first dose + 14. 
 
For patients taking docetaxel,  
Treatment duration = date of the last dose  date of first dose + 21. 
 
For patients taking irinotecan,  
Treatment duration = date of the last dose  date of first dose + 14. 
6.5.2 Adverse Events  
standardized medical terminology using Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be coded to MedDRA (Version 22.0 or higher) lower level term closest to the 
verbatim term. The linked MedDRA System Organ Class (SOC) and Preferred Term (PT) are also 
classified. All adverse event summaries are based on safety analysis set. 
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset date or a 
worsening in severity from baseline (pre-treatment) on or after the first dose of study drug up to 
30 days following study drug discontinuation or initiation of new anti-cancer therapy, whichever 
occurs first. TEAEs also include all immune-mediated adverse events up to 90 days after the last 
dose of study drug regardless of whether or not 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. 
6.5.2.1 Treatment Emergent Adverse Event 
An overall summary of TEAEs will summarize the number (%) of patients with  
o At least one TEAE 
o At least one TEAE with NCI-
 
o At least one treatment-related TEAE 
o At least one serious TEAE 
o At least one TEAE leading to death 
o At least one TEAE leading to discontinuation of study drug 
o At least one TEAE leading to dose modification of study drug 


 
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o At least one immune-mediated adverse event 
o At least one immune-mediated adverse event with NCI-
 
o At least one infusion-related reaction 
o At least one infusion-related reaction with NCI-
 
Summaries of the following TEAEs will be provided:  
o All TEAEs  
o All TEAEs by SOC 
o All TEAEs by SOC and PT 
o All TEAEs by SOC and PT by Region 
o Most frequently reported (incidence  5% in any treatment arm) TEAEs by SOC 
and PT 
o Treatment-related TEAEs by SOC 
o Treatment-related TEAEs by SOC and PT 
o Treatment-related TEAEs by SOC and PT by Region 
o 
 5% in any treatment arm) Treatment-related 
TEAE by SOC and PT 
o Serious TEAEs by SOC and PT 
o 
 1% in any treatment arm) serious TEAE by 
SOC and PT 
o Treatment-related Serious TEAE by SOC and PT 
o 
1% in any treatment arm) Treatment-related 
serious TEAE by SOC and PT 
o TEAEs with NCI-
 
o TEAEs with NCI-
 by Region 
o 
1% in any treatment arm) TEAE with NCI-
CTCAE grade 
by SOC and PT 
o Treatment-related TEAE with NCI-
 3 by SOC and PT 
o Treatment-related TEAE with NCI-
 by Region 
o 
1% in any treatment arm) Treatment-related 
TEAE with NCI-
by SOC and PT 
o TEAEs leading to death by SOC and PT 
o Treatment-related TEAE Leading to Death by SOC and PT 


 
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o TEAEs Leading to Death Occurring in 
 2 Patients by System Organ Class and 
Preferred Term 
o TEAEs leading to treatment discontinuation by SOC and PT 
o Treatment-related TEAE Leading to Treatment Discontinuation by SOC and PT 
o TEAEs leading to dose modification by SOC and PT 
o Treatment-related TEAE Leading to Dose Modification by SOC and PT 
The types of Dose modification include dose held, dose interruption and dose reduction for ICC 
arm; dose held and dose interruption for tislelizumab arm. 
In addition, different cutoff of AE summary may be provided. 
6.5.2.2 Immune-related Adverse Event 
Immune-mediated adverse events are of special interest and summarized by category within a pre-
defined list in Appendix 10.5. 
For immune-mediated adverse events, a summary of incidence based on the number of patients 
dosed or within the immune-mediated adverse event follow up period will be presented by 
category in the descending order of incidence based on the tislelizumab column.  
Summaries of the following incidence of immune-mediated adverse events will be provided: 
o Immune-mediated adverse events by category  
o Immune-mediated adverse events by category by region  
o Immune-mediated adverse events with NCI-
 
o Immune-mediated adverse events with NCI-
 by region 
o Immune-mediated adverse events by category and worst grade 
o Immune-mediated adverse events leading to treatment discontinuation by category 
o Immune-mediated adverse events leading to death by category 
o Immune-mediated adverse events leading to dose modification by category 
6.5.2.3 Infusion-related Adverse Event 
For IRRs, a summary of incidence by SOC, PT and maximum severity will be provided, sorted 
by descending order of incidence within each SOC and PT based on tislelizumab column. 
Summaries of IRRs, IRRs with NCI-
, IRRs leading to treatment 
discontinuation, and IRRs leading to dose modification will also be provided by PT only, in 
descending order. 
6.5.3 Death 
Number and causes of deaths, classified by deaths within 30 days of last dose of study drug and 
deaths more than 30 days after the last dose, will be summarized based on ITT analysis set. 
Patient data listings of death and reason will be provided.  


