A Phase 2, Multicenter, Open-label, 2-Cohort Study to Investigate the Efficacy and Safety of PET Guided Neoadjuvant Treatment With Tislelizumab (BGB-A317) Plus Chemotherapy/Chemoradiotherapy in Patients With Resectable Esophageal Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Resectable Esophageal Squamous Cell Carcinoma
Sponsor: BeiGene

BGB-A317-213 
BeiGene 
Protocol Amendment 1.0 
22 Jul 2022 
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CLINICAL STUDY PROTOCOL 
TITLE PAGE 
A Phase 2, Multicenter, Open-label, 2-Cohort Study to 
Investigate the Efficacy and Safety of PET Guided 
Neoadjuvant Treatment With Tislelizumab (BGB-A317) 
Plus Chemotherapy/Chemoradiotherapy in Patients With 
Resectable Esophageal Squamous Cell Carcinoma 
BGB-A317-213 
2 
Tislelizumab (BGB-A317) 
Neo-adjuvant treatment of resectable esophageal squamous 
cell carcinoma 
NCT04974047
Protocol Title: 
Protocol Identifier: Phase: 
Investigational Product(s): 
Indication: 
Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
4th Floor, Building D 
780 Cailun Road 
China (Shanghai) Pilot-Free Trade Zone 
Shanghai, 201203 China 
Sponsor Medical Monitor: 
Email: 
Original Protocol Version 0.0: 30 January 2021 
Protocol Amendment 1.0: 
22 July 2022 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, 
Ltd., and its subsidiaries.  This document is for use by individuals and their designated 
representatives for their confidential review, consideration, and/or participation in investigational 
trial(s).  This document may not be copied or distributed for review by any unauthorized 
individuals without the prior written authorization of BeiGene, Ltd., or one of its subsidiaries.  
Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without the prior written authorization from BeiGene, 
Ltd., or one of its subsidiaries. 
Approved Date
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Approved Date
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INVESTIGATOR SIGNATURE PAGE 
  
Protocol Title: A Phase 2, Multicenter, Open-label, 2- Cohort Study to Investigate the Efficacy 
and Safety of PET Guided Neoadjuvant Treatment with Tislelizumab (BGB-A317) Plus 
Chemotherapy/Chemoradiotherapy in Patients With Resectable Esophageal Squamous Cell 
Carcinoma 
Protocol Identifier: 
BGB-A317-213 
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 and 
address of the center in which the study will be conducted.   
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: _______________________________ 
Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET .............. ERROR! BOOKMARK NOT DEFINED. 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
SYNOPSIS. ....................................................................................................................................11 
LIST OF ABBREVIATIONS AND TERMS ................................................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background Information on Esophageal Carcinoma ..................................................21 
1.2. 
Current Treatment of Resectable Esophageal Carcinoma and Unmet Clinical 
Needs ..........................................................................................................................21 
1.3. 
Anti-PD-1 Therapy for Esophageal Squamous Cell Carcinoma ................................24 
1.3.1. 
Tislelizumab ...............................................................................................................24 
1.3.2. 
Pembrolizumab ...........................................................................................................25 
1.3.3. 
Nivolumab ..................................................................................................................26 
1.4. 
Background Information on Tislelizumab ..................................................................27 
1.4.1. 
Pharmacology .............................................................................................................27 
1.4.2. 
Toxicology ..................................................................................................................28 
1.4.3. 
Clinical Pharmacology ................................................................................................28 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................29 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................29 
1.5. 
Study Rationales .........................................................................................................34 
1.5.1. 
Rationale for Tislelizumab in the Treatment of Esophageal Carcinoma ....................34 
1.5.2. 
Rationale for Selection of Tislelizumab Dose ............................................................34 
1.5.3. 
Rationale for Study Population ...................................................................................35 
1.5.4. 
Rationale for Tislelizumab in the Perioperative Treatment of Resectable 
ESCC ..........................................................................................................................35 
1.5.5. 
Rationale for Tislelizumab in Combination with Chemotherapy for Cohort A .........36 
1.5.6. 
Rationale for Tislelizumab in Combination with CRT for Cohort B .........................37 
1.6. 
Benefit-Risk Assessment ............................................................................................37 
1.6.1. 
Benefit-Risk Assessment of Cohort A ........................................................................37 
1.6.2. 
Benefit-Risk Assessment of Cohort B ........................................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................39 
2.1. 
Study Objectives .........................................................................................................39 
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2.1.1. 
Primary Objective .......................................................................................................39 
2.1.2. 
Secondary Objectives .................................................................................................39 
2.1.3. 
Exploratory Objectives ...............................................................................................39 
2.2. 
Study Endpoints ..........................................................................................................39 
2.2.1. 
Primary Endpoint ........................................................................................................39 
2.2.2. 
Secondary Endpoints ..................................................................................................39 
2.2.3. 
Exploratory Endpoints ................................................................................................40 
3. 
STUDY DESIGN .......................................................................................................41 
3.1. 
Summary of Study Design ..........................................................................................41 
3.2. 
Screening Period .........................................................................................................41 
3.3. 
Treatment Period ........................................................................................................42 
3.4. 
End of Treatment/Safety Follow-up ...........................................................................43 
3.5. 
Survival Follow-up .....................................................................................................43 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................44 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................44 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........44 
3.7. 
End of Study ...............................................................................................................45 
4. 
STUDY POPULATION .............................................................................................46 
4.1. 
Inclusion Criteria ........................................................................................................46 
4.2. 
Exclusion Criteria .......................................................................................................47 
5. 
STUDY TREATMENT ..............................................................................................50 
5.1. 
Formulation, Packaging, and Handling ......................................................................50 
5.1.1. 
Tislelizumab ...............................................................................................................50 
5.1.2. 
Chemotherapy .............................................................................................................50 
5.2. 
Dosage, Administration, and Compliance ..................................................................50 
5.2.1. 
Tislelizumab ...............................................................................................................51 
5.2.2. 
Cisplatin in Combination with Paclitaxel ...................................................................52 
5.2.3. 
Cisplatin in Combination with 5-Fluorouracil ............................................................53 
5.2.4. 
Radiotherapy ...............................................................................................................53 
5.2.5. 
Surgery ........................................................................................................................53 
5.3. 
Overdose .....................................................................................................................54 
5.4. 
Investigational Medicinal Product Accountability .....................................................54 
5.5. 
Dose Delay or Modification .......................................................................................54 
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5.5.1. 
General Guidance Regarding Dose Modifications .....................................................55 
5.5.2. 
Dose Delay or Modification for Tislelizumab ............................................................56 
5.5.3. 
Dose Delay, Interruption, or Modifications for Chemotherapy .................................56 
5.5.4. 
Dose Delay, Interruption, or Modifications for Radiotherapy (for Cohort B) ...........58 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................59 
6.1. 
Prior Therapy ..............................................................................................................59 
6.2. 
Concomitant Therapy .................................................................................................59 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................59 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................59 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................59 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................60 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................60 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................60 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................62 
7.1. 
Screening ....................................................................................................................62 
7.1.1. 
Informed Consent and Screening Log ........................................................................62 
7.1.2. 
Pulmonary Function Tests ..........................................................................................62 
7.2. 
Enrollment ..................................................................................................................63 
7.2.1. 
Confirmation of Eligibility .........................................................................................63 
7.2.2. 
Patient Numbering ......................................................................................................63 
7.3. 
Tislelizumab and Chemotherapy Dispensation ..........................................................63 
7.4. 
Safety Assessments .....................................................................................................63 
7.4.1. 
Vital Signs ..................................................................................................................63 
7.4.2. 
Physical Examinations ................................................................................................63 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................63 
7.4.4. 
Laboratory Safety Tests ..............................................................................................63 
7.4.4.1. 
Cardiac enzyme monitoring ........................................................................................64 
7.4.5. 
Electrocardiograms .....................................................................................................64 
7.4.6. 
Adverse Events ...........................................................................................................64 
7.4.7. 
Hepatitis B and C Testing ...........................................................................................64 
7.5. 
Tumor and Response Evaluations ..............................................................................64 
7.6. 
Biomarkers ..................................................................................................................65 
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7.7. 
Visit Windows ............................................................................................................65 
7.8. 
Unscheduled Visits .....................................................................................................66 
8. 
SAFETY MONITORING AND REPORTING .........................................................67 
8.1. 
Risks Associated with Study Drug .............................................................................67 
8.1.1. 
Risks Associated with Tislelizumab ...........................................................................67 
8.1.2. 
Risks Associated with Chemotherapy ........................................................................67 
8.1.3. 
Risks Associated with Radiotherapy ..........................................................................69 
8.2. 
General Plan to Manage Safety Concerns ..................................................................69 
8.2.1. 
Eligibility Criteria .......................................................................................................69 
8.2.2. 
Safety Monitoring Plan ...............................................................................................69 
8.3. 
Adverse Events ...........................................................................................................70 
8.3.1. 
Definitions and Reporting ...........................................................................................70 
8.3.2. 
Assessment of Severity ...............................................................................................71 
8.3.3. 
Assessment of Causality .............................................................................................71 
8.3.4. 
Follow-up of Adverse Events .....................................................................................72 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................72 
8.4. 
Definition of a Serious Adverse Event .......................................................................73 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................74 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................74 
8.6.1. 
Adverse Event Recording Period ................................................................................74 
8.6.2. 
Reporting Serious Adverse Events .............................................................................75 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................75 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................75 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................76 
8.6.3. 
Eliciting Adverse Events ............................................................................................76 
8.6.4. 
Disease Progression ....................................................................................................76 
8.6.5. 
Deaths .........................................................................................................................76 
8.6.6. 
Pregnancies .................................................................................................................76 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................77 
8.6.8. 
Assessing and Recording Immune-mediated Adverse Events ...................................77 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................77 
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8.7. 
Management of AE of Special Interest .......................................................................78 
8.7.1. 
Managing Infusion-Related Reactions .......................................................................78 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................80 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................80 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................82 
9.1. 
Statistical Analysis ......................................................................................................82 
9.1.1. 
Analysis Sets ...............................................................................................................82 
9.1.2. 
Patient Disposition ......................................................................................................82 
9.1.3. 
Demographic and Other Baseline Characteristics ......................................................82 
9.1.4. 
Prior and Concomitant Medications ...........................................................................82 
9.2. 
Efficacy Analyses .......................................................................................................83 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................83 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................83 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................84 
9.3. 
Safety Analyses ..........................................................................................................84 
9.3.1. 
Extent of Exposure .....................................................................................................84 
9.3.2. 
Adverse Events ...........................................................................................................85 
9.3.3. 
Laboratory Analyses ...................................................................................................85 
9.3.4. 
Vital Signs ..................................................................................................................86 
9.3.5. 
Pulmonary Function Test ............................................................................................86 
9.4. 
Sample Size Consideration .........................................................................................86 
10. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................88 
10.1. 
Access to Information for Monitoring ........................................................................88 
10.2. 
Access to Information for Auditing or Inspections ....................................................88 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................89 
11.1. 
Regulatory Authority Approval ..................................................................................89 
11.2. 
Quality Assurance .......................................................................................................89 
11.3. 
Study Site Inspections.................................................................................................89 
11.4. 
Drug Accountability ...................................................................................................89 
12. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................91 
12.1. 
Ethical Standard ..........................................................................................................91 
12.2. 
Institutional Review Board/Independent Ethics Committee ......................................91 
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12.2.1. 
Protocol Amendments ................................................................................................91 
12.3. 
Informed Consent .......................................................................................................92 
12.4. 
Patient and Data Confidentiality .................................................................................92 
12.5. 
Financial Disclosure ...................................................................................................93 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................94 
13.1. 
Data Collection and Management Responsibilities ....................................................94 
13.1.1. 
Data Entry in the Electronic Case Report Form .........................................................94 
13.1.2. 
Data Collection ...........................................................................................................94 
13.1.3. 
Data Management/Coding ..........................................................................................94 
13.2. 
Data Integrity and In-house Blinding .........................................................................95 
13.3. 
Study Records Retention ............................................................................................95 
13.4. 
Protocol Deviations ....................................................................................................96 
13.5. 
Study Report and Publications....................................................................................96 
13.6. 
Study and Study Center Closure .................................................................................97 
13.7. 
Information Disclosure and Inventions ......................................................................97 
14. 
REFERENCES ...........................................................................................................99 
 
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LIST OF TABLES 
Table 1: 
Outcomes of Neoadjuvant CRT Followed by Surgery for EC ...................................22 
Table 2: 
Outcomes of Neoadjuvant Chemotherapy Followed by Surgery for EC ...................23 
Table 3: 
Outcomes of Neoadjuvant CRT Followed by Surgery for EC Guided by PET 
After Induction Therapy .............................................................................................24 
Table 4: 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies of Solid Tumors ...........30 
Table 5: 
Immune-Mediated Adverse Events of Any Grade Occurring in ≥ 1% in 
Pooled Monotherapy Studies of Solid Tumors ...........................................................32 
Table 6: 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in 
Pooled Monotherapy Studies of Solid Tumors (in ≥ 2 patients) ................................33 
Table 7: 
Selection and Timing of Dose for Each Patient ..........................................................51 
Table 8: 
Dose Reduction Level of Chemotherapy ....................................................................56 
Table 9: 
Guidance for Duration of Recording New or Worsening Adverse Events ................74 
Table 10: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................75 
Table 11: Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) .........................................................................................................79 
Table 12: Examples of Immune-mediated Adverse Events ........................................................81 
Table 13: Estimates of 95% CI Using Clopper-Pearson After Enrollment of 23 
Evaluable Patients in Cohort A ...................................................................................86 
Table 14: Estimates of 95% CI Using Clopper-Pearson After Enrollment of 35 
Evaluable Patients in Cohort B ...................................................................................87 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................41 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene (Shanghai) Co., Ltd. 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Phase 2, Multicenter, Open-Label, 2-Cohort Study to Investigate the 
Efficacy and Safety of PET Guided Neoadjuvant Treatment with Tislelizumab (BGB-A317) 
Plus Chemotherapy/Chemoradiotherapy in Patients With Resectable Esophageal Squamous 
Cell Carcinoma 
Protocol Identifier: BGB-A317-213 
Phase of Development: 2 
Number of Patients: Approximately 65 
Study Centers: Approximately 5 centers (China) 
Study Objectives: 
Primary: 
• To evaluate the pathological complete response (pCR) in patients receiving 
tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
Secondary: 
• To evaluate the disease-free survival (DFS) of neoadjuvant treatment with tislelizumab 
plus chemotherapy/chemoradiotherapy after R0 resection. 
• To evaluate the event-free survival (EFS) of neoadjuvant treatment with tislelizumab 
plus chemotherapy/chemoradiotherapy. 
• To evaluate the R0 resection rate in patients receiving tislelizumab plus 
chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
• To evaluate the objective response rate (ORR) of neoadjuvant treatment with 
tislelizumab plus chemotherapy/chemoradiotherapy before surgery as assessed by the 
investigator. 
• To evaluate the safety of tislelizumab combined with 
chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
Exploratory: 
• To evaluate overall survival (OS) of neoadjuvant treatment with tislelizumab plus 
chemotherapy/chemoradiotherapy. 
• To evaluate the potential association of biomarkers with clinical efficacy in patients 
receiving tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant 
treatment. 
• To evaluate the major pathological response (MPR) rate in patients receiving 
tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
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Study Endpoints: 
Primary: 
• pCR rate - defined as the proportion of patients with absence of residual tumor in the 
resected primary tumor and all resected lymph nodes after completion of neoadjuvant 
treatment in the Efficacy Evaluable (EE) Analysis Set.  
Secondary: 
• 1-year/3-year DFS rate - defined as the proportion of patients free from disease events 
at the 1st year and 3rd year after the first date of no disease (R0 resection as surgery 
outcome) in an EE analysis set. DFS is defined as the time from the first date of no 
disease to local or distant recurrence or death due to any cause, whichever occurs first. 
DFS rate will be analyzed only for patients who undergo R0 resection. 
• 1-year/3-year EFS rate - defined as the proportion of patients free from EFS events at 
1st year and 3rd year after the first dose in the Safety Analysis Set. EFS is defined as 
time from first dose date to any of the following events whichever occurs first: 
progression of disease that precludes definitive surgery, local or distant recurrence, or 
death due to any cause. 
• R0 resection rate - defined as the proportion of patients with R0 resection in an EE 
analysis set. 
• ORR - defined as the proportion of patients with measurable disease at baseline who 
have a complete response or partial response before surgery as assessed by the 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the 
Safety Analysis Set. 
• The incidence and severity of treatment-emergent adverse events (TEAEs) are 
determined according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE v5.0). 
Exploratory: 
• 1-year/3-year OS rate – defined as the proportion of patients alive at 1st year and 3rd 
year after first dose in the Safety Analysis Set. 
• To evaluate the potential association of biomarkers (including PD-L1 expression and 
gene expression profile) with clinical efficacy (including but not limited to pCR, DFS, 
EFS, R0 resection, ORR, OS and MPR). 
• MPR rate - defined as the proportion of patients with ≤ 10% residual viable tumor in 
the resected primary tumor and all resected lymph nodes after completion of 
neoadjuvant therapy in an EE analysis set. 
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Study Design: 
This is a Phase 2, multicenter, open-label, 2-cohort study to investigate the efficacy and safety 
of Positron Emission Tomography (PET)-guided neoadjuvant treatment with tislelizumab plus 
chemotherapy/chemoradiotherapy in resectable esophageal squamous cell carcinoma (ESCC). 
Evaluation with positron emission tomography-computed tomography (PET-CT) will be 
performed 2 times.  
 
The first time: After informed consent form is signed. 
 
The second time: 15 to 21 days after the last dose of induction therapy. 
The study consists of a screening phase, treatment phase (includes induction phase, 
neoadjuvant phase, and surgery phase), safety follow-up phase, and disease/survival follow-up 
phase. 
Induction Therapy (One 21-day Cycle): 
 
Chemotherapy doublet (cisplatin and paclitaxel) (1 cycle). 
Neoadjuvant Phase (Three 21-day Cycles): 
Patients will be grouped into 2 cohorts based on the change of PET Standardized Uptake 
Value (SUV)max. 
o Cohort A (responder: decrease in PET SUVmax ≥ 35%):  
 
Tislelizumab 3 cycles + chemotherapy doublet (Cisplatin + Paclitaxel) 2 cycles 
o Cohort B (non-responder: decrease in PET SUVmax < 35%): 
 
Tislelizumab 3 cycles + investigator-chosen chemotherapy doublet (Paclitaxel + 
Cisplatin/5-Fu + Cisplatin) 2 cycles + concurrent radiotherapy (40 Gy/20 F). 
Surgery: 
Upon completion of neoadjuvant therapy, patients will undergo surgical resection of tumor 
after reassessment to reconfirm disease resectability. Surgical specimens will be assessed for 
pathological response (pCR and MPR). 
The surgical procedure should be performed within 4-6 weeks from the last administered dose 
of chemotherapy treatment (the last dose of chemoradiotherapy in Cohort B). 
The study schema is presented as below with estimates of patients in each cohort: 
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Abbreviations: A317: Tislelizumab; PET-CT, Positron Emission Tomography-Computed 
Tomography; Chemo, Chemotherapy; RT, Radiotherapy; 5-Fu, 5-fluorouracil; ESCC, 
esophageal squamous cell carcinoma; ECOG, Eastern Cooperative Oncology Group; N, 
number of patients; Q3W, once every 3 weeks. 
Study Assessments: 
Patients will undergo surgical resection of tumor and surgical specimens will be assessed for 
pathological response (pCR and MPR). 
PET-CT will be performed at screening and 15-21 days after the last dose of induction, for 
evaluating SUVmax and to determine the subsequent treatment cohort. Before surgery, the 
investigator will reassess the patient to reconfirm disease resectability. The presurgical visit 
and associated assessments should occur within 7 days prior to surgery and in accordance with 
local institutional practice. After surgery, disease follow-up tumor assessment will be 
performed by neck, chest, and abdominal CT every 3 months for the first 2 years, every 6 
months for Year 3 based on RECIST v1.1. Tumor assessments should continue per protocol 
until disease recurrence/progression, withdrawal of consent, death, loss to follow-up, or study 
termination by the sponsor, whichever occurs first. 
All patients will be assessed for safety and tolerability on Day 1 of each cycle in the induction 
and neoadjuvant phases. Adverse events (AEs) will be evaluated according to NCI-CTCAE 
v5.0. After initiation of study drug(s), all AEs (serious or nonserious), regardless of 
relationship to study treatment will be reported until 30 days after the last study treatment 
(including chemotherapy, radiotherapy, tislelizumab and surgery). Immune- mediated AEs 
(imAE)(serious or nonserious) should be reported until 90 days after the last dose of  
tislelizumab, regardless of whether the patient starts a new anticancer therapy.  
After the safety follow-up visit, survival follow-up will be periodically performed for survival 
status and any additional anticancer treatment every 3 months (± 14 days) via in-person or 
phone contact. 
Duration of Patient Participation: 
Duration of study participation will vary by patient, depending on the duration of treatment 
and treatment outcomes. The duration from first dose to surgery is approximately 71-86 days. 
The duration of the study from first enrolled patient to final analysis for pathological response 
is approximately 18 months. 
Study Population: Approximately 65 patients who have histologically confirmed ESCC at 
Stage cT1-2N+M0 and cT3NanyM0 (AJCC 8th Edition, Rice et al 2017). 
Key Eligibility Criteria: 
Key Inclusion Criteria: 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
• 
Histologically confirmed ESCC  
• 
Stage cT1-2N+M0 and cT3NanyM0 (per AJCC 8th Edition) 
• 
Evaluation by the investigator to confirm eligibility for an R0 resection with curative intent 
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• 
Adequate hematologic and organ function, defined by protocol-specified laboratory test 
results obtained within 14 days before first dose 
Key Exclusion Criteria: 
• 
Ineligible for treatment with any of the chemotherapy doublets of protocol-specified 
chemotherapy 
• 
Any prior therapy for current ESCC, including investigational agents, chemotherapy, 
radiotherapy, targeted therapy, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or 
any other antibody or drug specifically targeting T-Cell co-stimulation or checkpoint pathways 
• 
History of fistula due to primary tumor invasion 
• 
Patients with high risk of fistula or sign of perforation evaluated by investigator 
• 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalent) or other immunosuppressive medications within 14 days before first 
dose 
o 
Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) and 
topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption, and short course (≤ 7 days) of corticosteroid prescribed 
prophylactically or for the treatment of a non-autoimmune condition are 
permitted. 
• 
Active autoimmune diseases or history of autoimmune diseases that may relapse 
o 
Controlled Type I diabetes, hypothyroidism only requiring hormone replacement, 
controlled celiac disease, skin diseases (such as vitiligo, psoriasis, or alopecia) 
not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll. 
• 
History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases 
including pulmonary fibrosis, acute lung diseases, etc. 
• 
With infections requiring systemic antibacterial, antifungal, or antiviral therapy, including 
tuberculosis infection, etc. 
o 
Severe infections within 4 weeks before first dose, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
o 
Receive therapeutic oral or intravenous (IV) antibiotics within 2 weeks before 
first dose. 
Investigational Product, Dose, and Mode of Administration: 
Tislelizumab will be administered at a dose of 200 mg intravenously on Day 1 of every 21-day 
cycle, cumulative 3 cycles. Tislelizumab will be given in combination with the chemotherapy 
doublet or concurrent chemoradiotherapy after induction therapy, and as a monotherapy for 
Cycle 4 (1 to 3 weeks before surgery). 
Reference Therapy, Dose, and Mode of Administration: 
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•  Cisplatin + paclitaxel:  
o Cisplatin 80 mg/m2 IV on Day 1 Q3W 
o Paclitaxel 135 mg/m2 IV on Day 1 Q3W 
▪ Depending on local guidelines, cisplatin may be given in 3 divided doses 
on Days 1, 2, and 3. The total dose given must be 80 mg/m2 per cycle. 
• Cisplatin + 5-FU (PET-Non-responder Cohort, by the investigator’s choice, 
chemotherapy regimen could be changed to Cisplatin + 5-FU):  
o Cisplatin 80 mg/m2 IV on Day 1, Q3W 
o 5-FU 1000 mg/m2 IV on Days 1-4, Q3W 
• 
Radiotherapy: A total dose of 40 Gy in 20 fractions (2 Gy/fraction and 5 fractions/week)  
Statistical Methods: 
This study is designed to evaluate the safety and efficacy of neoadjuvant treatment with 
Tislelizumab (BGB-A317, an anti-PD-1 antibody) plus chemotherapy/chemoradiotherapy in 
resectable ESCC. Details of statistical analyses will be described in Statistical Analysis Plan. 
Analysis Sets: 
• The Efficacy Evaluable (EE) Analysis Set includes all patients who receive 
neoadjuvant treatment followed by surgery. This will be the primary analysis set 
for the efficacy analyses. 
• The Safety Analysis Set includes all enrolled patients who receive ≥ 1 dose of any 
component of study drugs; it will be the primary analysis set for the safety 
analyses. Patients will be analyzed according to the actual treatment regimen 
received. 
 