 
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6.5.4 Laboratory Values 
Hematology, serum chemistry, thyroid function, will be summarized/listed for selected 
parameters described in Table 5.  The coagulation, urinalysis, HBV/HCV serology, and 
pregnancy test results will be listed only. 
Laboratory results will be summarized/listed using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Table 5, Error! Reference source not found.the actual 
value and the change from baseline will be summarized by visit and worst post-baseline visit using 
descriptive statistics. Plots of laboratory values/change from baseline over time will be provided 
for selected lab parameters. 
Laboratory parameters are also graded according to CTCAE v4.03 and will be summarized by 
shifts from baseline CTCAE grades to maximum post-baseline grades. Laboratory parameters 
(e.g., glucose, potassium, sodium) with CTCAE grading in both high and low directions will be 
summarized separately. Shift tables will be used to summarize the grade change from baseline to 
worst post baseline value with counts and percentages for hematology and serum chemistry. The 
lab parameters with grades increased in more than 2 from baseline to worst post baseline will 
also be summarized. 
Table 5
Clinical Laboratory Assessments  
Serum Chemistry 
Hematology 
Coagulation
Urinalysis 
Thyroid 
function  
HBV and 
HCV serology 
glucose, blood 
urea nitrogen 
[BUN] [or serum 
urea], creatinine, 
sodium, 
potassium, 
chloride, 
phosphorus, total 
bilirubin, ALT, 
AST, alkaline 
phosphatase, 
lactate 
dehydrogenase 
[LDH] [optional], 
total protein, 
albumin, creatine 
kinase (CK) and 
creatine kinase-
cardiac muscle 
isoenzyme (CK-
MB) 
complete blood 
count [CBC], 
including red 
blood cell [RBC] 
count, 
hemoglobin, 
hematocrit, white 
blood cell 
[WBC] count 
with automated 
differential 
[neutrophils, 
eosinophils, 
lymphocytes, 
monocytes, and 
basophils], and 
platelet count 
 
Prothrombin 
time (PT) and 
International 
Normalized 
Ratio (INR) 
complete 
[including, 
but not 
limited to 
glucose, 
protein, 
ketones, and 
blood] 
and/or 
microscopic, 
if clinically 
indicated 
 
TSH 
Free T3 
Free T4 
HBsAg, 
HBcAb and 
HCV antibody 
 


 
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6.5.5 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], pulse 
rate, temperature, and weight) and changes from baseline will be presented by visit. For 
tislelizumab, the change from post-dose (end of infusion) to pre-dose also need to be 
summarized for all vital sign parameters except for weight. Vital signs will be listed by patients 
and visits. Descriptive statistics for vital sign parameters. 
6.5.6 Ophthalmology Examination 
Ophthalmology examination findings will be listed by patients and visits. 
6.5.7 Electrocardiograms (ECG) 
12-lead ECG recordings are required at Screening, End of Treatment and as clinically indicated. 
Patient listing of ECG will be provided for all ECG recordings. 
The actual value and the change from baseline for QTc intervals will be summarized by visit and 
treatment arm using descriptive statistics.  
Abnormal post-baseline QTcF results will be summarized with the following categories: increase 
of >30 msec, increase of > 60 msec, value of > 450 msec, value of > 480 msec, value of > 500 
msec for each visit by treatment arm. 
6.5.8 ECOG 
A shift table from baseline to worst post baseline will be provided. Patient listing of ECOG 
performance score comparison between IRT and CRF will be provided for all ECOG recordings. 
6.6 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic samples were collected in this study as outlined in Appendix 1 in Protocol 
Amendment v4.0 and only from patients randomized to receive tislelizumab and in sites that are 
able to adequately perform sampling, handling and processing procedures outlined in the 
laboratory manual.  
Tislelizumab (as well as by region and race) serum concentration data,including but not limited 
to Ctrough, will be tabulated and summarized for each cycle at which pharmacokinetics are 
collected. Descriptive statistics will include means, medians, ranges, standard deviations and 
coefficient of variation (CV),  and geometric mean, geometric CV as appropriate.  
Additional PK analyses may be conducted as appropriate. 
6.7 
IMMUNOGENICITY 
Samples to assess anti tislelizumab antibodies will be collected only in patients randomized to 
receive tislelizumab and in sites that are able to adequately perform sampling, handling and 
processing procedures outlined in the laboratory manual. 
ADA attributes: 
 
Treatment boosted ADA is defined as ADA positive at baseline that was boosted to a 4-
fold or higher-level following drug administration.  


 
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Treatment-emergent ADA is defined as ADA negative at baseline and ADA positive 
post-baseline.  
 
Transient ADA response is defined as Treatment-emergent ADA detected only at 1 time 
point during treatment or follow-up, excluding last time point; or detected at 2 or more 
time points during treatment or follow-up, where the first and last positive samples are 
separated by less than 16 weeks and the last time point is negative. 
 
Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more 
time points during treatment or follow-up, where the first and last ADA positive samples 
are separated by 16 weeks or longer; or detected only in the last time point or at a time 
point less than 16 weeks before a negative last sample. 
 
Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological 
activity. 
ADA response endpoints: 
 ADA incidence is defined as sum of treatment-induced and treatment-boosted ADA-
positive patients as a proportion of the ADA evaluable population.  
 ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
6.8 
OTHER ANALYSIS 
Distribution of PD-L1 expression, gene expression profile, tumor mutation burden (tumor tissue 
and/or blood), MSI and tumor-infiltrated immune cells may be examined in the ITT analysis set. 
Same analysis may be examined in on-progression samples if any collected. BOR, ORR, and 
PFS may be present by PD-L1 category. Other potential predictive markers may be assessed with 
the same approach. 
Detailed information about biomarker analysis for exploratory endpoints will be in separate 
statistical analysis document and will not be described in the clinical study report. 
The impact of COVID-19 to patient disposition, adverse events, exposure with dose 
modification, protocol violation/deviation will be summarized.  
7 
INTERIM ANALYSIS 
There is no planned interim analysis for this study. 
8 
CHANGES IN THE PLANNED ANALYSIS 
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will be 
documented and described in the clinical study report. 


 
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9 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F. The European Organisation for Research and Treatment of 
Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. 
Journal of the National Cancer Institute 1993; 85: 365-376. 
Eisenhauer EA, et al. (2009). New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 45(2), 228-47. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published 
by European Organisation for Research and Treatment of Cancer, Brussels 2001. 
Hwang IK, Shih WJ, and DeCani JS. Group sequential designs using a family of type 1 error 
probability spending functions. Statistics in Medicine, 9:1439 1445, 1990. 
National Comprehensive Cancer Network (NCCN) Guidelines Version 1. (2017). Esophageal and 
Esophagogastric Junction Cancers. Retrieved from  
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#esophageal  
U.S. Food and Drug Administration Cencer for Drug Evaluation Research (CDER) and Center for 
Biologics Evaluation and Research. (2007). Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 
Wen Y, Pan XF, Huang WZ, Zhao ZM, Wei WQ, Chen F, Lan H, Huang H, Yang CX, Qiao YL. 
Quality of Life for Patients with Esophageal/Gastric Cardia Precursor Lesions or Cancer: A One-
year Prospective Study. Asian Pacific Journal of Cancer Prevention, Vol 16: 45-51, 2015. 


 
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10  APPENDIX  
10.1 IMPUTE PARTIAL DATES FOR CONCOMITANT MEDICATION  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
o If both month and day are missing, then set to January 01 
o If only day is missing, then set to the first of the month 
o If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
o If both month and day are missing, then set to December 31 
o If only day is missing, then set to last day of the month 
o If the imputed end date > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
10.2 IMPUTE PARTIAL DATES FOR ADVERSE EVENTS 
If year of the start date is missing or start date is completely missing, do not impute.  Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
o If both month and day are missing, then set to December 31 
o If only day is missing, then set to last day of the month 
o If the imputed end date > death date, then set to death date 
If year of the end date is missing or end date is completely missing, do not impute.  If start date 
of an adverse event is partially missing, impute as follows: 
o If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
o 
January 01 
o If day is missing and month and year = month and year of treatment start date, the set 
to treatment start date 
o 
to first of the month 
o If the imputed AE start date is after AE end date (maybe imputed), then update AE 
start date with AE end date as final imputed AE start date. If the imputed end date > 