Efficacy Analysis: 
The efficacy endpoints pCR, 1-year/3-year DFS rate, 1-year/3-year EFS rate, R0 resection 
rate, ORR, 1-year/3-year OS rate and MPR will be summarized to evaluate the efficacy of 
neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in resectable 
Esophageal Squamous Cell Carcinoma. 
Descriptive statistics will be used to summarize the efficacy analysis in Cohorts A and B. The 
95% confidence interval (CI) will be calculated for pCR, 1-year/3-year DFS rate, 1-year/3-
year EFS rate, R0 resection rate, ORR, 1-year/3-year OS rate and MPR.  
Primary Efficacy Endpoint Analyses: 
pCR rate is the primary endpoint of the study.  
The pCR rate in cohort A (Responder: decrease in PET SUVmax ≥ 35%) and the pCR rate in 
Cohort B (Non-Responder: decrease in PET SUVmax < 35%) will be summarized. Clopper-
Pearson 95% confidence interval (CI) of pCR rate in cohort A and B will be calculated. 
These analyses will be performed in the EE analysis set as the primary analysis. The analysis 
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of pCR rate will occur after all the patients in the EE analysis set have been assessed for 
pathological response. 
Secondary Efficacy Endpoint Analyses: 
DFS rate will be estimated by Kaplan-Meier method with 95% CIs estimated using the 
Greenwood's formula for patients who undergo R0 resection in cohorts A and B in the EE 
analysis set.  
1-year/3-year Event-Free Survival (EFS) rate will be estimated in cohorts A and B by Kaplan-
Meier method with 95% CIs estimated using the Greenwood's formula for patients in the 
Safety Analysis Set. 
R0 resection rate defined as the proportion of patients with R0 resection will be summarized in 
cohorts A and B in the EE analysis set. 
Objective response rate (ORR) is the proportion of patients who have a complete response or 
partial response before surgery as assessed by the investigator per RECIST v1.1 in all patients 
with measurable disease at baseline in the Safety Analysis Set. ORR will be summarized in 
cohorts A and B. 
Safety Analyses: 
All AEs graded by NCI-CTCAE v5.0, 2018 and verbatim AE terms will be mapped to the 
corresponding Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms. All 
TEAEs will be summarized. A TEAE is defined as an AE that has an onset date or a 
worsening in severity from baseline (pre-treatment) on or after the first dose of study treatment 
and up to 30 days following study treatment discontinuation or initiation of new anti-cancer 
therapy, whichever occurs first. Immune-mediated AEs will be identified from all adverse 
events that have an onset date or a worsening in severity from baseline (pretreatment) on or 
after the first dose of tislelizumab and up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new anticancer therapy.  If an imAE occurs outside of 
the above-mentioned treatment-emergent adverse event window, it will not be classified as a 
treatment-emergent adverse event. All imAEs will be reported separately. TEAEs of ≥ Grade 
3; treatment-related TEAEs, serious TEAEs, deaths, TEAEs that lead to treatment 
discontinuation and TEAEs that lead to treatment modification will be summarized. 
 
Sample Size Considerations: 
Approximately 65 patients are expected to be enrolled in this study, considering approximately 
10% of patients not receiving surgery. It is assumed that 25 patients will be categorized into 
cohort A and 40 patients will be categorized into cohort B according to their PET SUVmax 
decrease. The actual number of patients in each cohort will be based on the actual ratio of 
responders and non-responders observed in the study and may vary from this assumption. 
The pCR rate of responders was reported about 21.9% - 31.8% in historical studies 
(Buschenfelde et al 2011; Ilson et al 2012; Greally et al 2018). The pCR rate in cohort A is assumed 
to be 37%. If there are 23 evaluable patients in cohort A, it will provide the probability of 
66.2% to observe 8 pCRs out of 23 evaluable patients with an estimated pCR rate of 34.7% for 
cohort A, which is greater than the historical pCR rate.  
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The pCR rate of non-responders was reported about 4% - 13.6% in historical studies 
(Buschenfelde et al 2011; Ilson et al 2012; Greally et al 2018). The pCR rate in cohort B is assumed 
to be 22%. If there are 35 evaluable patients in cohort B, it will provide a probability of 91.0% 
to observe 5 pCR out of 35 evaluable patients with an estimated pCR rate of 14.3%, which is 
greater than the historical pCR rate in cohort B.  
 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody dependent cellular phagocytosis 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-A317 
Tislelizumab 
cCRT 
concurrent chemoradiotherapy 
CL 
clearance 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DFS 
disease-free survival 
DOR 
duration of response 
EC 
esophageal carcinoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
Efficacy Evaluable  
ESCC 
esophageal squamous cell carcinoma 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EFS 
event-free survival 
FcγR 
fragment crystallizable region (typically, of immunoglobulin G) 
FDG 
Fluorodeoxyglucose 
GEJ 
gastroesophageal junction 
HBV 
hepatitis B virus 
HCC 
hepatocellular cancer 
HCV 
hepatitis C virus 
IB 
investigator’s brochure  
ICC 
investigator chosen chemotherapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
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IV 
intravenous 
Ig 
immunoglobulin  
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion related reaction 
MedDRA 
Medical Dictionary for Regulatory Activities  
MPR 
major pathological response 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
pCR 
pathological complete response 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PD-L2 
programmed cell death protein ligand-2 
PET-CT 
positron emission tomography-computed tomography 
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-related adverse event 
ULN 
upper limit of normal 
Vc 
central volume  
 
 
 
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1. 
INTRODUCTION  
1.1. 
Background Information on Esophageal Carcinoma  
Esophageal cancer is the seventh most common cancer worldwide (572,000 new cases) and the 
sixth most common cause of death (509,000 deaths) from cancer (Bray et al 2018). The 
incidence, prevalence, and histologic type of esophageal cancer vary between geographic regions 
(Arnold et al 2015), approximately 75% of all cases occur in Asia with China bearing the largest 
burden, accounting for about 50% of total cases and cancer-specific deaths. In China, esophageal 
cancer is the third most common cancer and the fourth leading cause of death from cancer, based 
on an estimation of 477,900 new esophagus cancer cases and 375,000 deaths from this disease 
expected in 2015 (Chen et al 2016).  
Two most common histologic subtypes (esophageal squamous cell carcinoma [ESCC] and 
adenocarcinoma have quite different etiologies. Heavy drinking and smoking and their 
synergistic effects are the major risk factors for SCC in Western settings (Blot et al 2017). 
However, in low-income countries, such as in parts of Asia and Sub-Saharan Africa, the major 
risk factors for ESCC (which usually comprises over 90% of all esophageal cancer cases) have 
yet to be elucidated.  
In the early and locally advanced stages, esophagectomy is recognized as the curative treatment. 
However, for patients with locally advanced ESCC, neo-adjuvant therapy followed by surgery 
showed a better clinical benefit compared with surgery only (Joel et al 2015). But prognostic for 
locally advanced ESCC is still poor, from 2009 to 2015, the overall 5-year relative survival rate 
for esophageal cancer (EC) was 21.4%, and the corresponding 5-year relative survival rates were 
46.7% for localized cancer, 25.1% for regional metastasis, 4.8% for distant metastasis (Noone et 
al 2017). Poor prognostic factors for survival in patients with ESCC include advanced stage of 
disease at the initial diagnosis, poor performance status, and malnutrition with unintentional 
weight loss, etc. 
1.2. 
Current Treatment of Resectable Esophageal Carcinoma and Unmet 
Clinical Needs  
For patients with early stage of ESCC (pTis, T1a, T1b, N0), resection is a recommended 
modality, which includes endoscopic therapies and esophagectomy; for patients with locally 
advanced ESCC, preoperative chemoradiation followed by esophagectomy is recommended by 
international treatment guidelines ((NCCN) Guidelines Version 4, 2020). Postoperative 
chemotherapy or chemoradiation is commonly given to patients who have positive lymph nodes 
after R0 resection, or to those with microscopic or macroscopic residual cancer (R1 and R2 
resection, respectively) after surgery. 
The status of preoperative concurrent chemoradiotherapy as standard of care for ESCC is based 
on the CROSS study (van et al 2008), which demonstrated overall survival benefit with 
neoadjuvant concurrent chemoradiotherapy followed by surgery compared with surgery alone. 
Long-term results of the CROSS study (Joel et al 2015) showed that, median overall survival has 
been prolonged from 24.0 months to 48.6 months; and for patients with ESCC, median overall 
survival has been prolonged from 21.1 months to 81.6 months. Another study, NEOCRTEC5010 
(Hong et al 2018)  showed a similar trend, median overall survival was 100.1 months in neo-
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adjuvant concurrent chemoradiotherapy (cCRT) followed by surgery group versus 66.5 months 
in surgery alone group.  
In the preoperative setting for locally advanced esophageal cancer, preoperative chemotherapy 
also shows survival benefits compared with surgery alone. In the Medical Research Council 
OEO2 Trial (Allum et al 2009), median survival was 16.8 months in the preoperative 
chemotherapy group compared with 13.3 months in the surgery alone group, and the 2-year 
survival rates were 43% and 34%, respectively; Long-term follow-up confirmed the survival 
benefit of preoperative chemotherapy, with a 23% 5-year survival rate in the preoperative 
chemotherapy group compared with 17.1% in the surgery alone group. Although the benefit for 
neoadjuvant chemotherapy was not as great as for neoadjuvant chemoradiotherapy, a clear 
advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been 
established and further trials are warranted. (Shown in Table 2). In previous studies, although no 
difference has been demonstrated between the treatment groups in the frequency of postoperative 
complications, complications were significantly more severe in the (neoadjuvant 
chemoradiotherapy )nCRT arm, for example, increased the numbers of postoperative deaths 
(Klevebro et al 2016; Stahl et al 2017). 
However, in clinical practice, because of safety concerns on adding radiotherapy to neo-adjuvant 
therapy and difficulties in collaborations cross clinical departments, patients with locally 
advanced ESCC who received preoperative chemotherapy rather than preoperative 
chemoradiotherapy may not receive the full benefit of neoadjuvant treatment.  Other checkpoint 
inhibitors have data to suggest that adding immune-therapy and radiation to neoadjuvant 
chemotherapy can improve clinical outcomes.  
Positron Emission Tomography-Computed Tomography (PET-CT) showed positive predictive 
data in PET-guided Studies (Buschenfelde et al 2011; Greally et al 2018’ Ilson 2012) (shown in 
Table 3). After induction therapy, patients were divided into PET responders (SUVmax ≥ 35%) 
and non-responders (SUVmax < 35%), pCR rates of 21.9-31.8% and 4-13.6% were observed in 
responders and non-responders who underwent surgery, respectively. Regarding the OS and PFS, 
PET-CT responders showed a median PFS of 24.7-70 months and a median OS of 40.2-85 
months, while non responders showed a poorer prognosis with a median PFS of 7-7.7 months 
and a median OS of 17-25.5 months. Therefore, improving the survival benefit for the population 
of PET-CT non-responders is also an unmet medical need. 
Table 1: 
Outcomes of Neoadjuvant CRT Followed by Surgery for EC  
Reference Population 
Phase 
Sample 
Size 
treatment 
Pathological 
Complete 
Response 
Rate 
DFS 
(median 
months) 
OS 
(median 
months) 
Van et al, 
2008  
II – III 
(EC) 
3 
366 
41.4Gy/23F 
CBP (AUC=2) 
+PTX 
50mg/m2  
weekly * 5w 
EC:29% 
ESCC: 49% 
EC: 
37.7 
ESCC: 
74.7 
EC: 
49.4 
ESCC: 
81.6 
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Reference Population 
Phase 
Sample 
Size 
treatment 
Pathological 
Complete 
Response 
Rate 
DFS 
(median 
months) 
OS 
(median 
months) 
Lv et al, 
2010 
I- III 
（ESCC） 
NA 
238 
40Gy/20F 
DDP 20mg/m2 
d1-3+PTX 
135mg/m2 
2 cycles 
NA 
46.5 
53 
Christophe 
et al, 2014 
I- II (EC) 
3 
195 
45Gy/25F 
DDP 
75mg/m2+5FU 
800mg/m2  
2 cycles 
NA 
27.8 
31.8 
Yang et al, 
2018  
II – III 
(ESCC) 
3 
451 
40Gy/20F 
Vinorelbine 
25mg/m2 d1,8 
+ DDP 
75mg/m2 
 2 cycles 
43.2% 
100.1 
100.1 
Table 2: 
Outcomes of Neoadjuvant Chemotherapy Followed by Surgery for EC  
Reference Population Phase Sample 
Size 
treatment 
Pathological 
Complete 
Response 
Rate 
DFS 
(median 
months) 
OS 
(median 
months) 
David et 
al, 2007 
I- III 
(EC) 
NA 
227 
Cisplatin and 
fluorouracil 
NA 
27.8 
31.8 
Jurjen et 
al, 2011  
I – III 
(ESCC) 
NA 
195 
Cisplatin 80 
mg/m2 (d1), +  
Etoposide（d1-
2） 100 mg/m2 + 
etoposide 200 
mg/m2 (d3,5) , 
2-4 cycles 
7% 
NA 
16 
Klevebro 
et al, 2010 
I- III 
(EC) 
2 
181 
Cisplatin, 100 
mg/m2 d1, and 
fluorouracil 750 
mg/m2/24 h, d 1–
5, Q3w,  
3 cycles 
9% 
3 yr 
DFS 
Rate: 
44% 
3 yr OS 
Rate: 
49%  
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Reference Population Phase Sample 
Size 
treatment 
Pathological 
Complete 
Response 
Rate 
DFS 
(median 
months) 
OS 
(median 
months) 
Girling et 
al, 2002 
Resectable 
(EC) 
3 
802 
Cisplatin, 80 
mg/m2 d1, and 
fluorouracil 1000 
mg/m2/24 h, d 1–
4, 
Q3w,  
2 cycles 
NA 
NA 
16.8 
Table 3: 
Outcomes of Neoadjuvant CRT Followed by Surgery for EC Guided by PET 
After Induction Therapy  
Referen
ce 
Populatio
n 
Phase 
Sample 
Size 
Pathological 
Complete 
Response Rate 
PFS 
(median 
months) 
OS 
(median months) 
Greally 
et al, 
2018 
locally 
advanced 
(ESCC) 
2 
111 
 R：31.8% 
 NR：11.1% 
 R：70  
 NR：7 
 R：85 
NR：17  
Ilson et 
al, 2012 
I – III  
(EC) 
2 
55 
 R：32% 
NR：4% 
R：24.1  
 NR：7.7  
R：40.2  
NR：25.5  
Goodma
n et al, 
2010 
Resectabl
e 
(EAC/EG
J AC) 
2 
181 
R：21.9% 
NR：13.6% 
NA 
R：2y OS 71% 
 NR：2y OS 42% 
Abbreviations: R: PET Responder; NR: PET Non-responder; EC: esophageal carcinoma; EAC: esophageal 
adenocarcinoma; EGJAC: Esophagogastric junction carcinoma; PTX: paclitaxel; DDP: cisplatin; CBP: 
carboplatin; 5-FU: 5- fluorouracil. 
1.3. 
Anti-PD-1 Therapy for Esophageal Squamous Cell Carcinoma  
Clinical outcome data are available from early phase to late phase studies, from disease setting of 
metastases to locally advanced stage studies, to evaluate tislelizumab, nivolumab, and 
pembrolizumab in patients with advanced esophageal carcinoma. All data described below are 
supportive of the safety and antitumor activity of antiprogrammed cell death protein-1 (PD-1) 
monoclonal antibodies in esophageal carcinoma. 
1.3.1. 
 Tislelizumab  
BGB-A317-205 (NCT03469557) (Xu et al 2020) is an open label Phase 2 study. As of 31 March 
2019, 30 Chinese patients (Gastric/ gastroesophageal junction [GEJ], n =15; ESCC, n=15) were 
enrolled in the study BGB-A317-205. In the ESCC cohort, the median age of enrolled patients 
was 61 years (range: 47 to 68 years). Patients did not receive prior systemic therapy for advanced 
or metastatic disease. All patients experienced at least 1 treatment-emergent adverse event 
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(TEAE). Anemia (n=11) decreased appetite (n=11), nausea (9), and leukopenia (n=8) were the 
most common treatment-related AEs. Five patients experienced Grade 3 to 4 TEAE, in which the 
most common was vomiting (n=4). Fatal AE (hepatic dysfunction) was reported in 1 patient, 
mainly attributed to progressive disease, which may possibly be related to study treatment or 
confounded by underlying HBV infection. Efficacy data shows that the confirmed ORR is 46.7% 
(95% CI: 21.27, 73.4), disease control rate (DCR) is 80% (95% CI: 51.91, 95.67), duration of 
response (DOR) is 12.8 months (95% CI: 3.5, 12.8), and median OS is 14.31 months (95% CI: 
6.01-NA). 
BGB-A317-302 (NCT03430843) (Lin Shen et al 2022) is a global Phase 3 study comparing the 
efficacy of tislelizumab versus chemotherapy as second-line treatment in patients with advanced 
unresectable/metastatic ESCC. Overall, 512 patients (median age: 62 years; range 35-86 years) 
were randomized to receive either tislelizumab (n=256) or investigator chosen chemotherapy 
(ICC) (n=256). As of Dec 2020 (data cutoff), the study met its primary endpoint at its final 
analysis: tislelizumab clinically and significantly improved OS vs ICC in the ITT population 
(median OS: 8.6 vs 6.3 m; HR 0.70, 95% CI 0.57-0.85, p=0.0001). Survival benefit was 
consistently observed across pre-defined subgroups, including baseline PD-L1 status and region. 
Treatment with tislelizumab was also associated with a higher ORR (20.3% vs 9.8%) and more 
durable response (median DOR: 7.1 vs 4.0 m; HR 0.42, 95% CI 0.23-0.75) than ICC in the ITT 
population. The safety profile of tislelizumab was more favorable than ICC. Fewer patients had 
≥ Grade 3 (46% vs 68%) treatment-emergent adverse events with tislelizumab compared with 
ICC.  
BGB-A317-306 (NCT03783442) is a global Phase 3, randomized, placebo-controlled, double-
blind study of tislelizumab in combination with chemotherapy as first-line treatment versus 
chemotherapy alone in patients with unresectable, locally advanced recurrent or metastatic 
ESCC. Approximately 649 study participants were randomized 1:1 to receive either tislelizumab 
plus chemotherapy or chemotherapy alone. Tislelizumab plus chemotherapy demonstrated a 
median OS of 17.2 months (CI, 15.8-20.1 months) versus 10.6 months (CI, 9.3-12.1 months) in 
patients receiving chemotherapy plus placebo and reduced the risk of death by 34% (hazard 
ratio=0.66; CI, 0.54-0.80, p<0.0001). Survival benefit was consistent across all other subgroups, 
including race, geographical region and investigator choice of chemotherapy. Tislelizumab plus 
chemotherapy also significantly improved progression-free survival (7.3 months vs 5.6 months; 
HR=0.62; CI, 0.52-0.75, p<0.0001) and objective response rate (63.5% vs 42.4%; odds 
ratio=2.38, p<0.0001). The incidence of treatment-related adverse events (TRAEs) was similar in 
both arms. The most common TRAEs for tislelizumab plus chemotherapy versus chemotherapy 
were anemia (68% vs 61%), decreased neutrophils (78% vs 80%), decreased white blood cell 
count (55% vs 65%), decreased appetite (39% vs 38%), nausea (37% vs 42%) and peripheral 
sensory neuropathy (26% vs 21%). Tislelizumab plus chemotherapy had a manageable safety 
profile in patients with advanced ESCC, with no new safety signal identified. 
1.3.2. 
Pembrolizumab  
KEYNOTE-181 (NCT 02564263), a Phase 3, open-label randomized study (Kojima et al 2019), 
recruited 628 patients with metastatic esophageal cancer and ≥ 2 prior lines of therapy. In the 
Pembrolizumab group, 63.1% of patients had ESCC, who received pembrolizumab 200 mg once 
every 3 weeks for up to 35 cycles, in control group, patients received investigator choose 
chemotherapy from paclitaxel 80-100 mg/m2 on days 1, 8, 15 Q4W, Docetaxel 75 mg/m2 Q3W, 
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or irinotecan 180 mg/m2 Q2W. As of 15 October 2018, in Intent-to-Treat (ITT) population, 
median overall survival was 7.1 months in both groups, in ESCC population, median overall 
survival in Pembrolizumab group was 8.2 months versus 7.1 months in control group, but P-
value didn’t meet statistical significance, and in PD-L1 CPS ≥10 population, median overall 
survival increased statistical significantly, which was 9.3 months in Pembrolizumab group versus 
6.7 months in control group. In Pembrolizumab group, 202 (64.3%) experienced at least 1 
treatment-related AE, 57 (18.2%) patients experienced Grade 3-5 treatment-related AE, and 18 
(6.1%) lead to discontinuation, and 5 (1.5%) lead to death. Treatment-related AE ≥ 20% includes 
fatigue (22.3%), decreased appetite (24.8). Immune-mediated AEs and infusion reactions is 73 
(23.2%). 
KEYNOTE-590 (NCT 03189719), a phase 3, double-blinded randomized study (Kato 2020), 
recruited 749 patients with metastatic esophageal cancer with treatment naive; randomized 
patients received pembrolizumab or placebo plus chemotherapy. In Pembrolizumab plus 
chemotherapy group, 73.5% of patients had ESCC, who received pembrolizumab 200 mg once 
every 3 weeks for up to 35 cycles, 5-FU 800 mg/m2 for Days 1-5 every 3 weeks for ≤ 35 cycles, 
and Cisplatin 80 mg/m2 every 3 weeks for ≤ 6 cycles. As of 2 July 2020, in each predefined 
population, statistically significant overall survival benefit was observed. In Intent to Treat (ITT) 
population, the median overall survival was 12.4 months in the Pembrolizumab plus 
chemotherapy group versus 9.8 months in the placebo plus chemotherapy group; in the PD-L1 
CPS ≥ 10 population, the median overall survival was 13.5 months versus 9.4 months; in the 
ESCC population, the median overall survival was 12.6 months versus 9.8 months; and in ESCC 
PD-L1 CPS ≥ 10 population, the median overall survival was 13.9 months versus 8.8 months. In 
the Pembrolizumab plus chemotherapy group, all patients experienced at least 1 treatment-
related AE, 71.9% patients experienced Grade 3-5 treatment-related AE, 19.5% AEs lead to 
discontinuation, and 2.4% patients lead to death. Immune-mediated AEs and infusion reactions 
were 25.7%, in which ≥ Grade 3 was 7.0%. 
NCT 02844075, a phase 2 trial preoperative chemoradiotherapy and Pembrolizumab (Lee et al 
2019), recruited 28 patients with resectable locally advanced ESCC. Enrolled patients  received 
chemoradiotherapy in combination with pembrolizumab followed by surgery. The median age of 
enrolled patients was 60 years (range: 46 to 76 years). As of February 2019, 26 patients 
underwent esophagectomy. The pCR rate was 23.1% for ypT0N0 and 46.1% for ypT0, 6-month 
OS rate was 89.3%, 12-month OS rate was 82.1%, 6-month Event Free Survival (EFS) rate was 
85.3%, and 12-month EFS rate was 60.3%. The most common treatment-related AEs were 
neutropenia (50%), nausea (25%), esophagitis (21%), and leukopenia (21%); neutropenia was 
the only more than 10% treatment related AEs with Grade 3 -4 (18%); and no treatment 
discontinuation occurred due to AEs. 
1.3.3. 
Nivolumab  
Attraction 3 (NCT02569242), a Phase 3, open-label randomized study (Cho et al 2019), 
recruited 419 ESCC patients with refractory or intolerant to previous chemotherapy; patients 
were randomized to either nivolumab (240 mg for 30 minutes once every 2 weeks) or 
investigator’s choice of chemotherapy (paclitaxel 100 mg/m² for at least 60 minutes once a week 
for 6 weeks then 1 week off or docetaxel 75 mg/m² for at least 60 minutes once every 3 weeks). 
As of 12 November 2018, median follow-up for overall survival was 10.5 months (4.5–19.0) in 
the nivolumab group and 8.0 months (4.6–15.2) in the chemotherapy group. At a minimum 
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follow-up time of 17.6 months, overall survival was significantly improved in the nivolumab 
group compared with the chemotherapy group (median 10.9 months, 95% CI 9.2–13.3 versus 8.4 
months, 95% CI 7.2–9.9; hazard ratio for death 0.77, 95% CI 0.62–0.96; p = 0.019). Thirty-eight 
(18%) of 209 patients in the nivolumab group had Grade 3 or 4 treatment-related adverse events 
compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent Grade 3 
or 4 treatment-related adverse events were anemia (4 [2%]) in the nivolumab group and 
decreased neutrophil count (59 (28%)) in the chemotherapy group. Five deaths were deemed 
treatment-related: 2 in the nivolumab group (1 each of interstitial lung disease and pneumonitis) 
and 3 in the chemotherapy group. 
Checkmate 577 (NCT02743494) is a Phase 3, randomized, multi-center, double-blind study 
evaluating nivolumab as an adjuvant therapy in patients with resected esophageal or GEJ cancer 
who have received neoadjuvant CRT and have not achieved a pathological complete response. 
Adjuvant treatment with nivolumab demonstrated a statistically significant improvement in 
disease-free survival versus placebo (22.4 months vs 11.0 months; HR = 0.69; 96.4% CI: 0.56-
0.86; p=0.0003) in patients who received neoadjuvant CRT and had residual pathologic disease 
at a prespecified interim analysis. 
1.4. 
Background Information on Tislelizumab  
1.4.1. 
Pharmacology  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against programmed cell death protein-1 (PD-1) under clinical 
development for the treatment of several human malignancies. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD] = 0.15 nM).  It competitively blocks binding 
efforts by both programmed cell death protein ligand-1 (PD-L1) and programmed cell death 
protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T cells.  In in vitro 
cell-based assays, tislelizumab was observed to consistently and dose-dependently enhance the 
functional activity of human T cells and pre-activated, primary peripheral blood mononuclear 
cells.  Tislelizumab has demonstrated in vivo 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. 
Tislelizumab is an IgG4-variant antibody to gamma fragment crystallizable region (Fc) receptors 
(FcγR) such as FcγRI and FcγRIIIA, and it 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 phagocytosis 
(ADCP), or complement-dependent cytotoxicity effects in humans (Labrijn et al 2009; Zhang et 
al 2018).  Tislelizumab was specifically engineered to abrogate these potential mechanisms of T-
cell clearance and potential resistance to anti-PD-1 therapy. 
Please refer to the Tislelizumab  Investigator’s Brochure (IB) for additional details regarding 
nonclinical studies of tislelizumab. 
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1.4.2. 
Toxicology  
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys and in a 13-week, repeat-dose toxicology study in 
cynomolgus monkeys.  Tissue cross-reactivity was evaluated in normal frozen tissues from both 
humans and monkeys.  The cytokine release assays were conducted using fresh human whole 
blood cells.  The pivotal toxicology studies were conducted following Good Laboratory Practice  
regulations.  The single-dosing regimens spanned from the intended human doses to 10-fold 
higher than the maximum of the intended human doses, and the repeat-dosing regimens spanned 
to 3-fold higher than the maximum of the intended human doses.  Cynomolgus monkey was the 
only relevant species based on the target sequence homology and binding activity. 
Overall, no apparent toxicity was noted in mice or monkey toxicity studies.  No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in the human whole-blood assay.  The toxicokinetic profile was well 
characterized, with dose proportional increases in systemic exposure without apparent 
accumulation or sex difference.  Immunogenicity was observed without apparent 
immunotoxicity or effect on the systemic exposure.  The No Observed Adverse Effect Level of 
tislelizumab in the 13-week monkey toxicity study was considered to be 30 mg/kg.  The safety 
profile of tislelizumab is considered adequate to support the current study, BGB-A317-213. 
Please refer to the tislelizumab IB for more detailed information on the toxicology of 
tislelizumab. 
1.4.3. 
Clinical Pharmacology  
Population pharmacokinetic (PK) analysis was conducted using data from 798 patients with solid 
tumors or classical Hodgkin lymphoma who received doses of 0.5, 2.0, 5.0, and 10 mg/kg once 
every 2 weeks, 2.0 and 5.0 mg/kg once every 3 weeks, and 200 mg once every 3 weeks.  The PK 
of tislelizumab was best characterized using a 3-compartmental linear population PK model with 
linear clearance mechanisms.  No time-varying clearance was observed in tislelizumab PK.  The 
typical estimates of clearance (CL), central volume (Vc), and peripheral volumes (V2, V3), were 
0.164 L/day, 2.92 L, 0.928 L, and 1.39 L, respectively, with moderate inter-individual variability 
in CL (32.2%), Vc (16.7%), V2 (56.6%), and V3 (94.2%).  The volume of distribution at steady 
state was 5.238 L, which is typical of monoclonal antibodies with limited distribution, which is 
consistent with a standard IgG monoclonal antibody ((Deng R et al 2012) ; Dirks NLet al 2010; 
Keizer RJ et al 2020; Ryman JT et al 2017); .  Based on the population PK analysis, tislelizumab 
PK was characterized by a terminal half-life of approximately 25.5 days, which is consistent with 
other therapeutic IgG monoclonal antibodies. 
Population PK analysis demonstrated that baseline age, race, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin, lactate dehydrogenase, estimated glomerular 
filtration rate, ECOG Performance Status, immunogenicity, and sum of products of 
perpendicular diameters in classical Hodgkin lymphoma patients did not show statistically 
significant impact on the PK of tislelizumab.  Although tumor size, albumin, and tumor type 
were significant covariates on CL, while body weight, sex, and tumor type were significant 
covariates on Vc, these covariates are not expected to have a clinically relevant impact on 
tislelizumab exposure.  Exposure-response analysis indicated that there was a lack of clinically 
significant exposure-response relationships for ORR and safety endpoints across a variety of 
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advanced solid tumors and classical Hodgkin lymphoma for tislelizumab. Population PK analysis 
supports fixed dosing across different ethnic groups. 
1.4.4. 
Prior Clinical Experience of Tislelizumab  
As of 20 May 2021, there are 33 ongoing studies and 9 completed studies with over 
3498 patients (2150 patients treated with monotherapy and 1348 patients treated with 
combination therapy) treated with tislelizumab.  Of the 33 ongoing studies, 15 studies have 
preliminary data available in the IB Edition 9, 20 October 2021: 6 monotherapy studies, 
2 chemotherapy combination therapy studies, and 7 targeted therapy combination studies.  
Refer to the tislelizumab IB for more detailed information on tislelizumab safety and efficacy 
data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
A pooled analysis of 10 monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy.   
Overall, a total of 2150 patients were treated in the monotherapy studies included in the pooled 
safety analysis. Within the 7 solid tumor monotherapy studies, 1992 patients were treated. 
Within the 3 hematologic malignancy monotherapy studies, 158 patients were treated. 
The 7 solid tumor studies included the following: BGB-A317- 001 (Phase 1a /1b Advanced Solid 
Tumors), BGB-A317-102 (Phase 1 /2 Advanced Solid Tumors), BGB-A317-204 (Phase 2 
Locally Advanced or Metastatic Urothelial Bladder Cancer), BGB-A317-208 (Phase 2 Locally 
Advanced or Metastatic Urothelial Bladder Cancer), BGB-A317-209 (Phase 2 Previously 
Treated Locally Advanced Unresectable or Metastatic Microsatellite Instability-High (MSI-H) or 
Mismatch Repair Deficient (dMMR) Solid Tumors), BGB-A317-302 (Phase 3 Advanced 
Unresectable/Metastatic ESCC), and BGB-A317-303 (Phase 3 Non−Small Cell Lung Cancer Who 
Have Progressed on a Prior Platinum-Containing Regimen).  The 3 studies in hematologic 
malignancies are BGB-A317-203 (Phase 2 Relapsed or Refractory Classical Hodgkin Lymphoma), 
BGB-A317-207 (Phase 2 Relapsed or Refractory Mature T- and NK-cell Neoplasms) and 
BGB-A317-210 (Phase 2 Relapsed or Refractory Classical Hodgkin Lymphoma). 
Refer to the tislelizumab IB for more detailed information on tislelizumab safety data when 
given as monotherapy. 
1.4.4.1.1. Pooled Demographics and Baseline Characteristics  
Table 4 shows the demographics and baseline characteristics for the patients treated in the pooled 
monotherapy studies of solid tumors. 
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Table 4: 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies of Solid Tumors 
Measure 
Overalla   
N = 1992 
Age (years) 
 
   Median 
60.0 
   Min, Max 
18, 90 
Sex, n (%) 
 
   Male 
1437 (72.1) 
   Female 
555 (27.9) 
Race, n (%) 
 
   Asian 
1383 (69.4) 
   White 
532 (26.7) 
   Missing 
22 (1.1) 
   Other 
55 (2.8) 
Prior systemic anti-cancer therapy regimensb   
 
   Median 
1.0 
   Min, Max 
0, 12 
Prior systemic anti-cancer therapy regimens (grouped)b, n (%) 
   0 
318 (16.0) 
   1 
1055 (53.0)  
   2 
393 (19.7) 
   ≥3 
226 (11.3) 
Study treatment exposure duration (months) 
 
   Median 
4.070 
   Min, Max 
0.10, 41.46 
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Measure 
Overalla   
N = 1992 
Study follow-up duration (months) 
 
   Median 
 11.530 
   Min, Max 
0.07, 58.91 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: N, total number of patients treated; n, number of patients within each category. 
Data cut-off 20 May 2021. 
a Solid Tumor Studies include: A317-BGB-A317-001, BGB-A317-102, BGB-A317-204, BGB-
A317-208, BGB-A317-209, BGB-A317-302, and BGB-A317-303 and Hematology Studies 
include: BGB-A317-203, BGB-A317-207, and BGB-A317-210 
b Only systemic therapies were selected. 
The patients in the solid tumor group of pooled monotherapy studies had a median treatment 
exposure duration of 4.07 months (range: 0.10 to 41.46) and median study follow-up duration of 
11.53 months (range: 0.07 to 58.91). The median age of the patients was 60 years and 72.1% 
were male. These patients had a median of 1.0 prior systemic anticancer therapy regimens 
(range: 0 to 12) and their most common tumor types were non-small cell lung cancer (NSCLC) 
(639 of 1992 patients, 32.1%), ESCC (15.9%), hepatocellular carcinoma (HCC; 15.9%), 
urothelial bladder cancer (5.7%), and colorectal cancer (5.2%). 
1.4.4.1.2. Treatment-Emergent Adverse Events Assessed as Related to Treatment  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 1391 (69.8%) 
experienced ≥ 1 treatment related TEAE. The most commonly occurring treatment related 
TEAEs were AST increased (250 of 1992 patients, 12.6%), ALT increased (12.1%), 
hypothyroidism (9.9%), anaemia (9.3%), and rash (8.0%). 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 269 (13.5%) 
experienced ≥ 1 tislelizumab-related TEAE of ≥ Grade 3 severity. The most commonly occurring 
≥ Grade 3 TEAEs were AST increased (25 of 1992 patients, 1.3%), ALT increased (1.0%), and 
anemia (1.0%). All other events occurred in < 1% of patients. 
1.4.4.1.3. Treatment-Emergent Serious Treatment Emergent Adverse Events  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 706 (35.4%) 
experienced ≥ 1 treatment emergent serious TEAE. The most commonly occurring serious 
TEAEs were pneumonia (95 of 1992 patients, 4.8%), pneumonitis (1.7%), dysphagia (1.2%), 
pleural effusion (1.0%), and pyrexia (1.0%). 
1.4.4.1.4. Immune-Mediated Adverse Events  
Anti-PD1 therapies are known to cause immune mediated related adverse events (imAEs) in 
some patients and therefore have been defined as AEs of special interest in tislelizumab clinical 
studies and as such are being reported and close monitored. 
Immune-mediated AEs are consistent with an immune-mediated mechanism or immune-
mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) 
have been ruled out.  Immune-mediated AEs can include events with an alternate etiology which 
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were exacerbated by the induction of autoimmunity.  There is a potential temporal relationship 
between the initiation of treatment with tislelizumab and onset of an imAE that spans a window 
of days to several months. 
All imAEs presented here are assessed as related to study drug by the investigator and 
categorized by the BeiGene Safety/Pharmacovigilance team.  Certain imAEs have multiple 
Medical Dictionary for Regulatory Activities (MedDRA) terms associated with the same 
category.  Special categories have been created to group patients experiencing these events. 
All imAEs that occur in ≥ 1% in the total pooled monotherapy studies of solid tumors are shown 
in Table 5. 
Table 5: 
Immune-Mediated Adverse Events of Any Grade Occurring in ≥ 1% in 
Pooled Monotherapy Studies of Solid Tumors 
Categories 
   Preferred Term 
Total 
(N = 1912) 
Any Grade 
n (%)a   
Grade ≥ 3 
n (%)a 
Patients with at least one potential immune-mediated AEa 
286 (15.0)  
73 (3.8) 
Immune-Mediated Hypothyroidism 
118 (6.2) 
1 (0.1) 
Hypothyroidism 
115 (6.0) 
1 (0.1) 
Immune-Mediated Pneumonitis 
70 (3.7) 
28 (1.5) 
Pneumonitis 
41 (2.1) 
15 (0.8) 
Immune-Mediated Hepatitis 
34 (1.8) 
19 (1.0) 
Immune-Mediated Skin Adverse Reaction 
24 (1.3) 
9 (0.5) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: AE, adverse event; N, total number of patients treated; n, number of patients within each 
category; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PT, 
preferred term;. 
Note: Maximum NCI-CTCAE grade was selected per patient under each PT.  Potential immune-mediated 
AE is identified based on a predefined list of AEs and assessed as treatment-related by investigators. 
Sorted in descending order of the number of patients in SOC and PT in Any Grade under the Total column. 
Data cut-off 20 May 2021. 
a Percentages are based on the total population. 
Of the 1912 patients in the adjudicated solid tumor group of pooled monotherapy studies, 73 
(3.8%) experienced ≥ 1 imAE that was ≥ Grade 3 in severity. The most commonly occurring ≥ 
Grade 3 imAEs were pneumonitis (15 of 1912 patients, 0.8%), interstitial lung disease (0.4%), 
ALT increased (0.3%), AST increased (0.3%), and hepatitis (0.3%). 
1.4.4.1.5. Infusion-Related Reactions  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 58 (2.9%) 
experienced ≥ 1 infusion related reaction (IRR) of any grade. The most commonly occurring 
IRRs were “infusion-related reaction” (28 of 1992 patients, 1.4%), pyrexia (0.9%), rash (0.3%), 
hypotension (0.2%), nausea (0.2%), and pruritus (0.2%). 
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1.4.4.1.6. Fatal Adverse Events  
A summary of the treatment-emergent fatal AEs that occurred in the pooled monotherapy studies 
of solid tumors are shown in Table 6.  
Table 6: 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in Pooled 
Monotherapy Studies of Solid Tumors (in ≥ 2 patients) 
 
Overall 
(N = 1992) 
n (%) 
Patients with at Least One TEAE Leading to Death 
141 (7.1) 
General disorders and administration site conditions 
38 (1.9) 
  Death 
16 (0.8) 
  Multiple organ dysfunction syndrome 
11 (0.6) 
  General physical health deterioration 
10 (0.5) 
Respiratory, thoracic and mediastinal disorders 
32 (1.6) 
  Respiratory failure 
10 (0.5) 
  Acute respiratory failure 
3 (0.2) 
  Haemoptysis 
2 (0.1) 
  Pleural effusion 
2 (0.1) 
  Pneumonitis 
2 (0.1) 
  Pulmonary embolism 
2 (0.1) 
  Pulmonary haemorrhage 
2 (0.1) 
Infections and infestations 
20 (1.0) 
  Pneumonia 
14 (0.7) 
  Sepsis 
2 (0.1) 
Hepatobiliary disorders 
15 (0.8) 
  Hepatic failure 
10 (0.5) 
  Acute hepatic failure 
2 (0.1) 
Gastrointestinal disorders 
14 (0.7) 
  Upper gastrointestinal haemorrhage 
7 (0.4) 
  Ascites 
2 (0.1) 
Nervous system disorders 
10 (0.5) 
  Cerebral infarction 
2 (0.1) 
  Hepatic encephalopathy 
2 (0.1) 
Cardiac disorders 
8 (0.4) 
  Acute myocardial infarction 
2 (0.1) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: TEAE: treatment-emergent adverse event. N, total number of patients treated; n, 
number of patients within each category. 
Data cut-off 20 May 2021. 
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Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 141 (7.1%) 
experienced ≥ 1 TEAE leading to death. The most commonly occurring TEAEs leading to death 
were “death” (16 of 1992 patients, 0.8%), pneumonia (0.7%), multiple organ dysfunction 
syndrome (0.6%), general physical health deterioration (0.5%), hepatic failure (0.5%), and 
respiratory failure (0.5%). 
1.5. 
Study Rationales  
1.5.1. 
Rationale for Tislelizumab in the Treatment of Esophageal Carcinoma  
High levels of FcγR-expressing myeloid derived suppressor cells 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 ADCP depletion of effector T cells (Gül et al, 2015; 
Prieto et al 2015; Makarova-Rusher et al, 2015).  As a no- to low-FcγR-binding agent (thus 
causing minimal ADCC/ADCP effect), tislelizumab may show improved efficacy and reduced 
toxicity in esophageal carcinoma  Available data from a clinical study with other anti-PD-1 
monoclonal antibodies, nivolumab and pembrolizumab, has shown the drug to have both a 
manageable safety profile and promising antitumor activity in patients with EC (Section 1.1). 
Finally, according to the latest data collected from the Phase 1 BGB-A317_Study_001, 
tislelizumab monotherapy has established a manageable safety profile, with the most common 
side effects consistent with known class effects of other anti-PD-1 antibodies. 
1.5.2. 
Rationale for Selection of Tislelizumab Dose  
The clinical fixed dose of 200 mg intravenously once every 3 weeks was selected based on 
comparable safety and efficacy profiles between 2 and 5 mg/kg in BGB-A317_Study_001: 
• Rates of treatment-related AEs and serious adverse events (SAEs) observed in 
patients receiving 2 mg/kg and 5 mg/kg once every 2 weeks and once every 3 weeks 
were comparable, suggesting no clear dose-dependence across these regimens.  
Additionally, PK data also showed no relationship between exposure and treatment-
emergent imAEs (Wu et al 2019a). 
• Confirmed response rates in patients treated with tislelizumab on a once every 
3 weeks schedule were more favorable compared to those treated on a once every 
2 weeks schedule.  While there are differences in response rates between dose levels, 
this is more likely a reflection of small sample size and patient heterogeneity than 
dose response. 
• Clearance of tislelizumab was not dependent on body weight, and the observed serum 
exposure of a 200 mg dose fell between serum exposure observed after 2 mg/kg and 
5 mg/kg doses. Therefore, clinical activity with a manageable and tolerable safety 
profile is expected to be maintained in patients receiving tislelizumab 200 mg once 
every 3 weeks. 
• Exposure-response analysis indicated that there was a lack of clinically significant 
exposure-response relationships for ORR and safety endpoints across a variety of 
advanced solid tumors and classical Hodgkin lymphoma for tislelizumab.  These 
findings support 200 mg once every 3 weeks dose regimen for pivotal studies. 
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In conclusion, the observed clinical activity in patients with advanced tumors, coupled with a 
manageable safety profile and supportive data, support the proposed tislelizumab dose of 200 mg 
intravenously once every 3 weeks as the recommended dose for pivotal studies, please refer to 
the Tislelizumab Investigator’s Brochure. 
1.5.3. 
Rationale for Study Population  
This study will enroll patients with resectable cT1-2N+M0 and cT3NanyM0 ESCC as 
determined at screening regardless of PD-L1 expression.  
Esophageal cancer consists of two major histologic subtypes: esophageal squamous cell 
carcinoma (ESCC) and adenocarcinoma (EAC). Both histologic subtypes have distinct risk 
factors and epidemiology, and different response from immunotherapy. ESCC continues to be 
the major subtype of EC in China and showed better response from immunotherapy, which was 
demonstrated in Keynote-181 study, for ITT (Intent to Treated) population, patients with ESCC 
showed a lower HR (hazard ratio) than patients with EAC. Additionally, Attraction 3 Study 
demonstrated that there was not a significant difference for Hazard Ratio between patients with 
PD-L1 ≥ 1 and PD-L1 < 1, who were treated with nivolumab as the second-line therapy for 
ESCC, which means even with lower PD-L1 expression, patients may also get potential benefit 
from PD-1 inhibitor therapy. Therefore, this study will focus on resectable locally advanced 
ESCC regardless of PD-L1 expression. 
As in NCCN guidelines Version 4 2020 for esophageal and esophagogastric junction cancers, 
neoadjuvant chemoradiotherapy is recommended for ESCC with Stage cT1-2N+M0 or cT3-
T4aNanyM0. However, in this study, patients in Cohort A will receive neoadjuvant 
chemotherapy rather than chemoradiotherapy, and patients in Cohort B will receive neoadjuvant 
chemoradiotherapy. To ensure patients’ resectability after neoadjuvant therapy, patients with 
Stage T4a will not be included. Therefore, clinical stage of disease for eligibility is defined as 
cT1-2N+M0 and cT3NanyM0. 
Supporting clinical outcomes with neoadjuvant chemotherapy/chemoradiotherapy and 
encouraging data on the use of immunotherapy in the neoadjuvant setting have been provided in 
Section 1.2 and Section 1.3.2. Patients treated with neo-adjuvant chemotherapy followed by 
surgery demonstrated unsatisfied prognosis. It is worth to explore if treatment regimen selection 
could be guided with effective modality (PET), and if neoadjuvant systemic therapy could bring 
similar or better benefit than neoadjuvant chemoradiotherapy to patients with PET response after 
induction therapy, there may be an opportunity to avoid radiotherapy for these patients. 
1.5.4. 
Rationale for Tislelizumab in the Perioperative Treatment of Resectable ESCC  
As discussed in Section 1.3, PD-1 inhibitors have demonstrated significant benefit from 2nd Line 
therapy to 1st Line ESCC and in combination with chemotherapy in a number of early-stage 
solid tumors (Kato 2020; Kojima et al  2019; Lee et al 2019). Nonclinical studies showed that the 
immune-suppressive PD-1 axis is activated early in solid tumor (Chiari et al, 2018) and induction 
of an immune response before surgery may lead to durable protection. Immunotherapy effects 
could be even better prior to surgery considering that after surgical resection, tumor antigens 
decrease dramatically and intact blood vessels and lymph nodes for drug delivery are removed 
which may influence immunotherapy effects. Several Phase1/2 and phase 2 studies showed 
manageable safety profiles and preliminary efficacy when adding PD-1/PD-L1 inhibitor to 
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perioperative treatment for patients with resectable EC (Lee et al 2019; Ende et al  2019; Uboha 
et al 2019). 
Study BGB-A317-205, as discussed in Section 1.3.1, has also demonstrated preliminary 
antitumor activity in patients with ESCC, with a confirmed ORR of 46.7%, DCR of 80%, DOR 
of 12.8 months, and median OS of 14.31 months. Additionally, 3 Phase 3 pivotal studies in 
ESCC area are ongoing (Study BGB-A317-302, BGB-A317-306, and BGB-A317-311). 
As discussed in Section 1.3, PD-1 inhibitor has already demonstrated significant benefit from 
second-line therapy to first-line therapy. Given the evidence of clinical activity of 
immunotherapy in ESCC patients with advanced disease as well as the need to improve upon 
survival and decrease recurrence rates for patients with resectable early-stage disease, studies 
exploring anticancer activities of immunotherapies for the treatment of resectable disease 
emerged in large numbers. Preliminary data indicated promising signal of immunotherapy as 
neo-adjuvant therapy. (Lee et al 2019)  
Therefore, adding Tislelizumab to the neoadjuvant phase may be a potential regimen to improve 
benefit for patients with resectable locally advanced ESCC. 
1.5.5. 
Rationale for Tislelizumab in Combination with Chemotherapy for Cohort A  
Patient in Cohort A is the PET responders (decrease of SUVmax ≥ 35%) after induction 
chemotherapy. Induction chemotherapy is the first treatment phase in this study. Previous studies 
showed that the use of induction chemotherapy before neoadjuvant cCRT was associated with 
much fewer distant relapses, and favorable outcomes in patients with ESCC achieving pCR, and 
there was no significant difference in the rate of postoperative complications of Grade 2 or 
higher between the induction chemotherapy group and noninduction chemotherapy group. (Lu  
et al 2019; Satake et al 2013) 
As discussed in Section 1.3.2, interim analysis from Keynote-590 Study (Kato et al 2020)  
showed promising efficacy data for the ESCC population treated with pembrolizumab in 
combination with chemotherapy. As discussed in Section 1.3.1, Study BGB-A317-205 (Xu et al 
2020) showed Tislelizumab in combination with chemotherapy demonstrated preliminary 
efficacy and safety data. Based on the improvement of clinical benefit, Tislelizumab in 
combination with chemotherapy could be respected to synergistic antitumor activity for patients 
with locally advanced ESCC. 
In a subsequent review of therapeutic PET response in patients with ESCC who received 
preoperative chemotherapy, patients with a complete metabolic response following 
chemotherapy had improved clinical benefit (Yanagawa et al, 2012). Clinical evidence suggested 
PET responders had similar efficacy compared with patients who received cCRT. And safety 
profile favored that neoadjuvant chemotherapy may be a potential acceptable modality. 
Therefore, it is expected that patients with PET responses are supposed to achieve a similar 
benefit from the neoadjuvant chemotherapy (radiotherapy free) as the traditional neoadjuvant 
cCRT, and additional toxicities related to radiation could be avoided. In addition, shifting the 
immunotherapy in combination with chemotherapy to earlier treatment setting may further 
improve pathological response and outcome. 
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1.5.6. 
Rationale for Tislelizumab in Combination with CRT for Cohort B  
Patient in Cohort B is the PET non-responders (decrease of SUVmax < 35%) after induction 
chemotherapy. Induction chemotherapy followed by neoadjuvant chemoradiotherapy can be well 
tolerated, as discussed in Section 1.5.5, but the outcome for the PET nonresponse population is 
still very poor (Buschenfelde et al 2011; Greally et al  2018; Ilson et al 2012). 
It is now known that both chemotherapy and radiotherapy can upregulate the expression of PD-
L1 ((Zhang et al 2008; Deng et al 2014)) due to the release of cytokines and other inflammatory 
molecules, which could make such tumors sensitive to a PD-1/PD-L1 directed therapy. 
Elimination of cancer cells by chemoradiotherapy triggers release of antigens, which can turn 
poorly immunogenic or immunosuppressive tumors into an immunogenic environment 
(Vanneman et al 2012). In addition, radiotherapy has an impact on the immune system by 
engaging both the innate and the adaptive arms, eliciting tumor-specific T-cells and establishing 
an immune memory against the tumor. This prolongs the effect of radiation, improving 
locoregional control, decreasing metastatic spread, and increasing OS (Formenti et al 2013). 
Several early-stage studies have demonstrated preliminary antitumor activity and clinical benefit 
from PD-1 inhibitor in combination with neoadjuvant CRT. As discussed in Section 1.3.2, NCT 
02844075 (Lee et al 2019), a phase 2 trial of preoperative chemoradiotherapy and 
Pembrolizumab, in which the result showed that pCR rate was 23.1% for ypT0N0 and 46.1 for 
ypT0, 12-month OS rate was 82.1%, and 12-month EFS rate was 60.3%, and with no new 
toxicity signals observed. Based on the above interactional mechanism between PD-1 inhibitor 
and CRT, and clinical data, adding Tislelizumab to neo-adjuvant CRT may be a potential 
regimen to improve prognosis for PET non-responder patients. 
1.6. 
Benefit-Risk Assessment  
1.6.1. 
Benefit-Risk Assessment of Cohort A  
The use of PET to guide neoadjuvant chemotherapy for patients with resectable locally advanced 
ESCC, who may benefit from concurrent immunotherapy and chemotherapy similar to standard 
of care (SOC) but avoiding receiving radiotherapy in neoadjuvant phase, would meet great 
medical need. The overall safety experience with tislelizumab, as a monotherapy or in 
combination with other therapeutics, is based on experience in 1917 patients treated as of the 
cutoff date 20 May 2020. The safety profile is consistent with the known class effects of anti-
PD-1 antibodies and includes mostly mild/moderate AEs. Grade 3 or 4 imAEs have been 
observed and have been generally reversible and manageable with study drug interruption and/or 
steroid treatment. Fatal imAEs are rare. The safety profiles of combination therapy with 
tislelizumab have been consistent across different platinum-based doublet chemotherapy 
regimens. AEs with potentially immune-mediated causes consistent with an immunotherapeutic 
agent, including rash, influenza-like symptoms, endocrinopathies, hepatitis or transaminitis, 
pneumonitis, and colitis have been observed. AEs that were most frequently reported with 
combination therapy were generalized symptoms such as fatigue, nausea, and vomiting, as well 
as those specific to cytotoxic chemotherapy such as hematologic toxicities and peripheral 
neuropathy. As discussed in Section 1.3.1, BGB-A317-205 study, which enrolled 15 patients 
treated with tislelizumab in combination with chemotherapy in the ESCC cohort, demonstrated 
that tislelizumab in combination with chemotherapy has a manageable safety profile. Among the 
15 patients, 1 patient experienced a Grade 5 hepatic dysfunction (possibly from progressive 
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disease and underlying hepatitis) which was possibly related to study treatment according to the 
investigator. Four patients discontinued study treatment due to AEs (Grade 3 tracheal fistula, 
Grade 3 lung infection, Grade 2 pneumonitis, and Grade 3 increase in aspartate 
aminotransferase) (Xu et al  2020) To date, the adverse events could be manageable with 
treatment or interruption of tislelizumab treatment. Based on the benefit-risk assessment, it is 
expected that the PET responders can have at least similar efficacy outcomes and better 
tolerability by adding tislelizumab to neo-adjuvant chemotherapy comparing with neo-adjuvant 
cCRT. The result from this study will provide patients one more option of radiotherapy-free 
treatment in the neoadjuvant treatment setting. The benefit-risk ratio for tislelizumab plus 
cisplatin-based doublet chemotherapy in the neoadjuvant setting is expected to be favorable. 
1.6.2. 
Benefit-Risk Assessment of Cohort B  
Data from a Phase 2 clinical study of  Pembrolizumab (Lee et al 2019), another anti-PD-1 
antibody, in combination with cCRT followed by surgery indicated an increased pCR rate of 
23.1% for ypT0N0 and 46.1% for ypT0 compared with historical data, and showed a potential of 
durable response, which suggests the potential efficacy of anti-PD-1 antibodies in combination 
with neo-adjuvant concurrent chemoradiotherapy for patients with locally advanced ESCC (for 
additional discussion, see Section 1.3). No treatment discontinuation occurred due to AEs, and 
adding Pembrolizumab to CRT followed by surgery did not show new significant safety signal. 
Considering the extremely poor outcome of patients who did not respond to PET after induction 
chemotherapy, even if received standard neoadjuvant chemoradiotherapy, meanwhile, based on 
the mechanism of synergistic effect between PD-1/PD-L1 inhibitor and chemoradiotherapy, and 
the preliminary efficacy data of PD-1/PD-L1 inhibitors in combination with neoadjuvant 
chemoradiotherapy, it’s expected that PET non-responder can get better efficacy outcome with 
tolerable toxicities by adding Tislelizumab to neo-adjuvant cCRT comparing with neo-adjuvant 
cCRT only.  The benefit-risk ratio for Tislelizumab in combination with neoadjuvant 
chemoradiotherapy followed by surgery would be considered favorable. 
To assess the potential efficacy and safety of tislelizumab in combination with neo-adjuvant 
chemotherapy or chemoradiotherapy guided by PET, a phase 2 Study BGB-A317-213 will be 
conducted. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
• To evaluate the pathological complete response (pCR) in patients receiving 
tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
2.1.2. 
Secondary Objectives  
• To evaluate the disease-free survival (DFS) of neoadjuvant treatment with 
tislelizumab plus chemotherapy/ chemoradiotherapy after R0 resection. 
• To evaluate the Event-free survival (EFS) of neoadjuvant treatment with tislelizumab 
plus chemotherapy/chemoradiotherapy. 
• To evaluate the R0 resection rate in patients receiving tislelizumab plus 
chemotherapy/ chemoradiotherapy as neoadjuvant treatment. 
• To evaluate objective response rate (ORR) of neoadjuvant treatment with tislelizumab 
plus chemotherapy/chemoradiotherapy before surgery as assessed by the investigator.  
• To evaluate the safety of tislelizumab combined with 
chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
2.1.3. 
Exploratory Objectives  
• To evaluate overall survival (OS) of neoadjuvant treatment with tislelizumab plus 
chemotherapy/chemoradiotherapy. 
• To evaluate the potential association of biomarkers with clinical efficacy in patients 
receiving tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant 
treatment. 
• To evaluate the major pathological response (MPR) rate in patients receiving 
tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment. 
2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• pCR rate - defined as the proportion of patients with absence of residual tumor in the 
resected primary tumor and all resected lymph nodes (ypT0N0) after completion of 
neoadjuvant therapy in an EE analysis set. 
2.2.2. 
Secondary Endpoints  
• 1-year/3-year Disease-Free Survival (DFS) rate - defined as the proportion of patients 
free from disease events at 1st year and 3rd year after the first date of no disease in an 
EE analysis set. DFS is defined as the time from the first date of no disease (R0 
resection as surgery outcome) to local or distant recurrence or death due to any cause, 
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whichever occurs first. DFS rate will be analyzed only for patients who undergo R0 
resection. 
• 1-year/3-year Event-Free Survival (EFS) rate - defined as the proportion of patients 
free from EFS events at 1st year and 3rd year after the first dose in an Safety Analysis 
Set. EFS is defined as time from first dose date to any of the following events which 
occurs first: progression of disease that precludes definitive surgery, local or distant 
recurrence, or death due to any cause. 
• R0 resection rate - defined as the proportion of patients with R0 resection in an EE 
analysis set. 
• Objective response rate (ORR) is the proportion of patients who had complete 
response or partial response before surgery as assessed by the investigator per 
RECIST v1.1 in all patients with measurable disease at baseline in the Safety 
Analysis Set. 
• The incidence and severity of treatment-emergent adverse events (TEAEs) is 
determined according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE v5.0).  
2.2.3. 
Exploratory Endpoints  
• 1-year/3-year OS rate – defined as the proportion of patients alive at 1st year and 3rd 
year after first dose in the Safety Analysis Set. 
• To evaluate the potential association of biomarkers (including PD-L1 and gene 
expression profile) with clinical efficacy (including but not limited to pCR, DFS, 
EFS, R0 resection, ORR, OS and MPR). 
• MPR rate - defined as the proportion of patients with ≤ 10% residual viable tumor in 
the resected primary tumor and all resected lymph nodes after completion of 
neoadjuvant therapy in an EE analysis set. 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a Phase 2, multicenter, open-label, 2-cohort study to investigate the efficacy and safety of 
PET guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in 
resectable Esophageal Squamous cell Carcinoma. 
The study consists of a screening phase, treatment phase (includes induction phase, neoadjuvant 
phase, and surgery phase), safety follow-up phase, and survival/disease follow-up phase. 
The study design schematic is presented in Figure 1. 
Figure 1: 
Study Schema  
 
Abbreviations: A317: Tislelizumab; PET-CT, Positron Emission Tomography-Computed Tomography; 
Chemo, Chemotherapy; RT, Radiotherapy; 5-Fu, 5-fluorouracil; ESCC, esophageal squamous cell 
carcinoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; N, number of patients; 
Q3W, once every 3 weeks. 
For all study procedures, see Section 7 and Appendix 1. 
3.2. 
Screening Period  
Screening evaluations will be performed within 28 days prior to first dose of study drug.  
Patients who agree to participate in this study will sign the informed consent form (ICF) prior to 
undergoing any screening procedure. Screening evaluations may be repeated as needed within 
the screening period; the investigator is to assess preliminary patient eligibility according to the 
latest screening assessment results. After signing the ICF, patient will receive PET-CT 
evaluation at baseline. 
Archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] block [preferred] or 
approximately 15 [at least 6] freshly cut unstained slides) is highly recommended to be collected 
for purpose of biomarker analysis. Information on previous histopathology reports and previous 
molecular analysis (if applicable) is required to accompany the tissue samples. Fresh tumor 
biopsies are strongly recommended at baseline in patients with readily accessible tumor lesions 
and who consent to the biopsies. If archival tumor tissues are not available, a fresh tumor biopsy 
is optional at baseline. Baseline tumor tissue samples can be collected at any stage of this study 
after local regulation approval. Refer to Section 7.6 for details. 
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3.3. 
Treatment Period  
Induction Phase: 
After completing all screening activities, eligible patients will receive one cycle induction 
therapy of chemotherapy doublet (cisplatin and paclitaxel). (As described in Section 5.2) 
Neoadjuvant Phase: 
All patients will be grouped into two cohorts based on the change of PET SUVmax (15-21 days 
after the last dose of induction therapy):    
o Cohort A (Responder: decrease in PET SUVmax ≥ 35%):   
 
Tislelizumab 3 cycles + chemotherapy doublet (cisplatin and paclitaxel) 2 cycles (as 
described in Section 5.2) 
o Cohort B (Non-Responder: decrease in PET SUVmax < 35%): 
 
Tislelizumab 3 cycles + chemotherapy doublet 2 cycles + radiotherapy (40Gy/20F) 
Note: Chemotherapy doublets (Paclitaxel + Cisplatin/5-Fu + Cisplatin 
(Investigator-chosen)) (as described in Section 5.2) 
In Cycle 4 (neoadjuvant phase), Tislelizumab (without chemotherapy) will be administered 1-3 
weeks prior to surgery, which could ensure the exposure dose of Tislelizumab and enough 
duration for patients to recover from toxicities of chemotherapy/chemoradiotherapy. 
During the neoadjuvant phase, patients who are found to have disease progression assessed by 
the investigator at any time during neoadjuvant treatment and are still deemed resectable and 
nonmetastatic will proceed to receive surgery and will remain eligible for all on-study 
evaluations based on investigator’s judgement. Patients who discontinue neoadjuvant treatment 
early because of disease progression or intolerable AEs and do not proceed to surgery will be 
discontinued from further in-clinic study procedures and will proceed to receive other treatment 
as determined by the investigator. These patients will remain in the study for survival follow-up. 
Surgery 
Upon completion of neoadjuvant therapy, the investigator will reassess the patient to reconfirm 
disease resectability. The Presurgical Visit and associated assessments should occur within 7 
days of surgery and in accordance with local institutional guidelines. Patients will undergo 
surgical resection of tumor. Surgical specimens will be assessed for pathological response (MPR 
and pCR) by local pathological department. 
The surgical procedure should be performed within 4-6 weeks from the last administered dose of 
chemotherapy treatment (the last dose of chemoradiotherapy in Cohort B) regardless the last 
dose of Tislelizumab.  
After surgery, disease follow-up tumor assessment will be performed by neck, chest, abdominal 
CT every 3 months after surgery for the first 2 years, every 6 months Since Year 3 based on 
RECIST v1.1. 
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 
v5.0, 2018)) and laboratory results. Vital signs, physical examinations, ECOG Performance 
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Status change, electrocardiogram (ECG) results, and other examinations will also be used for 
safety assessment. Safety assessments are further detailed in Section 8 and the Schedule of 
Assessments. 
If patients undergo surgery, surgical tumor tissue (FFPE block [preferred] or approximately 15 
[≥ 6] freshly cut unstained slides) are required to be collected and will be sent to central 
laboratory for biomarker analysis (including PD-L1 expression and gene expression profile). 
Surgical tumor samples can be collected at any stage of this study after local regulation approval. 
3.4. 
End of Treatment/Safety Follow-up  
The End-of-Treatment (EOT) Visit/Safety Follow-up will be conducted as follows: 
EOT/ Safety Follow-up 1: Patients who receive surgery, will be asked to return to the clinic for 
the End of Treatment (EOT)/Safety Follow-up Visit (to occur within 30 days [± 7 days] after the 
surgery, or before the initiation of a new anticancer treatment, whichever occurs first.)   
EOT/ Safety Follow-up 2: Patients who discontinue preoperative treatment for any reason and 
surgery will not be conducted, will be asked to return to the clinic for the Safety Follow-up Visit 
(to occur within 30 days [± 7 days] after the last dose of study treatment [including 
chemotherapy, radiotherapy and tislelizumab], or before the initiation of a new anticancer 
treatment, whichever occurs first.) 
If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before 
the EOT/Safety Follow-up Visit, these tests need not be repeated. Tumor assessment is not 
required at the EOT/Safety Follow-up, and should follow the regular schedule of assessment in 
Section 7.5. 
In addition, telephone contacts with patients should be conducted to assess immune- mediated 
AEs and concomitant medications (if appropriate, i.e., associated with an immune-mediated AE 
or is a new anticancer therapy) at 60 days, and 90 days (± 14 days) after the last dose of 
tislelizumab, regardless of whether or not the patient starts a new anticancer therapy. If patients 
report a suspected immune-mediated AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visit. 
3.5. 
Survival Follow-up  
Patients who discontinue study drug(s) for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments according to Section 7.5 and the Schedule of 
Assessments (Appendix 1), until the patient experiences disease progression (precluding 
definitive surgery), local or distant recurrence, or death; until the patient withdraws consent, is 
lost to follow-up; or until study termination by the sponsor, whichever occurs first.  
Patients will be followed for survival and further anticancer therapy information after 
discontinuation of study treatment via telephone calls, patient medical records, and/or clinic 
visits approximately every 3 months (± 14 days) after the safety follow up visit or as directed by 
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the sponsor until death, loss to follow-up, withdrawal of consent, or study completion by the 
sponsor. 
3.6. 
Discontinuation From the Study Treatment or From the Study  
3.6.1. 
Patient Discontinuation from Study Treatment  
Patients have the right to discontinue study treatment at any time for any reason.  In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time.  Patients 
who discontinue study treatment for reasons other than disease progression should be followed 
for assessments of antitumor activity (Section 7.5), safety (Section 7.4), and survival, if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF).  Patients may discontinue study treatment for 
reasons which include, but are not limited to, the following: 
• Treatment completed 
• Disease Progression (radiographic progression or clinical progression as per 
investigator assessment) 
• Adverse event 
• Patient Decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent anticancer therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents  
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study drug 
compliance and drug accountability.  The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• Patient withdrawal of consent 
• Death 
• Lost to follow-up 
• Patients have completed all study assessments 
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3.7. 
End of Study  
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient has completed the last visit: completes the 3-
year survival/disease follow-up, dies, withdraws consent, or is lost to follow-up, whichever 
occurs first. Alternatively, the end of study is when the sponsor decides to terminate the study. 
The sponsor has the right to terminate this study at any time.  Reasons for terminating the study 
early may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• Overall patient enrollment is unsatisfactory. 
The sponsor will notify each investigator if a decision is made to terminate the study.  Should 
this be necessary, prematurely discontinued patients should be seen as soon as possible for an 
EOT Visit 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 Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments 
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of 
consent in the jurisdiction in which the study is taking place) 
3. Pathologically (histologically) confirmed diagnosis of potential resectable ESCC with 
Stage cT1-2N+M0 and cT3NanyM0 (AJCC Edition 8th [(Rice et al 2017)]) 
4. confirmed eligibility for an R0 resection with curative intent 
5. Evaluable disease as assessed by the investigator per RECIST v1.1 
6. ECOG Performance Status 0 or 1 
7. Adequate hematologic and organ function as indicated by the following laboratory values 
≤ 14 days prior to first dose of study drug: 
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
ii. Platelets ≥ 100 x 109/L  
iii. Hemoglobin ≥ 90 g/L 
b. Serum creatinine ≤ 1.5 x ULN (upper limit of normal) 
c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome). 
d. AST and ALT ≤ 2.5 x ULN  
8. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, for ≥ 120 days after the last dose of 
tislelizumab, and for ≥ 180 days after the last dose of chemotherapy and radiotherapy and 
have a negative urine or serum pregnancy test ≤ 7 days before first dose of study drug. 
See Appendix 9. 
9. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study, for ≥ 120 days after the last dose of tislelizumab and for ≥ 180 days 
after the last dose of chemotherapy and radiotherapy. 
 
A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination 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. 
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4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. Any prior therapy for current ESCC, including chemotherapy, radiotherapy, targeted 
therapy agents or prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways 
2. Ineligible to receive a platinum-based doublet chemotherapy regimen, 
chemoradiotherapy, or surgery 
3. Cervical esophageal squamous cell carcinoma 
4. History of fistula due to primary tumor invasion 
5. Patients with high risk of fistula or sign of perforation evaluated by investigator 
6. Severe malnutrition  
7. Prior participation in a tislelizumab study regardless of the treatment arm, until the 
primary and key secondary endpoints of the study have read out. 
8. Active autoimmune diseases or history of autoimmune diseases that may relapse. 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled Type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
9. Any active malignancy ≤ 2 years before first dose of study drug except for the specific 
cancer under investigation in this study and any locally recurring cancer that has been 
treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder 
cancer, carcinoma in situ of the cervix or breast) 
10. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
first dose of study drug 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen 
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11. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before first dose of study drug 
12. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 2 weeks of intervention) 
13. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc.   
14. Infection (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal, or antiviral therapy  
a. Severe infections within 4 weeks before first dose, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
b. Receive therapeutic oral or IV antibiotics within 2 weeks before first dose 
Note: Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) 
infection. 
15. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or 
> 2500 copies/mL) or patients with active hepatitis C virus (HCV) 
Note: Patients with non-active hepatitis C and inactive hepatitis B surface antigen 
(HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or 
< 2500 copies/mL) can be enrolled.  Patients with detectable hepatitis B surface antigen 
(HBsAg) or detectable HBV DNA should be managed per treatment guidelines.   
16. Known history of HIV infection 
17. Any major surgical procedure ≤ 28 days before first dose of study drug.  Patients must 
have recovered adequately from the toxicity and/or complications from the intervention 
prior to first dose of study drug. 
18. Prior allogeneic stem cell transplantation or organ transplantation 
19. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before first dose of study drug 
b. Pulmonary embolism ≤ 28 days before first dose of study drug 
c. Any history of acute myocardial infarction ≤ 6 months before first dose of study drug 
d. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV (Appendix 6) ≤ 6 months before first dose of study drug 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before first 
dose of study drug 
f. Any history of cerebrovascular accident ≤ 6 months before first dose of study drug 
g. Uncontrolled hypertension that cannot be managed by standard anti-hypertension 
medications ≤ 28 days before first dose of drug 
h. Any episode of syncope or seizure ≤ 28 days before first dose of study drug 
20. A history of severe hypersensitivity reactions to other monoclonal antibodies 
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21. Has received any immunotherapy (eg, interleukin, interferon, or thymosin) or any 
investigational therapies within 14 days or 5 half-lives (whichever is shorter) before the 
first dose of study drug.   
22. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy and specific laboratory abnormalities) 
23. Was administered a live vaccine ≤ 28 days before first dose of study drug 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
24. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, or 
affect the explanation of drug toxicity or AEs, or result in insufficient or impaired 
compliance with study conduct 
25. Women who are pregnant or are breastfeeding 
26. Concurrent participation in another therapeutic clinical study 
 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution.  Tislelizumab has been aseptically filled in a single-use glass vial 
with a rubber stopper and capped by an aluminum flip-off seal cap.  Each vial is packaged into a 
single carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal.  Please also refer to the IB for other details regarding tislelizumab. 
5.1.2. 
Chemotherapy  
Management (i.e., labeling, handling, storage, administration, and disposal) of these products 
will be in accordance with the relevant local guidelines and/or prescribing information. 
For further details, see the manufacturer’s prescribing information for the respective 
chemotherapy agents. 
5.2. 
Dosage, Administration, and Compliance  
Dosing schedules are provided in Table 7.  The first dose of study drug is to be administered 
within 2 business days of enrollment.  All patients will be monitored continuously for AEs.  
Treatment modifications (eg, dose delay, reduction, interruption, or discontinuation) will be 
based on specific laboratory and AE criteria, as described in Section 5.5. 
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Table 7: 
Selection and Timing of Dose for Each Patient  
Treatment 
phase 
Study Drug 
Dose 
Day(s) of 
treatment 
Route of 
Administration 
Duration of Treatment 
Induction phase 
Paclitaxel 
135 mg/m2 
1 
Intravenous 
1 cycle 
Cisplatin 
 80 mg/m2 
1 
Intravenous 
1 cycle 
Neo-adjuvant 
phase 
(Cohort A and 
Cohort B with 
regimen not 
changed) 
Tislelizumab 
200 mg 
1 
Intravenous  
3 cycles (Cycles 2-4) 
Cisplatin* 
 80 mg/m2 
1 
Intravenous 
2 cycles (Cycles 2-3) 
Paclitaxel 
135 mg/m2 
1 
Intravenous 
2 cycles (Cycles 2-3)  
Neo-adjuvant 
phase 
(Cohort B with 
regimen 
changed) 
Tislelizumab 
200 mg 
1 
Intravenous  
3 cycles (Cycles 2-4) 
Cisplatin* 
 80 mg/m2 
1 
Intravenous 
2 cycles (Cycles 2-3) 
5-Fluorouracil** 1000 mg/m2 
4 
Intravenous 
2 cycles (Cycles 2-3) 
Concurrent 
radiotherapy*** 
40Gy/20F (2 Gy/fraction and 5 fractions/week) 
Note: For patients who are PET non-responders, in neo-adjuvant phase, chemotherapy regimen can be switched 
from Paclitaxel plus Cisplatin to 5-Fluorouracil plus Cisplatin by investigator’s choice. 
*In regimen of Paclitaxel plus Cisplatin, cisplatin may be administered on Day 1 or 2, or in 3 divided doses on Days 
1, 2, and 3 depending on local guidelines. The total dose given must be 80 mg/m2 per cycle. 
**In Cohort B, chemotherapy may be switched from Paclitaxel+ Cisplatin to Fluorouracil + Cisplatin, by 
investigator’s choice. 
*** Concurrent radiotherapy will be conducted for patients in Cohort B 
5.2.1. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks). 
Tislelizumab will be administered by intravenous infusion through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on 
filter.  Specific instructions for product preparation and administration are provided in the 
Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 2 and Cycle 3, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents.  From Cycle 4 onward, a ≥ 30-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 2, Day 1) will be delivered ≥ 60 minutes; if this is well tolerated, then 
the subsequent infusions may be administered ≥ 30 minutes, which is the shortest time period 
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permissible for infusion.  Tislelizumab must not be concurrently administered with any other 
drug (refer to Section 6). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 7. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.2. 
Cisplatin in Combination with Paclitaxel  
After all procedures/assessments have been completed as detailed in Appendix 1 and 
ion 3.3, 
cisplatin will be administered on Day 1 or 2, given every 21 days at a dose of 80 mg/m2 by IV 
infusion over 6 to 8 hours (or in doses consistent with local or country-specific treatment 
guidelines, or according to manufacturer standards or institutional standards). Alternatively, 
depending on local guidelines, cisplatin may be given in 3 divided doses on Days 1, 2, and 3.  
The total dose given should be 80 mg/m2 per cycle.  Also, paclitaxel will be administered on 
Day 1, given Q3W at a dose of 135 mg/m2 by IV infusion for at least 3 hours. The initial 
treatment of cisplatin in combination with paclitaxel will be administered within 2 business days 
of eligibility confirmed by investigator. Alternate dose and dosing schedules are allowed 
according to local and institutional guidelines. 
Premedication is recommended prior to infusion of cisplatin according to the manufacturer’s 
instructions. The premedication regimen should be determined by the investigator and 
administered as close to treatment as possible. Premedication may consist of hydration with 1 to 
2 liters of fluid infused 8 to 12 hours prior to dosing.  
Premedication is recommended prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards. The premedication regimen should be determined by the 
investigator and administered as close to treatment as possible. Premedication may consist of an 
oral steroid (such as dexamethasone 8 to 20 mg or equivalent administered 6 to 12 hours orally 
or 30 to 60 minutes IV before paclitaxel), an antihistamine (H1 antagonist such as 
diphenhydramine hydrochloride 50 mg IV or equivalent, or H2 antagonist such as cimetidine 300 
mg IV or equivalent), and an antiemetic (such as ondansetron 8 mg 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 eCRF.  
There is a 3-day window for all treatments in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc), the 
subsequent dosing visit should be scheduled as clinically appropriate.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs.  Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of therapy. Guidelines for dosage modification and 
treatment interruption or discontinuation are provided in Section 5.5. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
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5.2.3. 
Cisplatin in Combination with 5-Fluorouracil  
Through evaluation with PET-CT after induction therapy, if patients divided into Cohort B (PET 
non-responders), chemotherapy regimen may be switched from paclitaxel plus cisplatin to 5-
fluorouracil plus cisplatin based on investigator’s choice. Cisplatin will be administered on Day 
1 given every 21 days at a dose of 80 mg/m2 by IV infusion over 6 to 8 hours (or in doses 
consistent with local or country-specific treatment guidelines, or according to manufacturer 
standards or institutional standards). Alternatively, depending on local guidelines, cisplatin may 
be given in divided doses.  The total dose given should be 80 mg/m2 per cycle.  Also, 5-FU will 
be administered on Days 1 to 4, given Q3W at a dose of 1000 mg/m2 per cycle by continuous IV 
infusion over 24 hours.  The actual infusion time of 5-FU should be recorded, and a total 
infusion time of 96 ± 3 hours is acceptable. Alternate dose and dosing schedules are allowed 
according to local and institutional guidelines. 
Premedication is recommended prior to infusion of cisplatin according to the manufacturer’s 
instructions. The premedication regimen should be determined by the investigator and 
administered as close to treatment as possible. Premedication may consist of hydration with 1 to 
2 liters of fluid infused 8 to 12 hours prior to dosing.  
There is a 3-day window for all treatments in subsequent cycles if the cycle length is 21 days. If 
dosing is delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc), the 
subsequent dosing visit should be scheduled as clinically appropriate.  
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs.  Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of therapy. Guidelines for dosage modification and 
treatment interruption or discontinuation are provided in Section 5.5. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.4. 
Radiotherapy  
All patients in Cohort B will receive preoperative chemoradiotherapy. The total dose of 
radiotherapy will be 40Gy, administered in 20 once-daily fractions of 2Gy and 5 fractions per 
week. Alternate dose and dosing schedules for radiotherapy are allowed according to local and 
institutional guidelines. 
Every effort should be made to continue the radiotherapy during the concurrent phase in an 
uninterrupted manner. Should a patient develop severe esophagitis necessitating interruption of 
chemotherapy, the radiotherapy may continue, provided that the investigator believes supportive 
care will enable the patient to complete this part of the therapy without excess risk. 
5.2.5. 
Surgery  
A thoracic surgeon with experience in locally advanced resectable ESCC should evaluate 
patients at screening to determine eligibility for surgical resection. Patients should be eligible for 
an R0 resection with curative intent at time of screening. Before surgery, the investigator will 
reassess the patient to reconfirm disease. The presurgical visit and associated assessments should 
occur within 7 days of surgery and in accordance with local institutional practice. Preoperative 
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evaluation should be performed per local standard of care (including, but not limited to, blood 
tests, organ function tests (as indicated), and other evaluation procedures). 
The surgical procedure should be performed within 4-6 weeks after the last dose of neoadjuvant 
study treatment (in Cohort A, the last dose of chemotherapy; in Cohort B, the last dose of 
chemoradiotherapy) as best as possible. If surgery cannot be performed within this time window 
(eg, because of a prolonged AE), the investigator and the medical monitor will determine the 
acceptable length of this time window. If surgery is planned beyond 8 weeks after the last dose 
of study treatment, a repeated-CT scan should be obtained before the planned surgery. Resection 
may be accomplished via an open or minimally invasive procedure (eg, video-assisted thoracic 
surgery). 
The performed surgical procedure should be documented and reported in the eCRF. If, after 
neoadjuvant treatment or during the operation, the surgeon determines that the patient should not 
proceed with the planned surgery, the reason should be documented and reported in the eCRF as 
well. 
5.3. 
Overdose  
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF.  
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 must be 
reported within 24 hours of awareness via the SAE reporting process described in Section 8.4. 
Supportive care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study 
(tislelizumab, cisplatin, 5-FU, and paclitaxel) will be provided by the sponsor, as required by 
local or country-specific guidance.  The investigational site will acknowledge receipt of IMPs.  
Any damaged shipments will be replaced. 
Accurate records of all IMP received, dispensed, returned, and disposed of should be recorded on 
the site’s Drug Inventory Log.  Refer to the Pharmacy Manual for details of IMP management. 
5.5. 
Dose Delay or Modification  
A dose delay is a deviation from prescribed dosing schedule (i.e., the drug is withheld beyond 
visit window).  A dose interruption is an interruption of an infusion. 
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule.  In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines below.  Reasons for dose modifications or delays, the supportive measures taken, 
and the outcome will be documented in the patient's chart and recorded in the eCRF. 
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5.5.1. 
General Guidance Regarding Dose Modifications  
Reasons for dose modifications or delays, the supportive measures taken, and the outcome will 
be documented in the patient's chart and recorded in the eCRF. The severity of AEs will be 
graded according to the NCI-CTCAE v5.0 grading system. The drug-related toxicities should be 
managed according to the prescribing information for the approved product or institutional 
standard practices. The general guidance in this section is for reference of this study:  
 The first doses of chemotherapy are dependent upon the patient’s baseline body 
weight. Subsequent doses must be recalculated if the change of body weight from 
baseline is ≥ 10%. Subsequent doses should not be recalculated if the change 
(increase or decrease) of body weight from baseline is < 10% unless there is 
persistent toxicity that requires dose adjustment. If the dose is recalculated because of 
a ≥ 10% change in body weight from baseline, this body weight will then be used as 
the new baseline to calculate the dose of chemotherapy in subsequent cycles. 
 In case of chemotherapy-related toxicity, chemotherapy will be delayed until it 
resolves to baseline or ≤ Grade 1 (whichever is more severe) prior to administering 
the next dose of chemotherapy, with the exception of alopecia, Grade 2 fatigue, or 
other AEs which, in the opinion of the investigator, would not affect the safety 
evaluation of the study drugs. If the AE resolves to baseline or ≤ Grade 1 within 21 
days from C1D1, chemotherapy will be administered on C2D1 as scheduled. If the 
AE dose not resolve within 21 days from C1D1, chemotherapy will be delayed until 
the AE is resolved. If AE dose not resolve within 21 days from planned C2D1, 
chemotherapy should be discontinued. For Cohort A, Tislelizumab should continue as 
scheduled if there is not safety impact. For Cohort B, Tislelizumab and radiotherapy 
should continue as scheduled if there is not safety impact. The administration of 
chemotherapy and tislelizumab will be resynchronized at the subsequent cycle, which 
will be scheduled according to the chemotherapy dose administration date.  
 In case of tislelizumab-related toxicity, tislelizumab will be delayed until it resolves 
to baseline or ≤ Grade 1 (whichever is more severe) prior to administering the next 
dose of tislelizumab or, with the exception of alopecia, Grade 2 fatigue, or other AEs 
which, in the opinion of the investigator, would not affect the safety evaluation of the 
study drugs. Chemotherapy and radiotherapy (for Cohort B) should continue as 
scheduled if there is not safety impact. If the AE resolves within 10 days, tislelizumab 
will be administered. The administration of chemotherapy and tislelizumab will be 
scheduled according to the chemotherapy dose administration date.  If the AE does 
not resolve within 10 days from the scheduled date of dose administration, 
tislelizumab will be omitted from the current cycle and administration should 
continue at the start of the next cycle. If AE resolves to baseline or ≤ Grade 1 in 
Cycle 4, tislelizumab will be administered on Cycle 4 Day 1. If AE dose not resolve 
to baseline or ≤ Grade 1 in Cycle 4, tislelizumab will be discontinued. 
 In case of both tislelizumab and chemotherapy toxicity, treatment in any patient may 
be temporarily withheld if the toxicity is considered to be related to tislelizumab and 
chemotherapy. If the administration delay is ≤ 10 days for any delayed drug, the 
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delayed drug will be administered; if the delay is >10 days, the delayed drug will be 
omitted in this cycle and the next cycle will be administered as planned as long as the 
AE resolves within 21 days. If the AE resolves to baseline or ≤ Grade 1 within 21 
days from C2D1, chemotherapy and tislelizumab will be administrated on C3D1 as 
scheduled. If the AE dose not resolve in planned C3D1, chemotherapy will be 
delayed until the AE is resolved. For Cohort B, radiotherapy should continue as 
scheduled if there is no safety impact. The administration of chemotherapy and 
tislelizumab will be resynchronized at the subsequent cycle, which will be scheduled 
according to the chemotherapy dose administration date. 
5.5.2. 
Dose Delay or Modification for Tislelizumab  
There will be no dose reduction for tislelizumab in this study.  
Tislelizumab treatment may be temporarily suspended if the patient experiences a toxicity that is 
considered related to tislelizumab and requires a dose to be withheld.  Tislelizumab treatment 
should resume as soon as possible after the AEs recover to baseline or Grade 1 (whichever is 
more severe). 
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, the 
patient may continue to receive tislelizumab after discussion and agreement with the medical 
monitor. 
Specific treatment modifications to manage tislelizumab-related toxicities, such as to imAEs and 
infusion-related reactions, are described in Section 8.7.1 and Appendix 7. 
5.5.3. 
Dose Delay, Interruption, or Modifications for Chemotherapy  
Dose modifications for chemotherapy should be performed per applicable local prescribing 
information and per local practice according to the investigator’s clinical judgment.  Dose 
modification guidelines for chemotherapy, described in this section, depend on the severity of 
toxicity and an assessment of the risk versus benefit for the patient. 
Recommended dose modifications in this section serve as guidelines and do not replace the 
investigator’s judgment and applicable local label recommendations. 
If the patient develops a confirmed allergic reaction to the chemotherapy, the investigator may 
change the chemotherapeutic agent to one of the other agents allowed per protocol.  Only one 
change in chemotherapeutic agent is allowed. 
Table 8: Dose Reduction Level of Chemotherapy  
Drug Dose 
Level 1 (Standard level) 
(Every 3 weeks as a cycle) 
 Level   -1 
Level    -2 
Cisplatin 
80 mg/m2 
60 mg/m2 
40 mg/m2 
Paclitaxel 
135 mg/m2 
100 mg/m2 
50 mg/m2 
5-FU 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
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Dose Modification based on Hematologic Nadir Values Prior to the Next Dose 
ANC x 109/L 
 
 PLT x 109/L  
Dose 
level 
for 
chemotherapy 
≥ 1  
and 
≥ 75  
1 
0.5-1  
or 
50-75  
-1 
< 0.5  
or 
< 50  
-2 
Abbreviations: ANC, absolute neutrophil count; PLT, platelets. 
Dose Modifications for Cisplatin 
A repeated course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 
mL, and/or the blood urea nitrogen (BUN) is below 25 mg/100 mL. A repeated course should not 
be given until circulating blood elements are at an acceptable level (platelets ≥ 100 x 109/L, 
white blood cell [WBC] ≥ 4 x 109/L). Subsequent doses of cisplatin should not be given until an 
audiometric analysis indicates that auditory acuity is within normal limits. 
Adverse Event 
Recommended Cisplatin Dose 
Serum creatinine ≥ 1.5 mg/100 mL 
Hold treatment until serum creatinine 
< 1.5 mg/100 mL 
BUN ≥ 25 mg/100 mL 
Hold treatment until BUN < 25 mg/100 mL 
Auditory acuity by audiometric analysis out 
of range 
Hold treatment until auditory acuity is within 
normal limits 
Abbreviations: BUN, blood urea nitrogen. 
Dose Modifications for 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, does of paclitaxel should be 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. 
Paclitaxel Dose Modification for Hepatic Impairment 
Degree of Hepatic Impairment 
Recommended Paclitaxel Dose 
Transaminase levels 
 
Bilirubin Levels 
< 10 x ULN 
and 
≤ 1.25 x ULN 
Continue dosing at Dose Level 1 
< 10 x ULN 
and 
1.26 - 2.0 x ULN 
Hold until recovery to Grade 1 
Restart paclitaxel at Dose Level -1 
< 10 x ULN 
and 
2.01 - 5 x ULN 
Hold until recovery to Grade 1 
Restart paclitaxel at Dose Level -2 
≥ 10 x ULN 
or 
> 5.0 x ULN 
Discontinue Paclitaxel 
Abbreviation: ULN, upper limit of normal. 
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If the liver function test abnormalities do not recover by the next planned cycle, paclitaxel must 
be discontinued. All dose reductions for liver function abnormalities are permanent. 
Allergic Reaction/Hypersensitivity 
Patients who experience severe or life-threatening symptoms of hypersensitivity despite standard 
pretreatment medications must discontinue paclitaxel permanently. 
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 will be reduced to the next level once the toxicity has recovered to Grade 0-1 
in severity.  
Dose Modifications for 5-Fluorouracil 
5-FU dose modification scheme described below is recommended for the management of 
adverse events. 
Adverse Event 
Recommended 5-Fluorouracil Dose 
Development of angina, myocardial 
infarction/ischemia, arrhythmia, or heart failure in 
patients with no history of coronary artery disease or 
myocardial dysfunction 
Hold treatment until resolution 
Hyperammonemic encephalopathy 
Hold treatment until resolution 
Acute cerebellar confusion, disorientation, ataxia, or 
visual disturbances 
Hold treatment until resolution 
Grade 3 or 4 diarrhea 
Hold treatment until resolution to 
Grade 2 or lower 
Grade 2 or 3 palmar-plantar erythrodysesthesia 
(hand-foot syndrome) 
Hold treatment until resolution to 
Grade 1 or lower 
Grade 3 or 4 mucositis 
Hold treatment until resolution to 
Grade 2 or lower 
Grade 4 myelosuppression 
Hold treatment until resolution to 
Grade 3 or lower 
5.5.4. 
Dose Delay, Interruption, or Modifications for Radiotherapy (for Cohort B)  
Radiotherapy may continue if a patient develops Grade 1-2 radiation related toxicities such as 
dermatitis, mucositis, pneumonia, or esophagitis. If a patient develops ≥ Grade 3 esophagitis and 
suspected esophageal fistula, all the anti-tumor treatment, including Tislelizumab, chemotherapy, 
and radiotherapy should be delayed until recovery through standard of treatment. If there is ≥ 
Grade 3 radiation pneumonia, severe esophagitis with weight loss more than 15%, esophageal 
fistula, or ≥ Grade 4 thrombocytopenia with infective fever (≥ 38°C), which are considered as 
unrecoverable, all the anti-tumor treatment, including Tislelizumab, chemotherapy and 
radiotherapy should be discontinued. 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
The exclusion criteria (Section 4.2) specify that patients must not have received prior therapy for 
current esophageal cancer, including chemotherapy and radiotherapy, and prior treatment with 
anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 (Section 4.2), or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways. All prior and concomitant 
medications (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
and nutritional supplements) given to patients within 30 days before the first dose and 30 days 
after the last dose of study treatment (as of safety follow-up visit) should be recorded on the 
CRF.  
6.2. 
Concomitant Therapy  
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care at the discretion of the investigator for supportive care (eg, antiemetics, 
antidiarrheals) and in a patient’s interest are allowed.  Opiates and other medication required for 
palliative management of patients are allowed.  Patients must notify the investigator of all 
concurrent medications used during the study. 
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. 
6.2.1.1. 
Systemic Corticosteroids  
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 7) and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration.  The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted. 
Premedication with steroids for chemotherapy is acceptable. 
6.2.1.2. 
Hepatitis B Treatment  
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL at screening, must initiate 
treatment 2 weeks before first dose, and continue until 6 months after the last dose of study 
drug(s).  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 may use other antiviral agents, if appropriate, following local guidelines.  However, 
interferon-based therapy for hepatitis B is not permitted on study. 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, as aligned with 
local guidance.  Such medications must be documented in the patient’s chart and recorded in the 
eCRF.  Patients receiving antivirals at Screening should be treated for > 2 weeks before 
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enrollment and continue treatment during the study and for 6 months after study drug treatment 
discontinuation. 
6.2.2. 
Prohibited Concomitant Medications/Procedures  
Live vaccines ≤ 28 days before first dose of study drug and ≤ 60 days after the last dose of study 
treatment are prohibited. 
The following medications are prohibited during Screening and through the End-of-Treatment 
visit: 
• Any concurrent anti-cancer therapy, including chemotherapy, hormonal therapy, 
targeted therapy, immunotherapy, and investigational anticancer agents. However, 
patient who underwent surgery with R1/R2 resection as the surgery outcome could 
receive adjuvant therapy according to the guideline/local practice. Medications 
approved for the adjuvant setting by the China National Medical Products 
Administration (NMPA) are allowed to be used according to their approved label. 
• Herbal remedies for the treatment of cancer or Chinese patent medicines with 
approval from the China NMPA for use as anticancer treatment (regardless of cancer 
type) 
• 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. 
6.2.3. 
Restricted Concomitant Medications/Procedures  
The following medications are restricted during the study: 
• Immunosuppressive agents (except to treat a drug-related AE) 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic 
treatment 
• Patients should not abuse alcohol or other drugs during the study. 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
The potential for drug-drug interaction between the study drugs (tislelizumab), standard 
chemotherapy, and small-molecule drug products is very low, given tislelizumab is a therapeutic 
monoclonal antibody.  Tislelizumab is unlikely to have an effect on drug-metabolizing enzymes 
or transporters because it is expected to be degraded into amino acids and recycle into other 
proteins. 
 
Cisplatin 
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During cisplatin use, concurrent therapy with drugs having a potential ototoxic or nephrotoxic effect 
(eg, aminoglycosides, cefalotin, furosemide, and amphotericin B) should be avoided or adequately 
monitored because this may lead to increased or exacerbated toxicity due to platin-induced changes 
in renal clearance of these substances. 
 
Paclitaxel 
The metabolism of paclitaxel is catalyzed by cytochrome P-450 (CYP)2C8 and CYP3A4. 
Caution should be exercised when administering paclitaxel concomitantly with medicines known 
to inhibit or induce either CYP2C8 or CYP3A4 (eg, ketoconazole and other imidazole 
antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, 
indinavir, and nelfinavir) because the toxicity of paclitaxel may be increased due to higher 
paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce 
either CYP2C8 or CYP3A4 (eg, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is 
not recommended because efficacy may be compromised because of lower paclitaxel exposures.  
 
5-Fluorouracil 
Elevated coagulation times have been reported in patients taking fluorouracil concomitantly with 
warfarin. While pharmacokinetic data are not available to assess the effect of fluorouracil 
administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with 
the fluorouracil prodrug capecitabine is accompanied by an increase in warfarin concentrations. 
Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by fluorouracil or its 
metabolites. The investigator should refer to the most current 5-fluorouracil SmPC for all 
potential interactions with 5-fluorouracil. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES  
A table of scheduled study assessments is provided in Appendix 1.  Patients will be closely 
monitored for safety and tolerability throughout the study.  All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Screening  
Screening evaluations will be performed within 28 days prior to first dose of study drug.  
Patients who agree to participate will sign the ICF prior to undergoing any screening procedure.  
The Screening period begins on the first day a screening procedure is conducted.  Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess 
patient eligibility according to the latest screening assessment results. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent 
and ≤ 28 days prior the first dose may be used for the purposes of screening rather than repeating 
the standard-of-care tests unless otherwise indicated. 
Procedures conducted during the Screening Visit only are described in this section. For the 
description of other assessments that are conducted during screening, as well as throughout the 
study, refer to Safety Assessments (Section 7.4), Tumor and Response Evaluations (Section 7.5)  
Rescreening under limited conditions may be allowed after consultation with BeiGene, eg, when 
a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression.  Rescreening is allowed only once. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  Informed consent forms for enrolled patients and for 
patients who are screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before the first dose of study drug.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
7.1.2. 
Pulmonary Function Tests  
All patients will undergo pulmonary function testing which may include, but is not limited to, 
spirometry and assessment of diffusion capacity done during the Screening Period to assist the 
determination of suitability on the study. 
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7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient.  All screening procedure 
results, and relevant medical history must be available before eligibility can be determined.  All 
inclusion criteria must be met and none of the exclusion criteria may apply.  No eligibility 
waivers will be granted. 
7.2.2. 
Patient Numbering  
Each patient enrolled in this study will receive a unique identification number after signing the 
ICF.  Patient numbers will be assigned in chronological order starting with the lowest number.  
Once an identification number has been assigned to a patient, it cannot be reassigned to any other 
patient.  Re-screened patients will sign a new ICF and receive a new identification number. 
7.3. 
Tislelizumab and Chemotherapy Dispensation  
Tislelizumab and chemotherapy will be dispensed and administered as described in Section 5. 2.  
7.4. 
Safety Assessments  
7.4.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic).  Pulse rate and blood pressure will be collected while the patient is in a 
seated position after resting for 10 minutes. 
7.4.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including 
evaluations of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) 
musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems.  Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed.  New or worsened clinically significant abnormalities are to be 
recorded as AEs on the eCRF.  Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 3) will be assessed during the study. 
7.4.4. 
Laboratory Safety Tests  
Local laboratory assessments of serum chemistry, hematology, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Appendix 2. 
If laboratory tests at screening are not performed within 7 days before the administration of study 
drug(s) on Cycle 1 of Day 1, these tests should be repeated and reviewed before administration 
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of study drug(s).  Hematology and serum chemistry (including liver function tests) as specified 
in Appendix 2 should be performed weekly for the first 3 cycles and at the beginning of Cycle 4.  
After Cycle 1, results are to be reviewed within 48 hours before study drug administration. 
Thyroid assessments will be performed as specified in Appendix 1. 
Details about sample collection and shipment will be provided in a separate instruction manual.  
Investigators may use results from local laboratories for assessing eligibility, safety monitoring, 
and dosing decision. 
7.4.4.1. 
Cardiac enzyme monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatinine kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all 
tislelizumab studies to protect study participants and to quantify the risk of muscle inflammation 
(see Appendix 1 for the blood collection schedule and Appendix 7 for guidelines for 
management of suspected immune-mediated myocarditis).  Serum troponins may be substituted 
per local guidelines if used consistently throughout the study. 
7.4.5. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings.  
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. Patients should rest for at least 10 minutes prior to ECG collection. 
7.4.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0.  
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.7. 
Hepatitis B and C Testing  
Testing will be performed by the local laboratory at Screening and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], 
and HCV antibody). If HBsAg is positive, then an HBV DNA test will be triggered. If HCV 
antibody is positive, an HCV RNA test will be triggered. 
7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed within 28 days before first dose of study drug.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and ≤ 28 
days prior to the first dose of study drug may be used for the purposes of screening rather than 
repeating the standard-of-care tests.  
Patient will undergo 2 times of PET-CT (including neck, chest, and abdomen), the first is at 
screening and the second is from 15 to 21 days after induction therapy.  Patient will undergo 
computed tomography (CT) scans or magnetic resonance imaging (MRI) of the neck, chest, and 
abdomen before surgery to re-confirm the resectability. Other known or suspected sites of 
disease must be included in the imaging assessments (bone, brain, etc). 
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Disease follow-up tumor assessment will be performed by CT or MRI (including neck, chest, 
and abdomen) every 3 months after study treatment discontinuation (including chemotherapy, 
radiotherapy, tislelizumab and surgery) for the first 2 years, every 6 months in Years 3 based on 
RECIST v1.1. The allowed time window for disease follow-up assessments is  2 weeks in 
Years 1 to 2, and  4 weeks in Year 3. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation.  The same radiographic procedure and 
parameters are required to be used throughout the study. 
If a CT scan for tumor assessment is performed on a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards of a diagnostic CT scan. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 4).   
7.6. 
Biomarkers  
Shipping, storage, and handling of archival tumor, fresh tumor, and leftover tumor tissue for the 
assessment of biomarkers will be managed through a central laboratory. Refer to the laboratory 
manual for details of sample handling. 
Archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] block (preferred) or 
approximately 15 [at least 6] freshly cut unstained slides) is highly recommended to be collected 
for the purpose of biomarker analysis (including PD-L1 expression and gene expression profile). 
Information on previous histopathology reports and previous molecular analysis (if applicable) is 
required to accompany the tissue samples. Fresh tumor biopsies are strongly recommended at 
baseline in patients with readily accessible tumor lesions and who consent to the biopsies. If 
archival tumor tissues are not available, a fresh tumor biopsy is optional at baseline. 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. 
If patients undergo surgery, surgical tumor tissue (FFPE block [preferred] or approximately 15 
[≥ 6] freshly cut unstained slides) are required to be collected and will be sent to central 
laboratory for biomarker analysis (including PD-L1 expression and gene expression profile). 
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. 
Written informed consent is required for any of the fresh tumor biopsies. Tumor tissue samples 
can be collected at any stage of this study after local regulation approval. 
7.7. 
Visit Windows  
All treatment visits must occur within ± 3 days from the scheduled date, unless otherwise noted 
(see Appendix 1).  All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified.  Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion/dose 
unless otherwise noted.  Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or justifiable 
event, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
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Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of Cycle 1 during preoperative treatment phase.  
7.8. 
Unscheduled Visits  
Unscheduled visits may be performed at any, time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; ECOG Performance Status; AE 
review; concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments.  The date and reason for the unscheduled visit 
must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated with Study Drug  
8.1.1. 
Risks Associated with Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development.  The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions.  AEs observed with anti-PD-1 therapy are presented in Section 8.7.3. 
Although most imAEs observed with immunomodulatory agents have been mild and self-
limiting, such events should be recognized early and treated promptly to avoid potential major 
complications.  Suggested evaluation and management guidelines for suspected imAEs are 
provided in Appendix 7. 
8.1.2. 
Risks Associated with Chemotherapy  
Cisplatin 
Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside 
antibiotics. The serum creatinine, BUN, creatinine clearance, and magnesium, sodium, 
potassium, and calcium levels should be measured prior to initiating therapy, and prior to each 
subsequent course. At the recommended dosage, cisplatin should not be given more frequently 
than once every 3 to 4 weeks. Elderly patients may be more susceptible to nephrotoxicity. A 
urine output of 100 mL/hour or greater will tend to minimize cisplatin nephrotoxicity. This can 
be accomplished by increased hydration, before and after treatment. 
There are reports of severe neuropathies in patients in whom regimens are employed using 
higher doses of cisplatin or greater dose frequencies than those recommended. These 
neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, 
areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more 
susceptible to peripheral neuropathy.  
Loss of motor function has also been reported.  
Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within 
minutes of administration to patients with prior exposure to cisplatin, and have been alleviated 
by administration of epinephrine, corticosteroids, and antihistamines.  
Ototoxicity has been observed in patients treated with a single dose of cisplatin. Hearing loss can 
be unilateral or bilateral and tends to become more frequent and severe with repeated doses; 
however, deafness after initial dose of cisplatin has been reported rarely. It is unclear whether 
cisplatin induced ototoxicity is reversible. Careful monitoring by audiometry should be 
performed prior to initiation of therapy and prior to subsequent doses of cisplatin.  
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Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic 
in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice, 
cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 
the fetus. Patients should be advised to avoid becoming pregnant.  
The development of acute leukemia coincident with the use of cisplatin has been reported. In 
these reports, cisplatin was generally given in combination with other leukemogenic agents.  
Injection site reactions may occur during the administration of cisplatin. Given the possibility of 
extravasation, it is recommended to closely monitor the infusion site for possible infiltration 
during drug administration. A specific treatment for extravasation reactions is unknown at this 
time. 
Paclitaxel 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite 
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 
antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug.  
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting 
toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be 
administered to patients with baseline neutrophil counts of less than 1.5 x 109/L and before 
platelets recover to a level of ≥ 100 x 109/L.  
Severe conduction abnormalities have been documented in < 1% of patients during paclitaxel 
therapy and in some cases requiring pacemaker placement. If patients develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered, 
and continuous cardiac monitoring should be performed during subsequent therapy with 
paclitaxel. 
5-Fluorouracil 
It is recommended that patients be hospitalized during their first course of treatment. 
Fluorouracil should be used with extreme caution in poor risk patients with a history of high-
dose pelvic irradiation or previous use of alkylating agents, those who have a widespread 
involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal 
function.  
Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) 
associated with 5-FU has been attributed to deficiency of dipyrimidine dehydrogenase activity. A 
few patients have been rechallenged with 5-FU and despite lowering the 5-FU dose, toxicity 
recurred and progressed with worse morbidity. Absence of this catabolic enzyme appears to 
result in prolonged clearance of 5-FU.  
Investigator must advise patients to take measures to minimize exposure to UV light for the 
duration of the study as 5-FU has phototoxicity potential. 
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Fluorouracil may cause fetal harm when administered to a pregnant woman. Fluorouracil has 
been shown to be teratogenic in laboratory animals.  
There are no adequate and well-controlled studies with fluorouracil in pregnant women. While 
there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind 
that other drugs which inhibit DNA synthesis (eg, methotrexate and aminopterin) have been 
reported to be teratogenic in humans. Women of childbearing potential should be advised to 
avoid becoming pregnant. If the drug is used during pregnancy, or if the patient becomes 
pregnant while taking the drug, the patient should be told of the potential hazard to the fetus. 
Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential 
risk to the fetus.  
Any form of therapy which adds to the stress of the patient, interferes with nutrition, or depresses 
bone marrow function will increase the toxicity of fluorouracil. 
8.1.3. 
Risks Associated with Radiotherapy  
The most notable AEs for radiotherapy included dermatitis, mucositis, hypothyroidism, 
pneumonia, esophageal obstruction, fistula, or esophagitis.  The majority of AEs were mild to 
moderate in severity and manageable.  Although not life-threatening, these AEs can severely 
impact the physical, psychological, and social well-being of patients receiving radiotherapy and 
can lead to dose reductions and discontinuations. 
Some toxicities are rare but can be fatal, including esophageal fistula, bleeding, or myocarditis. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study.  Results from the 
nonclinical toxicology studies and clinical data with tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered.  Specifically, 
patients at risk for study-emergent active autoimmune diseases or with a history of autoimmune 
diseases that may relapse, patients who have undergone allogeneic stem cell or organ 
transplantation, and patients who have received a live vaccine ≤ 28 days before first dose of 
study drug are excluded from the study.  Patients with contraindications for chemotherapy, 
chemoradiotherapy, or surgery are also excluded from the study (see Section 4.2 for the full list 
of exclusion criteria). 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0.  All enrolled patients will be evaluated clinically and with 
standard laboratory tests at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of AEs (see Table 9), physical 
examinations, laboratory measurements (hematology, chemistry, etc) and other assessments 
including those listed in Appendix 1.  In addition, patients will be closely monitored for the 
development of any signs or symptoms of infections or autoimmune conditions. 
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At the start of each cycle, study drug(s) will only be administered after clinical laboratory results 
have been reviewed.  Administration of study drug(s) will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (see Section 8.3). 
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing the informed consent) and for up to 30 days after the last study treatment 
(including chemotherapy, radiotherapy, tislelizumab and surgery) or until the initiation of 
another anticancer therapy, whichever occurs first.  At the EOT/Safety Follow-up Visit, ongoing 
AEs will be followed until the event has resolved to baseline or ≤ Grade 1, the event is assessed 
by the investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it 
has been determined that study treatment or participation is not the cause of the AE. 
Immune-mediated AEs will be recorded up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new anticancer therapy.  All drug-related SAEs will be 
recorded by the investigator after treatment discontinuation until 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 Section 8.7. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug administration, even 
though the condition may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor. 
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8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study.  AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(eg, 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 Error! Reference source 
not found.. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment.  Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated.  The investigator should 
consult the tislelizumab Investigator’s Brochure in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has 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, because 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 
(i.e., 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 
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• Mechanism of action of the study drug 
• Biological plausibility 
• An AE should be considered “related” to study drug if any of the following criteria 
are met, otherwise the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
8.3.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs.  This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and significantly worsen during the study.  The definition of clinically significant is 
left to the judgment of the investigator.  In general, these are the laboratory test abnormalities or 
other abnormal assessments that: 
• are associated with clinical signs or symptoms, or 
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• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (i.e., 
cholestasis) should be recorded on the Adverse Event eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE.  It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions, but do not constitute a substantial 
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 to be SAEs: 
• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
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• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (i.e., not present in the product’s Reference Safety Information [RSI]) and 
meets the definition of a serious adverse drug reaction, the specificity or severity of which is not 
consistent with those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Recording Period  
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last study treatment (including chemotherapy, radiotherapy, 
tislelizumab and surgery) or initiation of new anticancer therapy, whichever occurs first.  
Immune-mediated AEs (serious or non-serious) should be reported until 90 days after the last 
dose of tislelizumab, regardless of whether or not the patient starts a new anticancer therapy.  All 
SAEs considered related to the study drug(s) that are brought to the attention of the investigator 
should be reported regardless of time since the last dose of treatment. 
AEs and SAEs should be recorded according to the details in Table 9.  For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2. 
Table 9: 
Guidance for Duration of Recording New or Worsening Adverse Events  
Event type 
Record new or worsening events that occur during 
this period 
Begin 
End  
SAEs a 
Signing of 
informed consent 
Up to 30 days after last study 
treatment, initiation of new 
anticancer therapy, death, 
withdrawal of consent, or loss to 
follow-up, whichever occurs first 
Nonserious AEs due to 
PD 
Do not record (see Section 8.6.4) 
All nonserious AEs, 
except those due to PD 
First dose of study 
drug 
Up to 30 days after last study 
treatment, initiation of new 
anticancer therapy, death, 
withdrawal of consent, or loss to 
follow-up, whichever occurs first 
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Event type 
Record new or worsening events that occur during 
this period 
Begin 
End  
Immune-mediated AEs 
(serious or nonserious) 
First dose of study 
drug 
Up to 90 days after last dose of 
tislelizumab (regardless of 
initiation of new anticancer 
therapy), death, withdrawal of 
consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
a All SAEs considered related to the study drug(s) that are brought to the attention of the Investigator should be 
reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Error! Reference source not found.. 
Table 10: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for 
Sending Initial 
Report 
Documentation 
Method 
Timeframe 
for Sending 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24 hours 
of first 
knowledge of 
the SAE 
SAE Report 
As 
expeditiously 
as possible 
SAE Report 
Email or fax 
SAE Report 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section Error! Reference 
source not found..  The SAE Report will always be completed as thoroughly as possible with all 
available details of the event and forwarded to the sponsor or designee within the designated 
time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form.  The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
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8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section Error! Reference source not found..  The sponsor has a legal responsibility to notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the safety 
of a product under clinical investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC.  The investigator should place copies 
of Safety Reports from the sponsor in the Investigator Site File. 
8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.6.4. 
Disease Progression  
Disease progression, which is expected in this study population and measured as an efficacy 
endpoint, should not be recorded as an AE term.  Similarly, nonserious AEs that are clearly 
consistent with the pattern of progression of the underlying disease and are considered 
unequivocally due to disease progression should not be recorded.  However, if there is any 
uncertainty as to whether a nonserious AE is due to disease progression, it should be recorded as 
an AE.  All SAEs and deaths regardless of relatedness to disease progression should be recorded 
and reported (see Section Error! Reference source not found.). 
8.6.5. 
Deaths  
Death is an outcome and not usually considered an event.  If the only information available is 
death and the cause of death is unknown, then the death is reported as an AE, eg, “death,” “death 
of unknown cause,” or “death unexplained.” 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab or within 180 days 
after the last dose of chemotherapy, a pregnancy report form is required to be completed and 
expeditiously submitted to the sponsor to facilitate outcome follow-up.  Information on the status 
of the mother and child will be forwarded to the sponsor.  Generally, follow-up will be no longer 
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than 6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
• Tislelizumab Investigator’s Brochure 
• Cisplatin prescribing information  
• Paclitaxel prescribing information  
• 5-FU prescribing information  
8.6.8. 
Assessing and Recording Immune-mediated Adverse Events  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (see Section 8.7.3) should be classified as imAEs and 
identified as such in the eCRF AE page.  Not all tislelizumab studies include a section on the 
eCRF AE page where imAEs are clearly identified.  Therefore, all studies will rely on the 
company list of Potential imAEs to identify all cases in each study to be further assessed as 
immune-mediated AEs by the sponsor, in addition to those imAEs reported by the investigator 
via the AE CRF page. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 7. 
An extensive list of potential imAEs appears in Table 12.  All conditions similar to those listed 
should be evaluated to determine whether they are imAEs, based on a similar diagnostic process 
to those reactions that are presented in more detail in Appendix 7. 
8.6.9. 
Recording Infusion-Related Reactions  
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension.  Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.  These 
infusion-related AEs should be recorded as “infusion-related reaction” instead of the individual 
signs and symptoms. 
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8.7. 
Management of AE of Special Interest  
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 2 and Cycle 3, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents.  From Cycle 4 onward, a minimum of a 30-minute monitoring period is 
required in an area with resuscitation equipment and emergency agents. 
The management of infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Managing Infusion-Related Reactions  
Patients should be closely monitored for infusion-related reactions.  Immediate access to an 
Intensive Care Unit (ICU) or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) must be 
available to treat infusion-related reactions. 
Treatment modifications for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 11. 
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Table 11: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Any worsening is 
closely monitored.  Medical management as 
needed. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion.  Infusion may be resumed at 50% 
of previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity.  Any 
worsening is closely monitored.  Proper medical 
management should be instituted as described 
below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event; NSAIDs, 
nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions and be 
administered with premedication.  If the patient has a second infusion-related reaction 
(≥ Grade 2) on the slower infusion rate, infusion should be discontinued, and the patient should 
be withdrawn from tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted 
as indicated per the type of reaction.  This includes, but is not limited to, an antihistamine (eg, 
diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), and if considered 
indicated, oral or intravenous glucocorticoids, epinephrine, bronchodilators, and oxygen.  In the 
next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction.  This includes, but is not limited 
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to, oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar J 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 the infusion must be immediately 
stopped, and the patient discontinued from the study.  Systemic anaphylactic/anaphylactoid 
reactions typically manifest within minutes following administration of the drug/antigen and are 
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 patient will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed.  The patient should then 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 (i.e., 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 (i.e., paracetamol) may be given to patients at the discretion of 
the investigator. 
8.7.3. 
Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study.  If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression, or other neoplastic causes) with 
appropriate diagnostic tests that may include, but are not limited to, serologic, immunologic, and 
histologic (biopsy) data.  If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy; and is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 12.  All conditions similar to those listed 
should be evaluated in patients receiving tislelizumab to determine whether they are immune-
mediated. 
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines ( Haanen  et al 2017; Brahmer 2018), and common immune-mediated toxicities are 
detailed in Appendix 7.  For any AEs not included in Appendix 7, please refer to the ASCO 
Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-mediated toxicities. 
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Table 12: 
Examples of Immune-mediated Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or 
endoscopic/radiographic evidence of inflammation); pancreatitis; 
hepatitis; aminotransferase (ALT/AST) elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features 
of hypopituitarism, eg, fatigue, weakness, weight gain; insulin-
dependent diabetes mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; 
aseptic meningitis; myasthenic syndrome/myasthenia gravis, 
meningoencephalitis; myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 7. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade after restart of study drug should permanently discontinue 
treatment. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released.  Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan (SAP). 
9.1. 
Statistical Analysis  
9.1.1. 
Analysis Sets  
The Efficacy Evaluable (EE) Analysis Set includes all patients who receive neoadjuvant 
treatment followed by surgery. This will be the primary analysis set for the efficacy analyses. 
The Safety Analysis Set includes all enrolled patients who receive at least 1 dose of any 
component of study drugs; it will be the primary analysis set for the safety analyses. Patients will 
be analyzed according to the actual treatment regimen received. 
9.1.2. 
Patient Disposition  
The number of patients treated and discontinued from study drugs and/or study and those with 
important protocol deviations will be counted. The primary reason for study drug(s) and/or study 
discontinuation will be summarized according to the categories in the eCRF. The end-of-study 
status (alive, dead, withdrew consent, or lost to follow-up) at the data cutoff date will be 
summarized using the data from the eCRF.  
Important protocol deviations will be summarized and listed by each category. 
9.1.3. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics of the Safety Analysis Set will be summarized 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis, and time since current cancer diagnosis. Categorical variables include 
histology, stage of disease, gender, age, race. 
9.1.4. 
Prior and Concomitant Medications  
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
drug codes. Concomitant medications will be further coded to the appropriate Anatomical 
Therapeutic Chemical code indicating therapeutic classification. Prior and concomitant 
medications will be summarized and listed by drug and drug class in the clinical study report for 
this protocol. Prior medications will be defined as medications that were stopped before the day 
of first dose of study drugs. 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 day of the first dose of study drug up to 30 days after the 
patient’s last dose (as of Safety Follow-up Visit). In addition, telephone contacts with patients 
should be conducted to assess imAEs and concomitant medications (if appropriate, ie, associated 
with an imAE or is a new anticancer therapy) at 60 (± 14 days) and 90 days (± 14 days) after the 
last dose of tislelizumab regardless of whether or not the patient starts a new anticancer therapy. 
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9.2. 
Efficacy Analyses  
9.2.1. 
Primary Efficacy Analysis  
pCR rate 
pCR rate is the primary endpoint of the study. pCR rate is defined as the proportion of patients 
with absence of residual tumor in the resected primary tumor and all resected lymph nodes after 
completion of neoadjuvant therapy followed by surgery as assessed by the investigator in the EE 
set. 
The pCR rate in Cohort A (Responder: decrease in PET SUVmax ≥ 35%) and Cohort B (Non-
Responder: decrease in PET SUVmax<35%) will be summarized. Clopper-Pearson 95% 
confidence interval (CI) of pCR in Cohorts A and B will be calculated. 
These analyses will be performed in the EE analysis set as the primary analysis. A sensitivity 
analysis of the pCR rate will also be performed in the Safety Analysis Set, and those patients 
who are not receiving surgery will be treated as non-pCR. The analysis of pCR rate will occur 
after all the patients in the EE analysis set have been assessed for pathological response. 
9.2.2. 
Secondary Efficacy Analysis  
1-year/3-year disease-free survival (DFS) rate 
The 1-year/3-year Disease-Free Survival (DFS) rate is defined as the proportion of patients free 
from disease event at 1st year and 3rd year after the first date of no disease (R0 resection as 
surgery outcome). DFS is defined as the time from the first date of no disease to local or distant 
recurrence or death due to any cause, whichever occurs first. If patients were alive without 
recurrence, DFS would be determined from the first date of no disease to the date of last 
adequate tumor assessment and will be censored on the date of the last adequate tumor 
assessment. DFS rate will be estimated in cohort A and B by Kaplan-Meier method with 95% 
CIs estimated using the Greenwood's formula for patients who undergo R0 resection in the EE 
analysis set.  
1-year/3-year event-free survival (EFS) rate 
The 1-year/3-year Event-Free Survival (EFS) rate is defined as the proportion of patients free 
from EFS events including progression of disease that precludes definitive surgery, local or 
distant recurrence, or death due to any cause at the 1st year and 3rd year after the first dose date.  
Progression of disease that precludes definitive surgery is defined as radiographic progression 
per RECIST 1.1 as assessed by the investigator that precludes surgery for both curative intent 
and R0 outcome (i.e. definitive surgery). Local recurrence is defined as recurrence in the area of 
the anastomosis or regional lymph node diagnosed by radiological examination and/or 
histopathological confirmation after definitive surgery. Distant recurrence is defined as extra-
regional lymph node metastasis, distant organ metastasis, or pleural or peritoneal dissemination 
diagnosed by radiological examination and/or histopathological confirmation after definitive 
surgery.  
Patients who died without a disease progression precluding definitive surgery or disease 
recurrence will be considered to have experienced an event on the date of their death. Patients 
who did not report progression precluding definitive surgery or recurrence of disease or death 
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will be censored on the date of their last evaluable tumor assessment. Patients who started any 
subsequent anticancer therapy without a prior reported progression precluding definitive surgery 
or recurrence of disease will be censored at the last evaluable tumor assessment before initiation 
of subsequent anticancer therapy or missed ≥ 2 tumor assessments. The EFS rate will be 
estimated in cohorts A and B by the Kaplan-Meier method with 95% CIs estimated using the 
Greenwood's formula for patients in the Safety Analysis Set. 
The following scenarios are planned for sensitivity analysis of EFS: regardless of whether the 
patient starts a new anticancer therapy, regardless of patients missing 2 consecutive tumor 
assessments, and only considering curative surgery intent rather than outcome of the surgery for 
definitive surgery. 
R0 resection rate 
R0 resection rate defined as the proportion of patients with R0 resection will be summarized in 
cohort A and B in the EE analysis set. 
Objective response rate (ORR) 
Objective response rate (ORR) is the proportion of patients with measurable disease at baseline 
who have a complete response or partial response before surgery as assessed by the investigator 
per RECIST v1.1 in the Safety Analysis Set. ORR will be summarized in cohort A and B. 
9.2.3. 
Exploratory Efficacy Analysis  
1-year/3-year OS rate is defined as the proportion of patients alive at 1st year and 3rd year after 
first dose. Data for patients who are not reported as having died at the time of analysis will be 
censored at the date last known to be alive. OS rate will be estimated in cohort A and B by 
Kaplan-Meier method for patients in the Safety analysis set. 
Biomarker analysis including Programmed death ligand 1 [PD-L1] expression and gene 
expression profile will be examined in the EE analyses set. Any potential association between 
biomarkers and treatment effects (including but not limited to pCR, DFS, EFS, R0 resection, ORR, 
OS and MPR) may be explored. 
MPR rate is defined as the proportion of patients with ≤ 10% residual viable tumor in the 
resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy 
followed by surgery. MPR rate will be summarized in cohorts A and B in the EE analysis set. 
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry, urinalysis), dosing, vital signs, ECGs, and 
physical examinations will also be used in determining safety. Descriptive statistics will be used 
to analyze all safety data in the Safety Analysis Set. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg, mg/m2, and Gy), dose intensity, and relative dose intensity. 
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The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events  
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by lower level term, Preferred Term, and Primary 
System Organ Class.  
A TEAE is defined as an AE that has an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drugs and up to 30 days after study treatment 
discontinuation or initiation of new anticancer therapy, whichever occurs first. Only those AEs 
that were treatment emergent will be included in summary tables. Immune-mediated AEs will be 
identified from all adverse events that have an onset date or a worsening in severity from 
baseline (pretreatment) on or after the first dose of tislelizumab and up to 90 days after the last 
dose of tislelizumab, regardless of whether the patient starts a new anticancer therapy.  If an 
imAE occurs outside of the above-mentioned treatment-emergent adverse event window, it will 
not be classified as a treatment-emergent adverse event. All imAEs will be reported separately. 
All AEs, treatment emergent or otherwise, will be presented in patient data listings.  
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE v5.0 within a system organ class and preferred term, even if the 
patient experienced more than 1 TEAE within a specific system organ class and preferred term. 
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug(s). Treatment-related AEs include those events considered by the investigator to be 
related to study treatment or with missing assessment of the causal relationship. SAEs, deaths, 
TEAE with ≥ Grade 3 severity, imAEs, treatment related TEAEs, and TEAEs that led to 
treatment discontinuation, dose interruption, dose reduction, or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated for 
each laboratory parameter as appropriate. Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be included in the clinical study report for this protocol. Descriptive 
summary statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables) for laboratory parameters and their changes from 
baseline will be calculated. Laboratory values will be summarized by visit and by worst 
postbaseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 will be summarized by NCI-CTCAE 
Grade. In the summary of laboratory parameters by NCI-CTCAE Grade, parameters with 
NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, sodium) will be 
summarized separately. 
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9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit for all 
visits. Vital signs will be listed by patient and visit. 
9.3.5. 
Pulmonary Function Test  
Pulmonary function test results will be listed by patient. 
9.4. 
Sample Size Consideration  
Approximately 65 patients are expected to be enrolled in this study, considering about 10% 
patients not receiving surgery. It is assumed that 25 patients will be categorized into cohort A 
and 40 patients will be categorized into cohort B according to their PET SUVmax decrease. The 
actual number of patients in each cohort will be based on the actual ratio of responder versus 
non-responder and may vary from this assumption. 
The pCR rate of responders was reported about 21.9% - 31.8% in historical studies 
(Buschenfelde et al 2011; Ilson et al 2012; Greally et al 2018). The pCR rate in cohort A is 
assumed to be 37%. Assuming there are 23 evaluable patients in cohort A, it will provide the 
probability of 66.2% to observe 8 pCRs out of 23 evaluable patients with point of estimate of 
pCR rate = 34.7% greater than the historical pCR rate in cohort A.   
The pCR rate of non-responders was reported about 4% - 13.6% in historical studies 
(Buschenfelde et al 2011; Greally et al; 2018, Ilson et al 2012). The pCR rate in cohort B is 
assumed to be 22%. Assuming there are 35 evaluable patients in cohort B, it will provide a 
probability of 91.0% to observe 5 pCRs out of 35 evaluable patients with point of estimate of 
pCR rate = 14.3% greater than the historical pCR rate in cohort B.   
Table 13 presents the estimates of the 95% CI around the observed pCR in cohort A for several 
potential outcomes using the sample sizes of 23 evaluable patients using the Clopper-Pearson 
method. 
Table 13. 
Estimates of 95% CI Using Clopper-Pearson After Enrollment of 23 
Evaluable Patients in Cohort A 
Number of  
pCR  
Among 23 Evaluable Patients 
Observed pCR 
95% CI of Observed pCR 
7 
30.4% 
13.2% – 52.9% 
8 
34.7% 
16.4% – 57.3%  
9 
39.1% 
19.7% – 61.5% 
Table 14 presents the estimates of the 95% CI around the observed pCR in cohort B for several 
potential outcomes using the sample sizes of 35 evaluable patients using the Clopper-Pearson 
method. 
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Table 14. 
Estimates of 95% CI Using Clopper-Pearson After Enrollment of 35 
Evaluable Patients in Cohort B 
Number of  
pCR  
Among 35 Evaluable Patients 
Observed pCR 
95% CI of Observed pCR 
4 
11.4% 
3.2% – 26.7% 
5 
14.3% 
4.8% – 30.3% 
6 
17.1% 
6.6% – 33.6% 
7 
20.0% 
8.4% – 36.9% 
 
 
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10. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented.  Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals.  In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
10.1. 
Access to Information for Monitoring  
In accordance with International Council for Harmonisation (ICH) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
10.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study.  If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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11. 
QUALITY ASSURANCE AND QUALITY CONTROL  
11.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit.  Regulatory agencies may also conduct a regulatory inspection 
of this study.  Such audits/inspections can occur at any time during or after completion of the 
study.  If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
11.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines.  
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs.  The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
11.4. 
Drug Accountability  
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product.  Dispensation records will document quantities received from 
BeiGene’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, and the initials of the person 
dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements specified in the 
Pharmacy Manual.  At appropriate times during the conduct of the study or at the end of the 
study following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet BeiGene’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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12. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
12.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the 
Declaration of Helsinki or the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the patient.  The study will also comply 
with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting). 
12.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB/IEC.  
Copies of the 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.  Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments.  In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC.  Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor.  Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
12.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor.  All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements.  Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
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12.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The final IRB/IEC-approved ICFs must be provided 
to the sponsor for health authority submission purposes according to local requirements. 
The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate.  The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study.  For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
12.4. 
Patient and Data Confidentiality  
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study.  This 
approach ensures that patients’ names are not included in any dataset transmitted to any sponsor 
location. 
Patient medical information obtained during this study is confidential and may be disclosed only 
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 mediation steps and reporting 
obligations under applicable data privacy laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Data generated during this study must be available for inspection upon request by representatives 
of the China NMPA; by sponsor monitors, representatives, and collaborators; and by the 
IRBs/IECs for each study site, as appropriate. 
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The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  The investigator agrees that all information 
received from the sponsor, including but not limited to, the Investigator's Brochure, this protocol, 
eCRFs, the IND, and any other study information, remain the sole and exclusive property of the 
sponsor during the conduct of the study and thereafter.  This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor.  The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study 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. 
12.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators, and/or disclose those 
financial interests, as required, to the appropriate health authorities.  This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor.  
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (i.e., last patient, last visit). 
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13. 
DATA HANDLING AND RECORD KEEPING  
13.1. 
Data Collection and Management Responsibilities  
13.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs.  In no event should the entry of the study data into the eCRF be later 
than what is stipulated in the site contract after the data is collected or received by the 
investigator or study team without prior communication with and approval by the sponsor. 
13.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of 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. 
13.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol will be stored by BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.  Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study.  Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA.  AEs will be coded to MedDRA by lower level term, preferred term, and primary 
system organ class (SOC).  Concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary.  Concomitant diseases/medical history will be coded 
using MedDRA. 
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13.2. 
Data Integrity and In-house Blinding  
Functions/persons with access to the EDC system shall be prohibited from using the EDC system 
to generate unnecessary listings/summaries that may introduce unwanted bias or to share such 
outputs from the EDC system with other functions/persons who do not have access to the EDC.   
13.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file, and/or 2) 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent forms, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, 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 ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
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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. 
13.4. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to sponsor. 
The investigator is to document and explain any deviations from the approved protocol.  The 
investigator must promptly report any important deviations that might impact patient safety 
and/or data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
13.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies).  BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study.  The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential.  As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor.  Thereafter, any secondary publications will reference the original publication(s).  
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors, 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement.  This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy.  The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the investigator’s clinical study agreement.  Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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13.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including biomarkers) to the assay lab for central lab analysis 
according to protocol and lab manual requirements.  
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason.  
Potential reasons for suspension or discontinuation include, but are not limited to: safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations.  If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time.  When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons.  The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action.  If required by applicable regulations, the investigator must inform the IEC/IRB promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor.  In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
13.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 13.5 
If a written contract for the conduct of the study, which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
 
 
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14. 
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AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations 
for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 
2015;62(3):932-54 
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Allum W H , Stenning S P , Bancewicz J , et al. Long-Term Results of a Randomized Trial of 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screening a   
Treatment 
EOT/ 
Safety Follow-
up Visit  b 
Survival 
follow-upt 
preoperative treatment Cycles 1 to 4 
(every 21 days) 
Surgery 
Days (window) 
-28 to ~ -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
 
30 ± 7 Days 
after treatment 
Every 
3 Months 
(± 14) Days 
Informed consenta   
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/prior medications c 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/ 
height and weight d 
 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
 
Physical examination e  
 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
 
ECOG Performance Status 
 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
 
12-lead ECGf 
 
x 
 
 
 
 
 
 
 
x 
 
x 
 
 
Adverse eventsg 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
Concomitant medications 
 
x 
 
x 
 
x 
 
x  
 
x 
 
x 
 
 
Hematology h  
 
x a 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
Serum chemistryh 
 
x a 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
CK and CK-MB i  
 
xa 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
Coagulation parametersh 
 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
 
Urinalysis j 
 
x 
As clinically indicated 
 
 
Pregnancy testj  
 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
 
Thyroid functionk 
 
x   
 
 
 
 
 
 
 
x 
 
x 
 
 
HBV/HCV testsl 
 
x 
As clinically indicated 
 
 
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Assessment 
Screening a   
Treatment 
EOT/ 
Safety Follow-
up Visit  b 
Survival 
follow-upt 
preoperative treatment Cycles 1 to 4 
(every 21 days) 
Surgery 
Days (window) 
-28 to ~ -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
 
30 ± 7 Days 
after treatment 
Every 
3 Months 
(± 14) Days 
Pulmonary function tests m 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
Baseline tumor tissue sample n 
x 
 
 
 
 
 
 
Surgical tumor tissue and 
lymph node sample o 
 
 
 
 
x 
(after surgery) 
 
 
Pathological response 
assessment 
 
 
 
 
x 
(after surgery) 
 
 
PET-CT p 
 
x 
15-21 days after the last dose of induction therapy 
 
 
 
Tumor assessment q 
xq 
 
 
 
xq  
(prior to 
surgery) 
 
xq 
Tislelizumab administration r 
 
 
x 
(Cycles 2-
4) 
 
 
 
 
 
 
 
 
 
 
Chemotherapy administration 
s 
 
x 
(Cycles 1-
3) 
 
 
 
 
 
Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle isoenzyme; CT, computed tomography; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end-of-treatment; FFPE, formalin-fixed paraffin-embedded; FT3, free triiodothyronine; 
FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, 
hepatitis C virus; IRB, institutional review board; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; PET, positron emission tomography;  SAE, serious adverse event; TSH, thyroid stimulating hormone; v, version. 
a 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 the first dose may be used for screening assessments rather than repeating such tests. 
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 b The EOT Visit /Safety Follow-up is conducted when the investigator determines that study treatment will no longer be used, or all the study treatment is 
complete.  If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT Visit, tests need not be repeated.  Patients 
who discontinue study treatment prior to disease progression will need to undergo tumor assessments as outlined in Section 7.5. 
The EOT/Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last study treatment (including chemotherapy, radiotherapy, 
tislelizumab and surgery), or before the initiation of a new anticancer treatment, whichever occurs first. 
c Includes age or year of birth, gender, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior medication, loco-regional 
treatment(s), and surgical treatment(s).  Information on radiographic studies performed prior to study entry may be collected for review by the investigator. Pre-
existing AEs at baseline should be recorded as medical history. 
d Vital signs collected on study include temperature, pulse rate, and blood pressure (systolic and diastolic) while the patient is in a seated position after resting for 
10 minutes.  The patient’s vital signs are required to be recorded within 60 minutes before, during, and within 30 minutes after the first infusion of tislelizumab.  
For subsequent infusions, vital signs will be collected within 60 minutes before infusion and, if clinically indicated, during and 30 minutes after the infusion. 
e 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. 
f The ECG recordings will be obtained during screening, Safety Follow-up Visit, before surgery and as clinically indicated at other time points.   
g The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0.  All AEs will also be evaluated for seriousness.  After the informed consent form 
has been signed, but prior to the first administration of study drug, only SAEs should be recorded.  After initiation of study drug, all AEs and SAEs, regardless 
of relationship to study drug, will be reported until either 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first.  
Immune-mediated AEs (serious or non-serious) should be reported until 90 days after the last dose of tislelizumab, regardless of whether or not the patient 
starts a new anticancer therapy.  All SAEs considered related to the study drug(s) that are brought to the attention of the investigator should be reported 
regardless of time since the last dose of treatment. 
h Local laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will be collected as 
specified in Appendix 2.  If laboratory tests at screening are not performed within 7 days of first dose, these tests should be repeated and reviewed before 
dosing.  Hematology and serum chemistry (including liver function tests) will be performed weekly for the first 3 cycles and then at the beginning of Cycle 
4(data collected as specified in Appendix 2).  After Cycle 1, results are to be reviewed within 48 hours before study drug administration.  Urinalysis is to be 
conducted during the treatment period only if clinically warranted.  Refer to Section 8.3.5 for additional information regarding clinical assessment and 
management of clinical laboratory abnormalities. 
i All patients will have CK and CK-MB testing at screening, repeated at all scheduled visits.  If CK-MB fractionation is not available, troponin I and/or troponin 
T may be tested instead.  Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
j Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days prior to the first dose.  Urine pregnancy tests will be performed at each visit prior to dosing, and at the EOT/Safety Follow-up Visit.  A 
serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
k Analysis of FT3, FT4, and TSH will be performed by the local study site laboratory.  Thyroid function tests will be performed at screening, Presurgical Visit , 
and at Safety Follow-up Visit. 
l Testing will be performed by the local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody). If HBsAg 
or HBcAb is positive, then an HBV DNA test will be triggered. If HCV antibody is positive, an HCV RNA test will be triggered. 
m All patients will have pulmonary function testing which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
Screening Period to assist the determination of suitability on the study. 
n A pretreatment tumor tissue (archival or freshly obtained, FFPE block [preferred] or approximately 15 [≥ 6] unstained freshly cut slides), is highly 
recommended to be collected. If archival tissue is unavailable or is deemed to be unsuitable for testing, a pretreatment tumor biopsy is optional. PD-L1 
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expression and gene expression profile at baseline will be assessed at the central laboratory. Baseline tumor tissue samples can be collected at any stage of this 
study after local regulation approval.  Refer to Section 7.6 for more details. 
o Tumor tissue and lymph node tissue obtained from surgical resection is required for pathological response analysis. Assessments on surgical specimen will be 
done for MPR, pCR, and exploratory biomarker analysis (including PD-L1 expression and gene expression profile) Surgical tumor tissue samples can be 
collected at any stage of this study after local regulation approval.  (Section 7.6) 
p The first PET-CT will be performed as the baseline data after the informed consent form is signed, and the second PET-CT will be performed 15-21 days after 
the last dose of induction therapy. Patients will be allocated to 2 cohorts based on the change of SUVmax of PET-CT, in which, patients with a decrease of 
SUVmax ≥ 35% will be defined as PET responders and allocated to Cohort A, while patients with a decrease of SUVmax < 35% will be defined as PET non-
responders and allocated to Cohort B. 
q For screening period, if the CT scan performed on a PET-CT scanner is consistent with the standards of a diagnostic CT scan, there is no need to perform a 
separate CT; otherwise, a sperate CT scan is needed. After study treatment discontinuation, patients will undergo scheduled disease follow-up assessments by 
CT or MRI of the neck, chest, and abdomen every 3 months for the first 2 years based on RECIST v1.1. Patients who have not experienced recurrence of 
disease will continue disease follow-up assessments every 6 months during Year 3. Disease follow-up assessments should occur within the allowed time 
window. The allowed time window for disease follow-up assessments is ± 2 weeks in Years 1 to 2, and ± 4 weeks in Year 3. See also Section 7.5 . 
r 21 days after induction therapy, Tislelizumab will be given intravenously once every 3 weeks (totally 3 cycles).  The initial infusion will be delivered for ≥ 
60 minutes.  If well tolerated, subsequent infusions can be administered for at least 30 minutes. Patients must be monitored for 60 minutes after infusion of 
tislelizumab on Cycle 2 and Cycle 3 of tislelizumab administration, on Cycle 4 of tislelizumab administration, at least a 30-minute monitoring period is 
required. 
s Chemotherapy (paclitaxel and cisplatin) will be administrated in Cycle 1 as induction therapy.  After induction therapy, in Cohort A, chemotherapy (paclitaxel 
and cisplatin, 2 cycles) in combination with Tislelizumab will be administrated once every 3 weeks.  In Cohort B, concurrent chemoradiotherapy (paclitaxel/5-
FU and cisplatin, 2 cycles, once every 3 weeks, plus radiotherapy: 40Gy/20F) in combination with Tislelizumab will be administrated. 
t  After the safety follow-up visit, information on survival follow-up and new anticancer therapy (including targeted therapy and immunotherapy) will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (± 14 days) (unless the patient withdraws consent or the 
sponsor terminates the study). If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the 
investigator. If the patient withdraws from study, the study staff may use a public information source (eg, county records) in accordance with local regulations 
to obtain information about survival status only.
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis c 
Thyroid 
function 
Alkaline phosphatase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Albumin 
Bicarbonate or total 
carbon dioxide  
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or 
urea 
Magnesium 
Chloride 
Phosphorus 
Potassium 
Sodium 
Corrected calcium a  
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
Creatinine Kinase b 
CK-MB b 
Lipase and/or Amylase 
RBC count 
Hemoglobin 
Hematocrit  
WBC count 
Platelet count 
Neutrophil 
count 
Eosinophil 
count 
Basophil count 
Monocyte 
count 
Lymphocyte 
count 
Prothrombin time 
Partial 
thromboplastin 
time or activated 
partial 
thromboplastin 
time 
 
International 
normalized ratio  
pH 
Specific gravity 
Glucose 
Protein  
Ketones 
Blood  
 
Free 
triiodothyronine 
Free thyroxine 
Thyroid 
stimulating 
hormone 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme; WBC, white blood cell. 
a Total calcium values will be corrected for patients with hypoproteinemia. 
b All patients will have creatine kinase and CK-MB testing at screening, and to be repeated at all scheduled visits if 
CK-MB fractionation is not available, assess troponin I and/or troponin T instead.  Refer to Section 8.3.5 for 
additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
c On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein. 
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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: (Oken et al 1982) .  Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 
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APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
Source: (Eisenhauer et al 2009) 
Definitions  
Response and progression will be evaluated in this trial using the international criteria proposed 
by the RECIST Committee (v1.1).  Changes in only the largest diameter (uni-dimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no 
less than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they 
are, by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, 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 by 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget 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 
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progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” 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 assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions.  However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
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normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain).  When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
Response Criteria  
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or nontarget) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note: The appearance 
of one or more new lesions is also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  Case report form may be designed to have target 
nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis <10 mm.  For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
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• Target lesions that become “too small to measure.”  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.” 
When this occurs, it is important that a value be recorded on the electronic case report 
form (eCRF).  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded 
by fat, such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well).  This default value is derived from the 
5 mm CT slice thickness (but should not be changed with varying CT slice thickness).  
The measurement of these lesions is potentially nonreproducible; 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 measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions.  
(Note: The appearance of one or more new lesions is also considered progression.) 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
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designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above; however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition: if all lesions are truly nonmeasurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in nonmeasurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in “volume” (which is equivalent to a 20% increase diameter 
in a measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large,” an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point.  While 
it would be ideal to have objective criteria to apply to nonmeasurable disease, the 
very nature of that disease makes it impossible to do so; therefore, the increase must 
be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression.  An example of this is the 
patient who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered that reveals metastases.  The patient’s brain metastases are considered to be evidence of 
PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
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: 
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• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
preexisting site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
• Timepoint Response 
• It is assumed that at each protocol specified time point, a response assessment occurs. 
The following table provides a summary of the overall response status calculation at 
each time point for patients who have measurable disease at baseline: 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; 
SD, stable disease. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
SD (Non-CR/non-PD) 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable 
disease. 
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 
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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 nontarget disease and will also take into consideration the appearance of new 
lesions.  Furthermore, depending on the nature of the trial and the protocol requirements, it may 
also require confirmatory measurement.  Specifically, in nonrandomized trials 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 trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a 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 time point response, the patient’s best response depends on the 
subsequent assessments.  For example, a patient who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD.  The same patient 
lost to follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero.” 
In trials where confirmation of response is required, repeated "NE" (not evaluable) time point 
assessments may complicate best response determination.  The analysis plan for the trial must 
address how missing data/assessments will be addressed in determination of response and 
progression.  For example, in most trials it is reasonable to consider a patient with time point 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
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lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response  
Confirmation 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
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APPENDIX 5. PREEXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves disease 
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome 
Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure 
at rest.  If any physical activity is undertaken, discomfort increases. 
Adapted from (Dolgin M et al 1994)  
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
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APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated AE 
(imAE) are intended as a guidance.  This document should be used in conjunction with expert 
clinical judgement (by specialist physicians experienced in the treatment of cancer using 
immunological agents), and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs.  In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of tislelizumab and the AE? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked. If further diagnostic evaluations change 
the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of 
Possible Immune-mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeated thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss, and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath, or hypoxia 
should be assessed by high-resolution CT.  Consider pulmonary function test 
including DLCO. 
Radiographic appearance is often nonspecific.  Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered.  Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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Recommended Diagnostic Tests in the Management of 
Possible Immune-mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications.  Conduct a diabetic 
screen and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology.  Consider the need for brain/spine MRI/MRA and nerve conduction 
study for peripheral neuropathy.  Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, and cryptosporidia (drug-resistant 
organism). 
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan.  If a 
patient experiences bleeding, pain, or distension, consider colonoscopy with 
biopsy and surgical intervention as appropriate. 
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation; 
blurred vision; or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management. 
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3 to 4; every 2 to 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 a nephrologist for further management 
assistance. 
Dermatology 
Consider other causes by conducting a physical examination.  Consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin, and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, 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-mediated Adverse Events  
• Immune-mediated AEs can escalate quickly.  Study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention as appropriate is 
required. 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the study medical monitor. 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor. 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]). 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy. 
• Tislelizumab must be permanently discontinued for any onset of Grade 4 or recurrent 
Grade 3 immune-mediated AEs. 
 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
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 
comorbidities, the suggested 
starting dose is 0.5 µg/kg/day).  
Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker 
and may require carbimazole 
until thyroiditis resolves. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1. 
 
Hypophysitis 
1-2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for hormone 
replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for patients 
with pituitary inflammation.  
Taper corticosteroids over at 
least 1 month. 
If there is no improvement in 
48 hours, treat as Grade 3-4. 
Continue study 
treatment. 
3-4 
Severe or life-threatening 
symptoms 
Refer patient to an 
endocrinologist for assessment 
and treatment. 
Initiate pulse intravenous 
methylprednisolone 1 mg/kg 
for patients with 
headache/visual disturbance 
due to pituitary inflammation.  
Convert to oral prednisolone 
and taper over at least 1 month. 
Maintain hormone replacement 
according to endocrinologist’s 
advice. 
Hold study 
treatment for 
patients with 
headache/visual 
disturbance due to 
pituitary 
inflammation until 
resolved/improved 
to ≤ Grade 2.  
Discontinuation is 
usually not 
necessary.  
 
Pneumonitis 
1 
Radiographic changes only 
Monitor symptoms every 2-
3 days.  
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment until 
appearance 
improves and cause 
is determined. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if 
infection suspected.  Add oral 
prednisolone 1 mg/kg/day if 
symptoms/appearance persist 
for 48 hours or worsen. 
Consider Pneumocystis 
infection prophylaxis.  Taper 
corticosteroids over at least 
6 weeks. 
Consider prophylaxis for 
adverse steroid effects: eg, 
blood glucose monitoring, 
vitamin D/calcium supplement. 
Hold study 
treatment.  
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms: breathless at rest 
Admit to a hospital and initiate 
treatment with intravenous 
methylprednisolone 
2-4 mg/kg/day.  If there is no 
improvement, or worsening 
after 48 hours, add infliximab 
5 mg/kg (if no hepatic 
involvement). 
Convert to oral prednisolone 
and taper over at least 
2 months. 
Cover with empiric antibiotics 
and consider prophylaxis for 
Pneumocystis infection and 
other adverse steroid effects, 
eg, blood glucose monitoring, 
vitamin D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 
0.5-1 mg/kg/day.  Taper over at 
least 4 weeks. 
Obtain neurology consultation. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1. 
3-4 
Severe/life-threatening symptoms 
Initiate treatment with oral 
prednisolone or intravenous 
methylprednisolone 
1-2 mg/kg/day, depending on 
symptoms.  Taper 
corticosteroids over at least 
4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response 
within 72-96 hours. 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
Colitis/Diarrhea 
1 
Mild symptoms: ≤ 3 liquid stools 
per day over baseline and feeling 
well 
Symptomatic management: 
fluids, loperamide, avoid high 
fiber/lactose diet. 
If Grade 1 persists 
for > 14 days, manage as a 
Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 liquid 
stools per day over baseline, or 
abdominal pain, or blood in stool, 
or nausea, or nocturnal episodes 
Oral prednisolone 
0.5 mg/kg/day (nonenteric 
coated). 
Do not wait for any diagnostic 
tests to start treatment.  Taper 
steroids over 2-4 weeks. 
Consider endoscopy if 
symptoms are recurring. 
Hold study 
treatment; resume 
when 
resolved/improved 
to baseline grade. 
3 
Severe symptoms: > 6 liquid stools 
per day over baseline, or if 
episodic within 1 hour of eating 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral prednisolone 
and taper over at least 4 weeks.  
Consider prophylaxis for 
adverse steroid effects, eg, 
blood glucose monitoring, 
vitamin D/calcium supplement. 
If no improvement in 72 hours 
or symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, 
hepatitis, NYHA Class III/IV 
CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study 
treatment; 
retreatment may be 
considered when 
resolved/improved 
to baseline grade 
and after discussion 
with the study 
medical monitor. 
 
4 
Life-threatening symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10%-30% of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate 
strength cream once a day or 
potent cream twice a day) ± 
oral or topical antihistamines 
for itch.  Consider a short 
course of oral steroids. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
Rash covers > 30% BSA or Grade 
2 with substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows 
based on clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day 
for 3 days then taper over 
2-4 weeks. 
For severe symptoms: 
intravenous 
methylprednisolone 0.5-
1 mg/kg/day; convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Hold study 
treatment. 
Re-treat when AE is 
resolved or 
improved to mild 
rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
4 
Skin sloughing > 30% BSA with 
associated symptoms (eg, 
erythema, purpura, epidermal 
detachment): including Stevens-
Johnson syndrome (all grades), and 
toxic epidermal necrolysis>> 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Admit to a hospital and seek 
urgent dermatology 
consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3 x ULN 
Check LFTs within 1 week and 
before the next dose; check 
LFTs to verify that there has 
been no worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs 
are unchanged or 
improving. 
Hold study 
treatment if LFTs 
are worsening until 
improvement is 
seen. 
2 
ALT or AST 3-5 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 at least 
4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day. 
When LFTs improve to 
Grade 2 or lower, convert to 
oral prednisolone and taper 
over at least 4 weeks.  
Hold study 
treatment until 
improved to 
baseline grade; 
reintroduce only 
after discussion with 
the study medical 
monitor.  
 
4 
ALT or AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at 
least 6 weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed intravenous methylprednisolone. 
• 
If on intravenous methylprednisolone, add mycophenolate mofetil (MMF) 
500 to 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 
intravenous 
(methyl)prednisolone 
1-2 mg/kg. Taper 
corticosteroids over at least 
4 weeks. 
Hold study 
treatment until the 
cause is 
investigated.  
If study drug 
suspected: 
Discontinue study 
treatment. 
 
4 
Creatinine > 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.  
Check for C-peptide and 
antibodies against glutamic 
acid decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-13.9 mmol/L 
Obtain a repeat blood glucose 
level at least every week.  
Manage according to local 
guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when 
blood glucose is 
stabilized at 
baseline or Grade 0-
1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9-27.8 mmol/L 
Admit patient to hospital and 
refer to a diabetologist for 
hyperglycemia management.  
Corticosteroids may exacerbate 
hyperglycemia and should be 
avoided. 
Hold study 
treatment until 
patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or Grade 0-
1. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
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. 
Hold study 
treatment until 
patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or Grade 0-
1. 
 
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. 
Hold study 
treatment until 
improved to 
Grade 0-1; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
 
4 
Blindness (at least 20/200) in the 
affected eyes 
Initiate intravenous 
(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 
intravenous 
(methyl)prednisolone 
1-2 mg/kg/day.  Convert to oral 
prednisolone when 
amylase/lipase improved to 
Grade 2 and taper over at least 
4 weeks. 
Hold study 
treatment; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
4 
Acute abdominal pain, surgical 
emergency 
Admit to hospital for 
emergency management and 
appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with inflammation, 
swelling 
Management per local 
guideline.  
Continue study 
treatment. 
2 
Moderate pain with inflammation, 
swelling, limited instrumental (fine 
motor) activities 
Management as per local 
guideline.  Consider referring 
patient to a rheumatologist. 
If symptoms worsen on 
treatment, manage as a Grade 3 
event. 
Continue treatment 
or, if symptoms 
continue to worsen, 
hold study treatment 
until symptoms 
improve to baseline 
or Grade 0-1. 
3 
Severe pain with inflammation or 
permanent joint damage, daily 
living activity limited 
Refer patient urgently to a 
rheumatologist for assessment 
and management. 
Initiate oral prednisolone 
0.5-1 mg/kg and taper over at 
least 4 weeks. 
Hold study 
treatment unless 
improved to 
Grade 0-1; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
 
Mucositis/ 
stomatitis 
1 
Test findings only or minimal 
symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced oral 
intake, limited instrumental 
activities 
As per local guidelines, treat 
with analgesics, topical 
treatments, and oral hygiene 
care. 
Ensure adequate hydration. 
If symptoms worsen or there is 
sepsis or bleeding, manage as a 
Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food and fluid 
intake, daily living activity limited 
Admit to hospital for 
appropriate management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral prednisolone 
when symptoms improve to 
Grade 2 and taper over at least 
4 weeks. 
Hold study 
treatment until 
improved to 
Grade 0-1. 
 
4 
Life-threatening complications or 
dehydration 
Admit to hospital for 
emergency care.  Consider 
intravenous corticosteroids if 
not contraindicated by 
infection. 
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 
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 intravenous 
(methyl)prednisolone and 1-
2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. 
If symptoms do not improve, 
add immunosuppressant 
therapy. 
Taper oral steroids over at least 
4 weeks. 
For Grade 3: Hold 
study treatment until 
improved to 
Grade 0-1. 
Discontinue upon 
any evidence of 
myocardial 
involvement. 
 
Myocarditis a 
< 2 
Asymptomatic but significantly 
increased CK-MB or increased 
troponin OR clinically significant 
intraventricular conduction delay 
Initiate cardiac evaluation 
under close monitoring with 
repeat serum testing and 
including ECG, cardiac 
echo/MUGA, and/or other 
interventions per institutional 
guidelines; 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 and 
considered immune-
mediated, 
permanently 
discontinue study 
treatment in patients 
with moderate or 
severe symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline 
and after discussion 
with the study 
medical monitor. 
2 
Symptoms on mild-moderate 
exertion 
Admit to hospital and initiate 
oral prednisolone or 
intravenous 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage 
symptoms of cardiac failure 
according to local guidelines. 
If no immediate response, 
change to pulsed doses of 
(methyl)prednisolone 1 g/day 
and add MMF, infliximab, or 
anti-thymocyte globulin. 
3 
Severe symptoms with mild 
exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; 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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a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation ((Levey et al  2009),  and the Modification of Diet in Renal Disease (MDRD) Study 
equation.  The National Kidney Disease Education Program (NKDEP) calculators rely on 
creatinine determinations which are isotope dilution mass spectrometry (IDMS) traceable.  All 
laboratories should be using creatinine methods calibrated to be IDMS traceable. 
This CKD-EPI equation calculator should be used when serum creatinine (Scr) is reported in 
mg/dL.  This equation is recommended when eGFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: 
https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators 
Approved Date
7/29/2022

BGB-A317-213 
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Protocol Amendment 1.0 
22 Jul 2022 
CONFIDENTIAL 
Page 135 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control (Clinical Trials 
Facilitation Group 2014).  These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized 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. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patients’ usual and preferred lifestyle.  Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, 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 
used in combination with one of the highly effective forms of birth control listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Approved Date
7/29/2022

BGB-A317-213 
BeiGene 
Protocol Amendment 1.0 
22 Jul 2022 
CONFIDENTIAL 
Page 136 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (i.e., through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 mIU/mL 
and all alternative medical causes for the lack of spontaneous menses for ≥ 12 
months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from (Clinical Trials Facilitation Group, 2014) . 
 
Approved Date
7/29/2022

BBG-A317-213 
BeiGene 
Protocol Amendment 1.0, Summary of Changes 
22 July 2022 
 
CONFIDENTIAL 
Page 1 
BGB-A317-213 
PROTOCOL AMENDMENT 1.0 
SUMMARY OF CHANGES 
 
BGB-A317-213 Protocol Amendment 1.0 Summary of Key Changes (Edition 1.0 to Edition 0.0) 
 
The main purpose is to update the sample size of responder cohort A (40→ approx. 25) and non-responder cohort B (25→ approx. 40) 
based on the actual ratio of responders vs non-responders observed, and Study LBL-007-CN-003, and to clarify the definition of EFS.  
Contents from IB 9.0 was included to update relevant sections in original protocol. 
Minor changes have been made to correct typos and to enhance clarity and readability. 
The key changes from Edition 1.0 to Edition 0.0 (Original) are summarized by section in the following table: 

BBG-A317-213 
BeiGene 
Protocol Amendment 1.0, Summary of Changes 
22 July 2022 
 
CONFIDENTIAL 
Page 2 
Section 
Key Change 
Rationale for change 
Substantial 
change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
1.3. Anti-PD-1 Therapy 
for Esophageal Squamous 
Cell Carcinoma 
• 
Update information about the latest 
readout of tislelizumab trial in ESCC 
 
Add most up-to-date 
readout of several Phase 
III clinical trials of 
tislelizumab in ESCC 
N 
N/A 
1.4.4. Prior Clinical 
Experience of 
Tislelizumab 
• 
Include information from IB 9.0 
 
To provide the latest 
safety information of 
tislelizumab based on IB 
9.0. 
N 
N/A 
2. Study Objectives and 
Endpoints 
• 
Clarification of the definition of EFS 
• 
Move MPR to exploratory objectives 
• 
To clarify the definition 
of EFS and keep 
consistency throughout 
the protocol.  
• 
MPR is common 
endpoint in lung cancer, 
but not well established 
in esophageal cancer 
N 
N/A 
3.4 End of 
Treatment/Safety Follow-
up 
• 
Update definition of last study 
treatment 
• 
Include surgery as study 
treatment 
N 
N/A 
4.1 Inclusion Criteria 
• 
Deleted Inclusion Criteria 7 ii: 
Platelets ≥ 75 x 109/L 
• 
Add: “and ≥ 180 days after the last 
dose of chemotherapy and 
radiotherapy” in Inclusion Criteria 9 
• 
Platelets ≥ 75 x 109/L is 
for Monotherapy  
• 
Add contraception period 
for chemotherapy and 
radiotherapy 
N 
N/A 
4.2 Exclusion Criteria 
• 
For Exclusion Criteria 1, Add “or 
other targeted therapy agents”. 
• 
Patient with prior 
targeted therapy agents 
for ESCC is not eligible 
N 
N/A 

BBG-A317-213 
BeiGene 
Protocol Amendment 1.0, Summary of Changes 
22 July 2022 
 
CONFIDENTIAL 
Page 3 
5.2.2 Cisplatin in 
Combination with 
Paclitaxel 
• 
ondansetron 8 mg/kg IV updated to 8 
mg IV or equivalent 
• 
paclitaxel will be administered on 
Day 1, given Q3W at a dose of 135 
mg/mg2 by IV infusion for at least 3 
hours, Update to 135mg/m2 
• 
Error of dose 
• 
Typo 
N 
N/A 
6.2.2 Prohibited 
Concomitant 
Medications/Procedures 
• 
Update prohibited medication for 
adjuvant treatment for patients with 
R1/R2 resection 
• 
Medications approved 
for the adjuvant setting 
by the NMPA are 
allowed to be used 
according to their 
approved label. 
N 
N/A 
7.4.7 Hepatitis B and C 
Testing AND Appendix 1 
point l 
• 
If HBsAg or HBcAb is positive, then 
an HBV DNA test will be triggered. 
Delete “or HBcAb” 
• 
Error wording 
N 
N/A 
7.6 Biomarkers 
• 
Delete blood in “Shipping, storage, 
and handling of blood, archival tumor, 
fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will 
be managed through a central 
laboratory”. 
• 
Blood biomarkers were 
not collected for this 
study. 
N 
N/A 
8.6.1 Adverse Event 
Recording Period 
• 
All AEs and SAEs, regardless of 
relationship to study drug, will be 
reported until either 30 days after last 
dose of study drug(s)  
Update to “30 days after last study 
treatment (including chemotherapy, 
radiotherapy, tislelizumab and 
surgery)” 
• 
Take surgery into 
consideration of AE 
reporting period  
N 
N/A 

BBG-A317-213 
BeiGene 
Protocol Amendment 1.0, Summary of Changes 
22 July 2022 
 
CONFIDENTIAL 
Page 4 
9.2 Efficacy Analyses 
• 
EFS rate will be analyzed similarly as 
the DFS rate for patients in the EE 
analysis set. 
Update to “SAF analysis set”. 
 
Delete ITT set 
 
Add definition for no disease in DFS 
(R0 resection as surgery outcome) 
 
Add scenarios of sensitivity analysis 
• 
The Efficacy Evaluable 
(EE) Analysis Set 
includes all patients who 
receive neoadjuvant 
treatment followed by 
surgery per protocol, but 
for EFS, there may be 
patient who didn’t have 
surgery. 
• 
Since 213 is not a 
randomized study, ITT 
set is not applicable 
• 
To clarify the definition 
of no disease of DFS 
N 
N/A 
9.3.2 Adverse Events 
• 
Update definition of imAE and TEAE 
to be consistent with tislelizumab 
compound level TEAE definition 
• 
Separate imAE from 
TEAE to be consistent 
with tislelizumab 
compound level TEAE 
definition 
N 
N/A 
9.4 Sample Size 
Consideration 
• 
Update the sample size of patients for 
Cohort A and B 
• 
Update Estimates of 95% CI Using 
Clopper-Pearson in Cohort A and B 
• 
Based on the actual ratio 
of responders vs non-
responders observed. 
N 
N/A 
Appendix 2 
• 
Add footnote for “Random urine 
protein to creatinine ratio”: if urine 
protein is ≥ 2+ by dipstick, then 
obtain a 24-hour urine sample for 
total protein or random urine protein 
to creatinine ratio 
• 
Add test of Thyroid function 
• 
To keep consistent with 
compound level protocol 
template 
N 
N/A 
Appendix 9 
• 
FSH concentration > 30 IU/mL 
updated to “>30 mIU/mL “ 
• 
Error unit 
N 
N/A 
List of Abbreviations and 
Definitions of Terms 
• 
Update to List of Abbreviations and 
Definitions of Terms 
• 
Update table of 
abbreviations 
N 
N/A 

BBG-A317-213 
BeiGene 
Protocol Amendment 1.0, Summary of Changes 
22 July 2022 
 
CONFIDENTIAL 
Page 5 
List of Tables 
• 
Up numbering, referring and naming 
of tables 
• 
Delete duplicate tables 2, 9 and 10 in 
the main text 
 
Numbering and 
references of tables were 
disordered. 
N 
N/A 
Table 5: Immune-
Mediated Adverse Events 
of Any Grade Occurring 
in ≥ 1% in Pooled 
Monotherapy Studies 
• 
Update footnote NCI CTCAE v4.03 
to v5.0 
 
To keep consistent with 
other parts in the 
protocol 
N 
N/A 
Table 7 Selection and 
Timing of Dose for Each 
Patient 
• 
Update footnote “The total dose given 
must be between 60 to 80 mg/m2 per 
cycle.” Delete “between 60 to”. 
 
To keep consistent with 
other part of the 
protocol, dose of 
cisplatin should be 80 
mg/m2 
N 
N/A 
Table 8: Dose 
Modification based on 
Hematologic Nadir 
Values Prior to the Next 
Dose 
• 
Delete “Level 1 (Standard level) 
(Every 3 weeks as a cycle)” in the 
second column 
 
Not relevant title 
N 
N/A 
Table 9: Guidance for 
Duration of Recording 
New or Worsening 
Adverse Events 
• 
Update reporting period of imAE to 
“Up to 90 days after last dose of 
tislelizumab” 
• 
Keep consistent with 
compound level imAE 
definition 
N 
N/A