 
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death date, then set to death date. 
10.3 IMPUTE PARTIAL DATES FOR SUBSEQUENT ANTI-CANCER SURGERY/PROCEDURE 
When the start date of subsequent anti-cancer therapy is partially missing, the following rules 
will be applied to impute partial dates. 
If start date of is partially missing, impute as follows: 
o If both month and day are missing, then set to December 31 
o If only day is missing, then set to last day of the month 
o If the imputed end date > death date, then set to death date 
If year of the start date is missing, do not impute. If imputed start date is after study 
discontinuation date, then set to study discontinuation date. 
10.4 IMPUTE PARTIAL DATES FOR PRIOR ANTI-CANCER THERAPY (DRUG, 
SURGERY/PROCEDURE, RADIOTHERAPY) 
The following rules will be applied to impute partial dates such as as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
o If start date of a disease history or prior therapy is partially missing, impute as 
follows: 
o If both month and day are missing, then set to January 01 
o If only day is missing, then set to the first of the month 
If the imputed start date > first dose date then set to first dose date  1 
If end date of a disease history or prior therapy is partially missing, impute as follows: 
o If both month and day are missing, then set to December 31 
o If only day is missing, then set to last day of the month 
o If the imputed end date > first dose date, then set to first dose date -1 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. If imputed start date/end date is after 
randomization date - 14 , then set to randomization date - 14.  
 
 
 


 
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BGB-A317-302
              (Statistical Analysis Plan) 
 
 
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10.5 IMMUNE-MEDIATED ADVERSE EVENT CATEGORY LIST 
 
 
 
Category 
Immune-mediated adrenal insufficiency
Immune-mediated anaemia 
Immune-mediated colitis 
Immune-mediated hepatitis 
Immune-mediated hyperthyroidism 
Immune-mediated hypothyroidism 
Immune-mediated myocarditis 
Immune-mediated myositis/rhabdomyolysis 
Immune-mediated nephritis and renal dysfunction 
Immune-mediated nervous system disorder  
Immune-mediated ocular disorder 
Immune-mediated pancreatitis 
Immune-mediated pituitary dysfunction 
Immune-mediated pneumonitis 
Immune-mediated skin adverse reaction 
Immune-mediated thrombocytopenia 
Immune-mediated thyroiditis 
Immune-mediated type 1 diabetes mellitus 
Other immune-mediated reactions 


 
BeiGene USA, Inc
BGB-A317-302
              (Statistical Analysis Plan) 
 
 
Version 3.0:  12/22/2020 
Page 38 of 38
CONFIDENTIAL
 
10.6 SENSITIVITY ANALYSES FOR SUBSEQUENT THERAPY 
Rank Perserving Structural Failure Time (RPSFT) survival analysis model of OS accounting for 
the use of subsequent anticancer therpy are planned.  
Due to there is no standard of care for 3rd line ESCC patients,  we assume the subsequent 
immune checkpoint inhibitors contribute most effect for OS than other subsequent anti-cancer 
therapy. Under this assumption, we only focus on adjustment of subsequent immune checkpoint 
inhibitors by using RPFST model.  RPSFT 
which implies that the treatment effect of tisleilizumab and other immune checkpoint inhibitors 
(ICI) are identical and the treatment effect is indedpendent of exposure timing in the trial. uses a 
conunterfactual framework to estimate the causal effect of immune checkpoint inhibitors, where 
counterfactual surival times refer to those that would have been observed if no subsequent 
immune checkpoint inhibitors had been given.  It is assumed that conunterfactual survival times 
are independent of treatment arm and grid method (g-estimation) is used to determine a value for 
the treatment effect. The p-value, median OS, hazard ratio will be constructed based on 
counterfactual dataset.  The symmetrical test-based 95% confidence intervals were obtabined by 
inflating the standard error of the log-hazard ratio to preserve the ITT p-value. 
The respective sandard error of the estimated hazard ratio of counterfactural dataset:  
 
The symmetrical test-based 95% confidence intervals: