A Single-Arm, Multicenter, Open-Label, Phase 2 Study to Investigate the Efficacy and Safety of Tislelizumab (BGB-A317) as Neo-Adjuvant Treatment in Patients With Early-Stage (Stage II-III) Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer
Sponsor: BeiGene

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CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Single-Arm, Multicenter, Open-Label, Phase 2 Study to 
Investigate the Efficacy and Safety of Tislelizumab 
(BGB-A317) as Neo-Adjuvant Treatment in Patients With 
Early-Stage (Stage II-III) Microsatellite Instability-High 
(MSI-H) or Mismatch Repair Deficient (dMMR) 
Colorectal Cancer  
Protocol Identifier: 
BGB-A317-214 
Phase: 
2 
Investigational Products: 
Tislelizumab (BGB-A317)  
Indication: 
Neo-adjuvant treatment of Stage II or III Colorectal Cancer 
Sponsors: 
BeiGene (Shanghai) Co., Ltd.  
4th floor, Building D, 780 Cailun Road,  
China (Shanghai) Pilot-Free Trade Zone 
Shanghai, 201203 China 
Sponsor Medical Monitor: 
 
Telephone: 
 
Email: 
 
Original Protocol Version 0.0: 31 March 2021  
Amendment 1.0: 
06 June 2022 
Amendment 2.0: 
25 July2022 
 
 
 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, 
Ltd., and its subsidiaries.  This document is for use by individuals and their designated 
representatives for their confidential review, consideration, and/or participation in investigational 
trial(s).  This document may not be copied or distributed for review by any unauthorized 
individuals without the prior written authorization of BeiGene, Ltd., or one of its subsidiaries.  
Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without the prior written authorization from BeiGene, 
Ltd., or one of its subsidiaries. 

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FINAL PROTOCOL APPROVAL SHEET  
 
Protocol Title: 
A Single-Arm, Multicenter, Open-Label, Phase 2 Study to Investigate the 
Efficacy and Safety of Tislelizumab (BGB-A317) as Neo-Adjuvant Treatment 
in Patients With Early-Stage (Stage II-III) Microsatellite Instability-High 
(MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer 
 
BeiGene (Shanghai) Co., Ltd. Approval: 
 
_____________________________________ 
 
Sponsor Medical Monitor 
 
 
_____________________________ 
Date 
 

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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A Single-Arm, Multicenter, Open-Label, Phase 2 Study to Investigate the 
Preliminary Efficacy and Safety of Tislelizumab (BGB-A317) as 
Neo-Adjuvant Treatment in Patients With Early-Stage (Stage II-III) 
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient 
(dMMR) Colorectal Cancer 
 
Protocol Identifier: BGB-A317-214 
 
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 before implementation 
of this sponsor-approved protocol. PRINT your name, title, and the name of the center in which the 
study will be conducted. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
 
_____________________________ Date: _____________ 
Printed Name:  
 
 
 
 
_______________________________ 
Investigator Title:  
 
 
 
_______________________________ 
Name/Address of Center:  
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 

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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
SYNOPSIS  .............……………………………………………………………………………...11 
LIST OF ABBREVIATIONS AND TERMS ................................................................................17 
1. 
INTRODUCTION AND RATIONALES ..................................................................19 
1.1. 
Background Information on Microsatellite Instability-High or Mismatch 
Repair Deficient Colorectal Cancer ............................................................................19 
1.2. 
Current Treatment of Resectable Stage II and III Microsatellite 
Instability-High or Mismatch Repair Deficient Colorectal Cancer and Unmet 
Clinical Needs .............................................................................................................20 
1.3. 
Background Information on Tislelizumab ..................................................................21 
1.3.1. 
Pharmacology .............................................................................................................21 
1.3.2. 
Toxicology ..................................................................................................................22 
1.3.3. 
Clinical Pharmacology ................................................................................................22 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................22 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................22 
1.3.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................30 
1.4. 
Study Rationales .........................................................................................................30 
1.4.1. 
Rationale for Tislelizumab as Neo-adjuvant Treatment of Resectable 
Microsatellite Instability-High or Mismatch Repair Deficient CRC ..........................30 
1.4.2. 
Rationale for Selection of Tislelizumab Dose and Treatment Duration .....................31 
1.4.3. 
Biomarker Strategy Rationale.....................................................................................32 
1.5. 
Benefit-Risk Assessment ............................................................................................33 
1.6. 
Study Conduct ............................................................................................................34 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................35 
2.1. 
Study Objectives .........................................................................................................35 
2.1.1. 
Primary Objective .......................................................................................................35 
2.1.2. 
Secondary Objectives .................................................................................................35 
2.1.3. 
Exploratory Objectives ...............................................................................................35 

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2.2. 
Study Endpoints ..........................................................................................................35 
2.2.1. 
Primary Endpoint ........................................................................................................35 
2.2.2. 
Secondary Endpoints ..................................................................................................35 
2.2.3. 
Exploratory Endpoints ................................................................................................36 
3. 
STUDY DESIGN .......................................................................................................37 
3.1. 
Summary of Study Design ..........................................................................................37 
3.2. 
Prescreening Period ....................................................................................................37 
3.3. 
Screening Period .........................................................................................................37 
3.4. 
Treatment Period ........................................................................................................38 
3.5. 
End-of-Treatment/Safety Follow-up ..........................................................................39 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................39 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................39 
3.6.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) ...........40 
3.7. 
End of Study ...............................................................................................................40 
4. 
STUDY POPULATION .............................................................................................42 
4.1. 
Inclusion Criteria ........................................................................................................42 
4.2. 
Exclusion Criteria .......................................................................................................43 
5. 
STUDY TREATMENT ..............................................................................................46 
5.1. 
Formulation, Packaging, and Handling ......................................................................46 
5.2. 
Dosage, Administration, and Compliance ..................................................................46 
5.3. 
Surgery ........................................................................................................................46 
5.4. 
Incorrect Administration or Overdose ........................................................................47 
5.5. 
Investigational Medicinal Product Accountability .....................................................47 
5.6. 
Dose Delay or Modification .......................................................................................47 
5.6.1. 
Dose Interruptions or Delay for Study Drugs .............................................................48 
5.6.2. 
Dose Reductions for Study Drugs ..............................................................................48 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................49 
6.1. 
Prior Therapy ..............................................................................................................49 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................49 
6.2.1. 
Systemic Corticosteroids ............................................................................................49 
6.2.2. 
Hepatitis B Treatment .................................................................................................49 
6.2.3. 
Hepatitis C Treatment .................................................................................................49 

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6.3. 
Prohibited Concomitant Medications/Procedures ......................................................50 
6.4. 
Restricted Concomitant Medications/Procedures .......................................................50 
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................50 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
7.1. 
Prescreening ................................................................................................................51 
7.2. 
Screening ....................................................................................................................51 
7.2.1. 
Informed Consent and Screening Log ........................................................................52 
7.2.2. 
Demographic Data and Medical History ....................................................................52 
7.2.3. 
Women of Childbearing Potential and Contraception ................................................52 
7.2.4. 
Pulmonary Function Tests ..........................................................................................52 
7.3. 
Enrollment ..................................................................................................................53 
7.3.1. 
Confirmation of Eligibility .........................................................................................53 
7.3.2. 
Patient Numbering ......................................................................................................53 
7.4. 
Study Drug Dispensation ............................................................................................53 
7.5. 
Safety Assessments .....................................................................................................53 
7.5.1. 
Vital Signs ..................................................................................................................53 
7.5.2. 
Physical Examinations ................................................................................................53 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status ........................................54 
7.5.4. 
Laboratory Safety Tests ..............................................................................................54 
7.5.4.1. 
Cardiac Enzyme Monitoring .......................................................................................54 
7.5.5. 
Electrocardiograms .....................................................................................................54 
7.5.6. 
Adverse Events ...........................................................................................................54 
7.5.7. 
Hepatitis B and C Testing ...........................................................................................54 
7.6. 
Tumor and Response Evaluations ..............................................................................55 
7.7. 
Biomarkers ..................................................................................................................55 
7.8. 
Visit Windows ............................................................................................................56 
7.9. 
Unscheduled Visits .....................................................................................................56 
8. 
SAFETY MONITORING AND REPORTING .........................................................57 
8.1. 
Risks Associated With Study Drugs ...........................................................................57 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................57 
8.2. 
General Plan to Manage Safety Concerns ..................................................................57 
8.2.1. 
Eligibility Criteria .......................................................................................................57 

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8.2.2. 
Safety Monitoring Plan ...............................................................................................57 
8.3. 
Adverse Events ...........................................................................................................58 
8.3.1. 
Definitions and Reporting ...........................................................................................58 
8.3.2. 
Assessment of Severity ...............................................................................................58 
8.3.3. 
Assessment of Causality .............................................................................................59 
8.3.4. 
Follow-up of Adverse Events .....................................................................................60 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................60 
8.4. 
Definition of a Serious Adverse Event .......................................................................61 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................62 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................62 
8.6.1. 
Adverse Event Reporting Period ................................................................................62 
8.6.2. 
Reporting Serious Adverse Events .............................................................................63 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................63 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................63 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................63 
8.6.3. 
Eliciting Adverse Events ............................................................................................64 
8.6.4. 
Disease Progression ....................................................................................................64 
8.6.5. 
Deaths .........................................................................................................................64 
8.6.6. 
Pregnancies .................................................................................................................64 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................64 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................65 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................65 
8.7. 
Management of Adverse Events of Special Interest ...................................................65 
8.7.1. 
Infusion-Related Reactions .........................................................................................65 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................67 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................67 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................69 
9.1. 
Statistical Analysis ......................................................................................................69 
9.1.1. 
Analysis Sets ...............................................................................................................69 
9.1.2. 
Patient Disposition ......................................................................................................69 
9.1.3. 
Demographic and Other Baseline Characteristics ......................................................69 

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9.1.4. 
Prior and Concomitant Medications ...........................................................................69 
9.2. 
Efficacy Analyses .......................................................................................................70 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................70 
9.2.2. 
Secondary Efficacy Analyses .....................................................................................70 
9.3. 
Biomarker Analysis ....................................................................................................70 
9.4. 
Safety Analyses ..........................................................................................................70 
9.4.1. 
Extent of Exposure .....................................................................................................71 
9.4.2. 
Adverse Events ...........................................................................................................71 
9.4.3. 
Laboratory Analyses ...................................................................................................71 
9.4.4. 
Vital Signs ..................................................................................................................72 
9.5. 
Sample Size Consideration .........................................................................................72 
9.6. 
Interim Analyses .........................................................................................................72 
10. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................73 
10.1. 
Access to Information for Monitoring ........................................................................73 
10.2. 
Access to Information for Auditing or Inspections ....................................................73 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................74 
11.1. 
Regulatory Authority Approval ..................................................................................74 
11.2. 
Quality Assurance .......................................................................................................74 
11.3. 
Study Site Inspections.................................................................................................74 
11.4. 
Drug Accountability ...................................................................................................74 
12. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................76 
12.1. 
Ethical Standard ..........................................................................................................76 
12.2. 
Institutional Review Board/Independent Ethics Committee ......................................76 
12.2.1. 
Protocol Amendments ................................................................................................76 
12.3. 
Informed Consent .......................................................................................................76 
12.4. 
Patient and Data Confidentiality .................................................................................77 
12.5. 
Financial Disclosure ...................................................................................................79 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................80 
13.1. 
Data Collection and Management Responsibilities ....................................................80 
13.1.1. 
Data Entry in the Electronic Case Report Form .........................................................80 
13.1.2. 
Data Collection ...........................................................................................................80 
13.1.3. 
Data Management/Coding ..........................................................................................80 

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13.2. 
Data Integrity and In-house Blinding .........................................................................81 
13.3. 
Study Records Retention ............................................................................................81 
13.4. 
Protocol Deviations ....................................................................................................82 
13.5. 
Study Report and Publications....................................................................................82 
13.6. 
Completion of the Study and Study Center Closure ...................................................82 
13.7. 
Information Disclosure and Inventions ......................................................................83 
14. 
REFERENCES ...........................................................................................................85 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................90 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ................................................94 
APPENDIX 3. ECOG PERFORMANCE STATUS...................................................................95 
APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ..................................................................96 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................105 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................106 
APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................107 
APPENDIX 8. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................117 
APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................119 
 
LIST OF TABLES  
Table 1: 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies.......................................23 
Table 2: 
Adjudicated Immune-Mediated Adverse Events of Any Grade Occurring in 
≥ 2 Patients in Pooled Monotherapy Studies ..............................................................25 
Table 3: 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in 
Pooled Monotherapy Studies ......................................................................................28 
Table 4: 
Guidance for Duration of Recording New or Worsening Adverse Events ................62 
Table 5: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................63 
Table 6: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Study Drugs ............................................................................................................66 

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Table 7: 
Immune-Mediated Adverse Events ............................................................................68 
Table 8:    95% CI of MPR rate under different assumptions of MPR estimate ...........................72 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................37 
 

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SYNOPSIS  
Name of Sponsor/Company:  BeiGene (Shanghai) Co., Ltd. 
Investigational Products: Tislelizumab (also known as BGB-A317) 
Title of Study: A Single-Arm, Multicenter, Open-Label, Phase 2 Study to Investigate the Efficacy and 
Safety of Tislelizumab (BGB-A317) as Neo-Adjuvant Treatment in Patients With Early-Stage (Stage II-
III) Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer 
Protocol Identifier: BGB-A317-214 
Phase of Development: 2 
Number of Patients: Approximately 38 
Study Centers: Approximately 8 sites in China 
Study Objectives: 
Primary: 
• 
To evaluate major pathological response (MPR) rate in patients receiving tislelizumab as 
neo adjuvant treatment. 
Secondary: 
• 
To evaluate pathological complete response (pCR) rate in patients receiving tislelizumab as 
neo-adjuvant treatment. 
• 
To evaluate event-free survival (EFS) in patients receiving tislelizumab as neo-adjuvant 
treatment.  
• 
To explore potential biomarkers that may correlate with clinical responses/resistance to 
tislelizumab as neo-adjuvant treatment. 
• 
To evaluate the safety and tolerability of neo-adjuvant treatment with tislelizumab in patients 
with early-stage (Stage II-III) Microsatellite Instability-High (MSI-H) or Mismatch Repair 
Deficient (dMMR) colorectal cancer. 
Exploratory: 
• 
To evaluate R0 resection rate in patients receiving tislelizumab as neo-adjuvant treatment  
• 
To evaluate perioperative events (including but not limited to treatment related surgery delay, 
postoperative complication) in patients receiving tislelizumab as neo-adjuvant treatment.  
Study Endpoints: 
Primary: 
• 
MPR rate is defined as the proportion of patients with ≤ 10% residual viable tumor in the 
resected primary tumor after completion of neo-adjuvant therapy in an efficacy analysis set. 
Secondary: 
• 
The 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 neo-adjuvant therapy in 

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an efficacy analysis set. 
• 
EFS is defined as the time from first dose until any of the following events, whichever occurs 
first: radiographic disease progression according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1, local or distant recurrence, or death due to any cause in an efficacy 
analysis set. 2-year/3-year EFS rate is defined as the proportion of patients free from EFS events 
at 2 years and 3 years estimated using the Kaplan-Meier method.  
• 
Potential biomarkers including immune cell infiltration, programmed cell death protein ligand-1 
(PD‑L1) expression, tumor mutational burden (TMB) and DNA mutation, gene expression 
profile (GEP) and the association of biomarkers with disease status, response/resistance to 
tislelizumab as neo-adjuvant treatment. 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs), including serious adverse 
events and immune-mediated adverse events (imAEs), with severity determined according to 
National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0 (NCI 
CTCAE v5.0) in a safety analysis set. 
Exploratory: 
• 
R0 resection rate - defined as the proportion of patients with R0 resection 
• 
To evaluate perioperative events (including but not limited to treatment related surgery delay, 
postoperative complication) in patients receiving tislelizumab as neo-adjuvant treatment. 
Study Design: 
This is an open-label, multicenter Phase 2 study designed to investigate the preliminary efficacy and safety 
of tislelizumab monotherapy as neo-adjuvant treatment in approximately 38 patients with early-stage 
(Stage II-III) Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR)colorectal 
cancer. 
The study consists of a prescreening and/or screening phase, a treatment phase that includes a neo-
adjuvant phase, surgery and disease follow-up phase. 
The study schema is presented in Figure 1, Section 3.1   
Neo-adjuvant Phase: 
During the neo-adjuvant phase, patients who are found to have disease progression at scheduled tumor 
assessments (before Cycle 3 and surgery) or at any time during neo-adjuvant treatment and are still 
deemed resectable and non-metastatic will proceed to receive surgery if amenable and will remain eligible 
for all on-study evaluations based on investigator’s judgement. 
Patients who discontinue neo-adjuvant treatment early because of urgent surgery (eg., because of intestinal 
obstruction, intestinal perforation, or intestinal bleeding), disease progression or intolerable AEs and do 
not proceed to a complete resection will proceed to receive other treatment as determined by the 
investigator. Further in-clinic study procedures of these patients should be discussed with the medical 
monitor. 
Surgery: 
Upon completion of neo-adjuvant therapy, patients will undergo surgical resection of their tumor. Surgical 
specimens will be assessed for pathological response (MPR and pCR). In addition, exploratory biomarker 
analysis of surgical specimens (primary tumor tissue and dissected lymph nodes) will be performed. 

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Before surgery, the investigator will reassess the patient to reconfirm disease resectability. The presurgical 
visit and associated assessments should occur within 14 days of surgery and in accordance with local 
institutional practice.  
The surgical procedure should be performed within 10 weeks from the first administered dose of study 
treatment. If surgery cannot be performed within this time window (eg, because of a prolonged AE), the 
medical monitor should be consulted. The investigator and the medical monitor will determine the 
acceptable length of this time window. Complete resection (R0) should be performed. 
Disease Follow-up Phase: 
Patients will continue adjuvant treatment and perform follow-up which will be determined by the 
investigator according to the stage of disease and benefit-risk assessment in accordance with the relevant 
clinical practice (eg. Colon and Rectal Cancer NCCN (National Comprehensive Cancer Network) 
guidelines, Chinese Society of Clinical Oncology (CSCO)guideline). Patients will continue to undergo 
tumor assessments following the original plan until the patient experiences disease progression or 
recurrent according to RECIST v 1.1, withdraws consent, is lost to follow up, death, begins a new 
anticancer therapy or until the study terminates, whichever occurs first. 
Study Assessments: 
Patients with the diagnosis of Stage II-III colorectal cancer and with unknown MSI and MMR status are 
required to provide blood and tumor tissues for central laboratory confirmation of MSI status during the 
prescreening period (defined as within 56 days prior to the first dose of the study drug). Approximately 
2 mL peripheral whole blood together with tumor tissues (archival formalin-fixed paraffin-embedded 
[FFPE] blocks or at least 10 freshly cut unstained slides) are required for central laboratory confirmation 
of MSI status. 
Patients with known MSI-H status by local laboratory must undergo central laboratory assessment of 
MSI-H during or after the screening period if tumor samples are obtainable. For patients with known 
dMMR status determined by local laboratory, central laboratory confirmation of MSI-H status will be 
performed during the screening period for enrollment. Approximately 2 mL peripheral whole blood 
together with tumor tissues (archival FFPE blocks or at least 10 freshly cut unstained slides) are required 
for central laboratory assessment/confirmation of MSI-H. Available paired tumor tissues need to be sent 
for retrospective analysis of other exploratory biomarkers related to response and resistance in sponsor 
designated central or test laboratory. A fresh biopsy is mandatory in the absence of archival tumor tissues.  
Tumor imaging will be performed ≤ 28 days before first dose. During the study, tumor assessment will be 
performed after neo-adjuvant treatment and before surgery (9 weeks ± 7 days after first dose). After 
surgery, the post-surgery treatment and the follow up will determined by investigator. During this period 
tumor assessment will be performed every 12 weeks (± 14 days) for the first 3 years, and then every 24 
weeks (± 28 days) for a total 5 years, and then once (± 28 days) each year thereafter based on RECIST 
v1.1. Patients will continue with the scheduled tumor assessments until radiographic disease progression 
or recurrent per RECIST v1.1, withdrawal of consent, loss to follow-up, study termination by the sponsor, 
start of a new anticancer therapy (excluding adjuvant therapy), or death, whichever occurs first. 
Patients will be evaluated for adverse events (AEs) and immune-mediated adverse events (imAEs) (all 
grades according to NCI-CTCAE v5.0). Serious adverse events (SAEs) and any AEs that lead to treatment 
discontinuation will be followed and documented until the event is resolved, the investigators assess the 
event as stable, or the patient is lost to follow-up, whichever occurs first.  
After initiation of study drug, all AEs and SAEs, regardless of the relationship to the study drug, will be 
reported until either 30 days after the last dose of study treatment or initiation of new anticancer therapy, 
whichever occurs first.  All imAEs (serious or nonserious) should be reported up to 90 days after the last 
dose of tislelizumab, regardless of whether the patient starts a new anticancer therapy. 

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Duration of Patient Participation: 
The duration of the study from the first enrolled patient to the final analysis for three-year EFS is 
estimated to be approximately 50 months and from the first enrolled patient to the time of primary analysis 
is estimated to be approximately 16 months 
Study Population:  
The study will enroll approximately 38 patients who meet the following inclusion/exclusion criteria. 
Key Eligibility Criteria: 
Key Inclusion Criteria: 
• 
Age ≥18 years on the day of signing the ICF.  
• 
ECOG Performance Status of 0 or 1.  
• 
Pathologically (histologically) confirmed diagnosis of potentially resectable Stage II or Stage III 
(per the Eighth American Joint Committee on Cancer staging system for Colon/Rectal Cancer) 
colorectal cancer (CRC) with MSI-H confirmed by sponsor designated central laboratory or 
known MSI-H status by local laboratory. Patients should be eligible for an R0 resection with 
curative intent. 
• 
Evaluable or measurable disease as assessed by the investigator per RECIST v1.1. 
• 
With unknown MSI status by local laboratory, patients must provide blood (approximately 2 mL 
peripheral whole blood) and tumor tissues (archival FFPE blocks or at least 10 freshly cut 
unstained slides) for central laboratory MSI confirmation. Patients must be able to provide paired 
tumor tissues (pre-treatment and post-treatment tumor tissues as FFPE blocks or approximately 
14 [≥ 10] freshly cut unstained slides) for retrospective analysis of other exploratory biomarkers 
related to response and resistance. A fresh biopsy is mandatory in the absence of pre-treatment 
archival tumor tissues.  
• 
Adequate hematologic and organ function, defined by protocol-specified laboratory test results, 
obtained within 14 days before first dose 
 
Key Exclusion Criteria: 
• 
Any prior therapy for current CRC, including chemotherapy or radiotherapy or immunotherapy 
• 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
or equivalent) or other immunosuppressive medications within 14 days before first dose. 
• 
Active autoimmune diseases or history of autoimmune diseases that may relapse 
Test Product, Dose, and Mode of Administration:  
Tislelizumab will be administered at a dose of 200 mg intravenously once every 3 weeks. 
Reference Therapy, Dose, and Mode of Administration:  
Not applicable.  
Statistical Methods: 

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This study is designed to evaluate the safety and efficacy of neo-adjuvant treatment with Tislelizumab 
(BGB-A317) in patients with early-stage (Stage II-III) Microsatellite Instability-High (MSI-H) or 
Mismatch Repair Deficient (dMMR) Colorectal Cancer. Details of statistical analyses will be described in 
Statistical Analysis Plan. 
Analysis Sets: 
The Safety Analysis Set (SAS) includes all enrolled patients who received ≥ 1 dose of study drug; it will 
be the analysis set for the safety analyses.  
The Efficacy Analysis Set (EAS) includes all enrolled patients who receive neo-adjuvant treatment 
followed by surgery. This will be the primary analysis set for the efficacy analyses. 
Safety Analyses: 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles received 
(number and percentage of patients), duration of exposure (days), cumulative total dose received per 
patient (mg), dose intensity, and relative dose intensity. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drugs and up to 30 days after study drug discontinuation 
or initiation of new anticancer therapy, whichever occurs first. Only those AEs that were treatment 
emergent will be included in summary tables of TEAEs. Immune-mediated AEs will be identified from all 
AEs that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first 
dose of tislelizumab and up to 90 days from the last dose of tislelizumab, regardless of whether the patient 
starts a new anticancer therapy. If an imAE occurs outside of the above-mentioned TEAE window, it will 
not be classified as a TEAE. All imAEs will be reported separately. All AEs, treatment emergent or 
otherwise, will be presented in patient data listings.  
Laboratory values (eg, hematology, clinical chemistry, and urinalysis), vital signs, electrocardiograms 
(ECGs), and the results of physical examinations will also be used to assess the safety profile. Descriptive 
statistics will be used to analyze all safety data in the SAS.  
Primary Efficacy Analysis: 
MPR rate is the primary endpoint of the study. MPR rate is defined as the proportion of patients in the 
EAS with ≤ 10% residual viable tumor in the resected primary tumor after completion of neo-adjuvant 
therapy in an efficacy analysis set. The MPR rate will be summarized descriptively, and the Clopper-
Pearson 95% confidence interval (CI) will be calculated to evaluate the precision of MPR estimate. The 
analysis of MPR rate will occur after all the patients in the efficacy analysis set have been assessed for 
pathological response 
Secondary Efficacy Analysis: 
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 neo-adjuvant therapy followed by surgery 
assessed by investigator in the efficacy analysis set. The pCR rate will be summarized descriptively and a 
Clopper-Pearson 95% CI will also be calculated. 
EFS is defined as the time from the time of first dose until any of the following events, whichever occurs 
first: radiographic disease progression according to RECIST v1.1, local or distant recurrence, or death due 
to any cause in the EAS. The median and other quartiles of EFS will be estimated using the Kaplan-Meier 
method. The 2-sided 95% CIs will be constructed with the generalized Brookmeyer and Crowley method 
(Brookmeyer et al, 1982). 2-year/3-year EFS rate is defined as the proportion of patients free from EFS 
events at 2 years and 3 years after the first dose. EFS rates will be estimated by the Kaplan-Meier method 
with 95% CI estimated using Greenwood’s formula (Greenwood et al, 1926).  

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Biomarker Analysis: 
Potential biomarkers will be analyzed, including immune cell infiltration, programmed cell death protein 
ligand-1 (PD‑L1) expression, tumor mutational burden (TMB) and DNA mutation, gene expression 
profile (GEP) and the association of biomarkers with disease status, response/resistance to tislelizumab as 
neo-adjuvant treatment. 
Sample Size Considerations: 
Sample size is based on clinical considerations. Thirty Evaluable patients will be enrolled to receive neo-
adjuvant treatment followed by surgery, and will provide a reasonably robust estimate and precision (95% CI) 
of the primary endpoint MPR rate. Table 8 (see Section 9.5) summarizes the 95% CI of MPR rate under 
different assumptions of MPR estimate. With 20% drop out rate, a total of 38 patients will be enrolled in 
this study. 
 

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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-A317 
tislelizumab  
BOR 
best overall response 
CC 
colon cancer 
CI 
confidence interval 
CL 
clearance 
CR 
complete response 
CT 
computed tomography 
CPI 
checkpoint inhibitor 
CRC 
colorectal cancer 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EFS 
event-free survival 
EOT 
end of treatment 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICI 
immune checkpoint inhibitor 
imAE 
immune-mediated adverse event 
IRC 
Independent Review Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
mismatch repair 
MPR 
major pathological response 

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Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
microsatellite instability-high 
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-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
R0 
complete resection 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEF 
treatment eligibility form  
TMB 
tumor mutational burden 
TTR 
time to response 
ULN 
upper limit of normal 
 

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1. 
INTRODUCTION AND RATIONALES  
1.1. 
Background Information on Microsatellite Instability-High or 
Mismatch Repair Deficient Colorectal Cancer  
Colorectal cancer (CRC) is the fourth most common malignancy and the fifth leading cause of 
cancer death in China, with an estimation of 376.300 newly diagnosed cases and approximately 
191.000 deaths in 2015 (Chen et al, 2016). Overall, the burden of CRC in China is relatively 
high. Moreover, the incidence of colorectal cancer continued to rise during the past 15 years 
(Zheng et al, 2018). Since 2004, the cancer screening programs promoted early detection and 
diagnosis of CRC. One mass screening study demonstrated that the detection ratios of localized 
CRCs were 17.4%, 23% and 25.9% for Stage I, Stage II and Stage III respectively (Lin et al, 
2019). The invasive cancers were found in the majority of new diagnosed CRCs.  
Microsatellite instability (MSI) is characterized by alterations in the genome-wide microsatellite 
repeats, consisting of repeated sequences of 1 to 6 nucleotides (Yamamoto et al, 2020; Li et al, 
2020). It is a molecular tumor phenotype resulting from genomic hypermutability. The gain or 
loss of nucleotides from microsatellite tracts - DNA elements composed of short repeating motifs 
- is the diagnostic hallmark of MSI (De la Chapelle et al, 2010). These changes can arise from 
impairments in the mismatch repair (MMR) system (Vilar et al, 2010; Oki et al, 1999). 
On the basis of mutation patterns, CRC can be categorized into two discrete groups: tumors that 
are a mismatch- repair-deficient (dMMR)or have high levels of microsatellite instability (MSI- 
H) (termed dMMR/MSI- H tumors) signature and high overall mutation burden and tumors that 
have a mismatch- repair-proficient (pMMR) and are microsatellite- stable (MSS) or have low 
levels of microsatellite instability (MSI- L) (termed pMMR/MSI-L tumors) signature with a 
much lower mutation burden(Cancer Genome Atlas Network, 2012). Importantly, MSI-
H/dMMR tumors lead to a high tumor mutational burden, with highly immunogenic neoantigens 
arising from frameshift mutations. As a consequence, tumors of this subgroup are highly 
infiltrated by cytotoxic T lymphocytes in comparison with other CRCs (Llosa et al, 2015; Marisa 
et al, 2018; Rosenbaum et al, 2016; Maby et al, 2015). 
Approximately 15-20% of all CRCs are MSI-H/dMMR. Germline mutations in MMR genes are 
found in patients with Lynch syndrome which is responsible for 2%-4% of colon cancer (CC) 
cases. Somatic defects in MMR gene function were reported occur in approximately 19% of 
colorectal tumors (NCCN Guidelines, 2021). MSI-H/dMMR is more common in localized 
cancer (10–15% compared to 5% of metastatic CRC) (André et al, 2015 ; Chalabi et al, 2020) and 
Stage II disease may have higher MSI-H frequency than Stage III disease (22% vs. 12%) (Roth 
et al, 2010).  
The presence of MSI-H/dMMR disease is prognostic, as Stage II MSI-H/dMMR tumors have a 
lower risk of recurrence than Stage II pMMR/MSI- L tumors (Popat et al, 2005). So MSI-
H/dMMR status has been used in the adjuvant setting as a positive prognostic parameter and it is 
also used for therapeutic management because fluoropyrimidines alone are not indicated in the 
adjuvant setting for patients with Stage II MSI-H/dMMR CRC, given their favorable survival 
and the lack of impact of chemotherapy in this situation (Ribic et al, 2003; Sargent et al, 2010). 
In contrast, patients with MSI-H/dMMR tumors that metastasize have a dismal prognosis 
(Venderbosch et al, 2014), but expression of programmed cell death protein-1 (PD-1), 

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programmed cell death protein-1 (PD-L1) and CTLA-4 is substantially upregulated in their 
cancers (Llosa et al, 2015). These observations suggested that MSI-H/dMMR CRCs might 
respond well to immune checkpoint blockade.  
1.2. 
Current Treatment of Resectable Stage II and III Microsatellite 
Instability-High or Mismatch Repair Deficient Colorectal Cancer 
and Unmet Clinical Needs  
Currently, for patients with resectable Stage II-III CC, resection is the recommended modality, 
which includes laparoscopic and conventional colectomy with en bloc removal of the regional 
lymph nodes. Post-surgery, adjuvant therapy with a fluoropyrimidine alone is the standard of 
care for Stage II CC harboring high-risk features. High-risk assessment should consider the 
potential risks of therapy compared to potential benefit including number of lymph nodes 
analyzed (less than 12), poor prognostic features (poor differentiation [exclusive of those that are 
MSI-H], lymphatic or venous invasion, perineural invasion, obstruction and perforation, positive 
margins) and other comorbidities and anticipated life expectancy. For Stage III diseases, 
combination therapy with fluoropyrimidine and oxaliplatin for 3–6 months is recommended as 
adjuvant therapy (Sobrero et al, 2020; Grothey et al, 2018; Iveson et al, 2019; NCCN Guidelines, 
2021). For patients with resectable Stage II-III rectal cancer, preoperative chemoradiation 
followed by radical surgery is recommended by International treatment guidelines (NCCN 
Guidelines, 2021).  
Data on neo-adjuvant chemotherapy in CCs are limited. The phase 3 FOxTROT study 
(NCT00647530) provided useful data about such strategies for CC patients (Seymour et al, 
2019). In this randomized trial, 1052 patients with localized CC were randomized to a 
perioperative sequence (6 weeks of FOLFOX, then surgery, then 18 weeks of FOLFOX) or the 
standard strategy (surgery then 24 weeks of FOLFOX). Neo-adjuvant treatment was well 
tolerated and associated with evidence of histological regression in 59% of patients (4% of 
pathological complete response [pCR]), histological downstaging and reduced rate of incomplete 
resections (5% vs. 10%). In this study a trend toward improved survival was found in patients 
receiving neo-adjuvant chemotherapy. Importantly, FOXTROT was the first study to show that 
pathological response to neo-adjuvant treatment in CCs is closely related to recurrence risk, with 
0% and 8% recurrences in patients with a pCR and marked regression, respectively, compared 
with 26% for patients with no regression. Based on these study results, the option for 
neo-adjuvant therapy with FOLFOX and CAPEOX was added to the NCCN guidelines for the 
treatment of CC. Furthermore, important data from the FOxTROT study relating to the MMR 
status was reported: 95% of patients with dMMR tumors who received neo-adjuvant 
chemotherapy (n = 106) showed little or no response, and only 8.1% of patients with pMMR 
tumors (n = 592) had major pathological responses (MPRs) to neo-adjuvant chemotherapy. 
With the knowledge of the immunogenic microenvironment in MSI-H/dMMR tumor, several 
clinical trials have demonstrated improved outcomes for patients with MSI-H/dMMR in 
metastatic CRC treated with inhibitors of PD-1(Le et al, 2016; Overman et al, 2017; Overman et 
al, 2018; Andre et al, 2018; Lenz et al, 2018). With these results, FDA granted approval for the 
PD-1 blocking antibodies, pembrolizumab and nivolumab for the indication of MSI-H/dMMR 
metastatic CRC, respectively. 

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After these initial successes with MSI-H/dMMR CRC in metastatic setting, the development of 
immune checkpoint inhibitors (ICI) for early-stage colorectal cancer specially as neo-adjuvant 
treatment also has demonstrated impressive tumor response. In the NICHE study, patients with 
early-stage CC received a neo-adjuvant treatment with ipilimumab plus nivolumab before 
surgery(Chalabi et al, 2020). Strikingly, total all 21 dMMR CC patients had a pathological 
response, with 95% of MPRs (≤10% of residual viable tumor in the surgical specimen), 
including 12 (60%) of pCRs. With a median follow-up of 8.1 months, all dMMR CC patients 
from the NICHE study were alive and disease free. The treatment was well tolerated, and only 5 
patients (13%) who experienced Grade 3 or 4 treatment-related toxicity.  
Although MSI-H/dMMR is a favorable prognostic feature in localized (Stage I–III) CCs, T4 
stage and N2 stage are currently the best-known prognosticators for the MSI-H/dMMR 
population (Sinicrope et al, 2019; Sinicrope et al, 2013). In this population, the 3 -year disease-
free survival rates are approximately 60–65% for T4 and/or N2 Stage III tumors, compared to 
90% for low-risk MSI-H/dMMR Stage III CC patients. There is an urgent need for therapeutic 
improvements for patients with high-risk Stage III MSI-H/dMMR CC. Furthermore, pathological 
response (pCR and marked regression) to neo-adjuvant treatment in CCs is closely related to 
recurrence risk. The neo-adjuvant treatment may improve disease-free survival by reducing 
primary tumor burden before surgery. However, the clinical research of immune checkpoint 
inhibitors (ICI) for early-stage colorectal cancer was scarce in China.  
In summary, for early-stage MSI-H/dMMR CRCs, identifying patients who are at risk of disease 
recurrence, providing appropriate neo-adjuvant treatment with immune checkpoint inhibitors 
(ICI) and refining therapeutic strategies, are urgently unmet needs to improve the prognostication 
of MSI-H/dMMR CRC patients. 
1.3. 
Background Information on Tislelizumab  
1.3.1. 
Pharmacology  
Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against 
PD-1 under clinical development for the treatment of several human malignancies.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity ([KD] = 0.15 nM). It competitively blocks binding efforts by both PD-L1 
and programmed cell death protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative 
signaling in T cells. In in vitro cell-based assays, tislelizumab was observed to consistently and 
dose-dependently enhance the functional activity of human T cells and to preactivated, primary 
peripheral blood mononuclear cells (PBMCs). In addition, tislelizumab has demonstrated 
antitumor activity in several allogeneic xenograft models, in which peripheral blood 
mononuclear cells were coinjected with human cancer cells (A431 [epidermoid carcinoma]) or 
tumor fragments (BCCO-028 [colon cancer]) into immunocompromised mice.  
Tislelizumab is an IgG4-variant antibody to FcγR such as FcγRI and FcγRIIIA, and it has very 
low binding affinity to C1q, a subunit of complement 1. In vitro assays with tislelizumab suggest 
either low or no ADCC, antibody-dependent cellular phagocytosis (ADCP) or 
complement-dependent cytotoxicity (CDC) effects in humans (Labrijn et al, 2009; Zhang et al, 
2018). Tislelizumab was specifically engineered to abrogate these potential mechanisms of T-
cell CL and potential resistance to anti-PD-1 therapy. 

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Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.3.2. 
Toxicology  
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys and in a 13-week repeated-dose toxicology study in 
cynomolgus monkeys. The tissue cross-reactivity was evaluated in the normal frozen tissues 
from both humans and monkeys. The cytokine release assays were also evaluated using fresh 
human peripheral blood mononuclear cells. The pivotal toxicology studies were conducted 
following GLP regulations. The single dosing regimens spanned from the intended human doses 
to 10-fold higher than the maximum of the intended human doses, and the repeat dosing 
regimens spanned to 3-fold higher than the maximum of the intended human doses. The 
cynomolgus monkey was the only relevant species based on the target sequence homology and 
binding activity.  
Overall, no apparent toxicity was noted in mouse 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 (NOAEL) 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-A317-214. 
Please refer to the Tislelizumab Investigator’s Brochure, for more detailed information on the 
toxicology of tislelizumab. 
1.3.3. 
Clinical Pharmacology  
Based on pooled data from 2596 patients across 12 clinical studies, the pharmacokinetic (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 
Cmax and AUC increased in a nearly dose-proportional manner from 0.5 to 10 mg/kg.  The 
terminal t1/2 was estimated to be approximately 23.8 days, and the steady state is expected to be 
reached in 12 weeks.  Tislelizumab PK was generally similar between Chinese patients and 
patients of other ethnic groups and across tumor types.  Please refer to the Tislelizumab 
Investigator’s Brochure for more detailed information on the clinical pharmacology of 
tislelizumab. 
1.3.4. 
Prior Clinical Experience of Tislelizumab  
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on safety 
and efficacy of tislelizumab. 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
As of 20 May 2021, there were 2150 patients in the pooled monotherapy studies: 1992 patients 
treated in 7 solid tumor studies and 158 patients treated in 3 hematologic malignancy studies.  

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Solid tumor studies included the following: BGB-A317_Study_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 previously-treated 
unresectable hepatocellular carcinoma [HCC]), BGB-A317-209 (Phase 2 previously-treated 
locally advanced unresectable or metastatic MSI-H or mismatch repair deficient [dMMR] solid 
tumors), BGB-A317-302 (Phase 3 advanced unresectable/metastatic esophageal squamous cell 
carcinoma), and BGB-A317-303 (Phase 3 non-small cell lung cancer [NSCLC]). 
A pooled monotherapy analysis in solid tumor was conducted to provide a comprehensive 
review of the tislelizumab safety profile.  Patients included in this analysis (N = 1992) had a 
median age of 60.0 years with 72.1% of them being male.  Median treatment exposure duration 
was 4.1 months (range: 0.1 to 41.5), and median study follow-up duration was 11.5 months 
(range: 0.1 to 58.9). 
1.3.4.1.1. Pooled Demographics and Baseline Characteristics  
Table 1 shows the demographics and baseline characteristics for the patients with solid tumors 
treated in the pooled monotherapy studies. 
Table 1: 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies 
Solid Tumor Studiesa 
(N = 1992) 
Age (Years) 
 
Median 
60.0 
Min, Max 
18, 90 
Sex, n(%) 
 
Male 
1437 (72.1) 
Female 
555 (27.9) 
Race, n(%) 
 
White 
532 (26.7) 
Asian 
1383 (69.4) 
Other 
55 (2.8) 
Missing 
22 (1.1) 
Time Since Diagnosis (Years) 
 
Median 
1.255 
Min, Max 
0.02, 40.96 
Baseline ECOG Performance Status, n(%) 
 
0 
654 (32.8) 
1 
1338 (67.2) 
2 
0 (0.0) 
Missing 
0 (0.0) 
Prior Systemic Anticancer Therapy Regimensb 
 
Median 
1.0 
Min, Max 
0, 12 
Prior Systemic Anticancer Therapy Regimensb (Grouped), n(%) 
 
0 
318 (16.0) 
1 
1055 (53.0) 
2 
393 (19.7) 

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Solid Tumor Studiesa 
(N = 1992) 
>=3 
226 (11.3) 
Treatment Exposure Duration for Tislelizumab (Months) 
 
Median 
4.070 
Min, Max 
0.10, 41.46 
Study Follow-up Duration (Months) 
 
Median 
11.530 
Min, Max 
0.07, 58.91 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: Max, maximum; Min, minimum; N, total number of patients treated; n, number of patients within each category.  
a Solid Tumor Studies include: BGB-A317_Study_001, BGB-A317-102, BGB-A317-204, BGB-A317-208, BGB-A317-209, 
BGB-A317-302, and BGB-A317-303.  
b Only systemic therapies were selected.  
Patients from the chemotherapy control arm were not included in studies BGB-A317-302 and BGB-A317-303. 
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 NSCLC (639 of 1992 patients, 
32.1%), esophageal squamous cell carcinoma (15.9%), HCC (15.9%), urothelial bladder cancer 
(5.7%), and colorectal cancer (5.2%). 
1.3.4.1.2. Treatment-Related Treatment-Emergent Adverse Events  
Of the 1992 patients with solid tumors treated with tislelizumab monotherapy, 1391 (69.8%) 
experienced ≥ 1 treatment-related TEAE.  The most commonly occurring TEAEs (≥ 5% of 
patients) assessed as related to tislelizumab irrespective of grade were aspartate aminotransferase 
(AST) increased (250 patients, 12.6%), alanine aminotransferase (ALT) increased (242 patients, 
12.1%), hypothyroidism (197 patients, 9.9%), anaemia (186 patients, 9.3%), rash (159 patients, 
8.0%), pruritus (142 patients, 7.1%), fatigue (138 patients, 6.9%), decreased appetite (115 
patients, 5.8%), blood bilirubin increased (111 patients, 5.6%), and diarrhoea (103 patients, 
5.2%). 
Two hundred sixty-nine patients (13.5%) experienced at least 1 ≥ Grade 3 TEAE assessed as 
related to tislelizumab.  The most frequent ≥ Grade 3 TEAEs that occurred in ≥ 1% of the 
patients were AST increased (25 patients, 1.3%) and ALT increased and anaemia (20 patients 
each, 1.0%). 
1.3.4.1.3. Treatment-Emergent Serious Adverse Events  
Of the 1992 patients with solid tumors treated with tislelizumab monotherapy, 706 patients 
(35.4%) experienced ≥ 1 treatment-emergent SAE.  The most commonly occurring 
treatment-emergent SAEs (irrespective of relationship to study drug) were pneumonia 
(95 patients, 4.8%), pneumonitis (33 patients, 1.7%), dysphagia (23 patients, 1.2%), and pleural 
effusion and pyrexia (20 patients each, 1.0%). 
Two hundred and nine patients (10.5%) experienced ≥ 1 tislelizumab-related treatment-emergent 
SAE.  The most common treatment-emergent SAEs deemed related to tislelizumab were 

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pneumonitis (31 patients, 1.6%).  All other tislelizumab-related treatment-emergent SAEs 
occurred in less than 1% of patients. 
1.3.4.1.4. Immune-Mediated Adverse Events  
Anti-PD1 therapies are known to cause imAEs in some patients, and therefore imAEs have been 
defined as AEs of special interest (AESI) in tislelizumab clinical studies and as such are being 
reported expeditiously and they are being closely monitored. 
ImAEs are consistent with an immune-mediated mechanism or immune-mediated component for 
which noninflammatory etiologies (eg, infection or tumor progression) have been ruled out.  
ImAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity.  There is a potential temporal relationship between the initiation of treatment with 
tislelizumab and onset of an imAE that spans several days to several months. 
All imAEs presented here are assessed as related to study drug by the investigator and 
categorized by the Safety/Pharmacovigilance team of the sponsor.  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 occurred in ≥ 2 patients with solid tumor in the total pooled monotherapy studies 
are shown in Table 2. 
Table 2: 
Adjudicated Immune-Mediated Adverse Events of Any Grade Occurring in 
≥ 2 Patients in Pooled Monotherapy Studies 
 
Solid Tumor Studiesa 
(N = 1912) 
Categories 
    Preferred Term 
Any Grade 
n (%) 
≥ Grade 3 
n (%) 
Patients with at Least One Immune-Mediated Adverse Event 
286 (15.0) 
73 (3.8) 
Immune-Mediated Hypothyroidism 
118 (6.2) 
1 (0.1) 
Hypothyroidism 
115 (6.0) 
1 (0.1) 
Tri-iodothyronine free decreased 
2 (0.1) 
0 (0.0) 
Primary hypothyroidism 
1 (0.1) 
0 (0.0) 
Thyroxine free decreased 
1 (0.1) 
0 (0.0) 
Tri-iodothyronine decreased 
1 (0.1) 
0 (0.0) 
Immune-Mediated Pneumonitis 
70 (3.7) 
28 (1.5) 
Pneumonitis 
41 (2.1) 
15 (0.8) 
Immune-mediated lung disease 
14 (0.7) 
4 (0.2) 
Interstitial lung disease 
10 (0.5) 
7 (0.4) 
Pneumonia 
5 (0.3) 
1 (0.1) 
Organising pneumonia 
1 (0.1) 
1 (0.1) 
Immune-Mediated Hepatitis 
34 (1.8) 
19 (1.0) 
Alanine aminotransferase increased 
12 (0.6) 
5 (0.3) 
Aspartate aminotransferase increased 
9 (0.5) 
5 (0.3) 
Hepatitis 
8 (0.4) 
5 (0.3) 
Immune-mediated hepatitis 
6 (0.3) 
2 (0.1) 
Liver injury 
3 (0.2) 
1 (0.1) 
Hepatic cytolysis 
2 (0.1) 
2 (0.1) 
Autoimmune hepatitis 
1 (0.1) 
0 (0.0) 

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Solid Tumor Studiesa 
(N = 1912) 
Categories 
    Preferred Term 
Any Grade 
n (%) 
≥ Grade 3 
n (%) 
Blood bilirubin increased 
1 (0.1) 
0 (0.0) 
Gamma-glutamyltransferase increased 
1 (0.1) 
1 (0.1) 
Hepatic failure 
1 (0.1) 
1 (0.1) 
Transaminases increased 
1 (0.1) 
1 (0.1) 
Immune-Mediated Skin Adverse Reaction 
24 (1.3) 
9 (0.5) 
Rash 
13 (0.7) 
4 (0.2) 
Drug eruption 
4 (0.2) 
2 (0.1) 
Rash maculo-papular 
2 (0.1) 
2 (0.1) 
Acute febrile neutrophilic dermatosis 
1 (0.1) 
0 (0.0) 
Dermatitis 
1 (0.1) 
1 (0.1) 
Erythema multiforme 
1 (0.1) 
0 (0.0) 
Pruritus 
1 (0.1) 
0 (0.0) 
Rash macular 
1 (0.1) 
1 (0.1) 
Rash papular 
1 (0.1) 
1 (0.1) 
Rash pruritic 
1 (0.1) 
0 (0.0) 
Immune-Mediated Colitis 
17 (0.9) 
6 (0.3) 
Colitis 
8 (0.4) 
3 (0.2) 
Diarrhoea 
8 (0.4) 
3 (0.2) 
Immune-mediated enterocolitis 
2 (0.1) 
1 (0.1) 
Rectal haemorrhage 
1 (0.1) 
0 (0.0) 
Immune-Mediated Myositis/Rhabdomyolysis 
14 (0.7) 
5 (0.3) 
Blood creatine phosphokinase increased 
7 (0.4) 
2 (0.1) 
Myositis 
5 (0.3) 
2 (0.1) 
Immune-mediated myositis 
3 (0.2) 
2 (0.1) 
Immune-Mediated Hyperthyroidism 
12 (0.6) 
1 (0.1) 
Hyperthyroidism 
12 (0.6) 
1 (0.1) 
Immune-Mediated Thyroiditis 
7 (0.4) 
0 (0.0) 
Autoimmune thyroiditis 
4 (0.2) 
0 (0.0) 
Thyroiditis 
2 (0.1) 
0 (0.0) 
Thyroiditis subacute 
1 (0.1) 
0 (0.0) 
Immune-Mediated Adrenal Insufficiency 
6 (0.3) 
1 (0.1) 
Adrenal insufficiency 
5 (0.3) 
1 (0.1) 
Glucocorticoid deficiency 
1 (0.1) 
0 (0.0) 
Immune-Mediated Myocarditis 
6 (0.3) 
3 (0.2) 
Immune-mediated myocarditis 
3 (0.2) 
3 (0.2) 
Myocarditis 
2 (0.1) 
0 (0.0) 
Autoimmune myocarditis 
1 (0.1) 
0 (0.0) 
Immune-Mediated Nephritis And Renal Dysfunction 
6 (0.3) 
2 (0.1) 
Renal failure 
2 (0.1) 
1 (0.1) 
Blood creatinine increased 
1 (0.1) 
0 (0.0) 
Immune-mediated nephritis 
1 (0.1) 
0 (0.0) 
Nephritis 
1 (0.1) 
0 (0.0) 
Renal impairment 
1 (0.1) 
1 (0.1) 
Focal segmental glomerulosclerosis 
0 (0.0) 
0 (0.0) 
Other Immune-Mediated Reactions 
6 (0.3) 
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Solid Tumor Studiesa 
(N = 1912) 
Categories 
    Preferred Term 
Any Grade 
n (%) 
≥ Grade 3 
n (%) 
Arthritis 
3 (0.2) 
0 (0.0) 
Immune-mediated arthritis 
1 (0.1) 
0 (0.0) 
Pericarditis 
1 (0.1) 
0 (0.0) 
Polymyalgia rheumatica 
1 (0.1) 
0 (0.0) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event; MedDRA, Medical Dictionary for 
Regulatory Activities.  
A patient with multiple occurrences of an AE is counted only once. The number (percentage) for System Organ 
Class represents all counts of patients with relevant Preferred Terms in that class. All AEs are coded using MedDRA 
v24.0.  
AEs with incidence ≥ 2 patients at category level in ‘Any Grade’ column of  ‘Solid Tumor Studies’ are included in 
this table.  
Sorted in descending order of the number of patients in System Organ Class then Preferred Terms in ‘Solid Tumor 
Studies’ column.  
a Solid Tumor Studies include: BGB-A317_Study_001, BGB-A317-102, BGB-A317-204, BGB-A317-208, BGB-
A317-302, and BGB-A317-303.  
Patients from the chemotherapy control arm were not included in studies BGB-A317-302 and BGB-A317-303. 
 
Of the 1912 patients with solid tumors included in the pooled analysis of imAEs, 286 patients 
(15.0%) experienced ≥ 1 imAE of any grade.  The most commonly occurring imAEs of any 
grade were hypothyroidism (115 patients, 6.0%), pneumonitis (41 patients, 2.1%), 
immune-mediated lung disease (14 patients, 0.7%), rash (13 patients, 0.7%), and ALT increased 
and hyperthyroidism (12 patients each, 0.6%). Analysis of the patients with ≥ 1 imAE that was 
also ≥ Grade 3 in severity showed that 73 patients (3.8%) experienced such events.  The most 
commonly occurring imAEs that were ≥ Grade 3 in severity were pneumonitis (15 patients, 
0.8%) and interstitial lung disease (7 patients, 0.4%). 
1.3.4.1.5. Infusion-Related Reactions  
Infusion-related reactions, including high-grade hypersensitivity reactions, following 
administration of tislelizumab are uncommon.  Of the 1992 patients treated with tislelizumab 
monotherapy, 58 patients (2.9%) experienced ≥ 1 infusion-related reaction of any grade.  The 
most commonly occurring infusion-related reactions of any grade were infusion-related reactions 
(28 patients, 1.4%); pyrexia (17 patients, 0.9%); rash (5 patients, 0.3%); and hypotension, nausea 
(4 patients, 0.2%), and pruritus (3 patients, 0.2%).  There were 5 patients (0.3%) with ≥ Grade 3 
infusion-related reactions. The most common ≥ Grade 3 IRRs was infusion-related reaction 
(2 patients, 0.1%).  All other ≥ Grade 3 IRRs occurred in single patients. 
1.3.4.1.6. Fatal Adverse Events  
A summary of the treatment-emergent fatal AEs that occurred in the pooled monotherapy studies 
in solid tumor are shown in Table 3. 

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Table 3: 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in Pooled 
Monotherapy Studies 
Solid Tumor Studiesa 
(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) 
Sudden death 
1 (0.1) 
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) 
Bronchiectasis 
1 (0.1) 
Dyspnoea 
1 (0.1) 
Haemothorax 
1 (0.1) 
Lung disorder 
1 (0.1) 
Oesophagobronchial fistula 
1 (0.1) 
Pulmonary arterial hypertension 
1 (0.1) 
Pulmonary thrombosis 
1 (0.1) 
Respiratory arrest 
1 (0.1) 
Tracheal stenosis 
1 (0.1) 
Infections and infestations 
20 (1.0) 
Pneumonia 
14 (0.7) 
Sepsis 
2 (0.1) 
Abdominal infection 
1 (0.1) 
Bronchitis 
1 (0.1) 
Mediastinitis 
1 (0.1) 
Septic shock 
1 (0.1) 
Staphylococcal sepsis 
0 (0.0) 
Hepatobiliary disorders 
15 (0.8) 
Hepatic failure 
10 (0.5) 
Acute hepatic failure 
2 (0.1) 
Hepatic function abnormal 
1 (0.1) 
Hepatitis 
1 (0.1) 
Hepatorenal syndrome 
1 (0.1) 
Gastrointestinal disorders 
14 (0.7) 
Upper gastrointestinal haemorrhage 
7 (0.4) 
Ascites 
2 (0.1) 
Dysphagia 
1 (0.1) 
Ileus 
1 (0.1) 
Large intestinal obstruction 
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Solid Tumor Studiesa 
(N = 1992) 
n (%) 
Oesophageal obstruction 
1 (0.1) 
Vomiting 
1 (0.1) 
Nervous system disorders 
10 (0.5) 
Cerebral infarction 
2 (0.1) 
Hepatic encephalopathy 
2 (0.1) 
Brain oedema 
1 (0.1) 
Cerebral artery embolism 
1 (0.1) 
Cerebral artery occlusion 
1 (0.1) 
Cerebral haemorrhage 
1 (0.1) 
Depressed level of consciousness 
1 (0.1) 
Headache 
1 (0.1) 
Cardiac disorders 
8 (0.4) 
Acute myocardial infarction 
2 (0.1) 
Cardiac failure 
1 (0.1) 
Cardiac tamponade 
1 (0.1) 
Cardio-respiratory arrest 
1 (0.1) 
Cardiopulmonary failure 
1 (0.1) 
Myocardial ischaemia 
1 (0.1) 
Pericardial effusion 
1 (0.1) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
3 (0.2) 
Metastases to liver 
1 (0.1) 
Tumour fistulisation 
1 (0.1) 
Tumour haemorrhage 
1 (0.1) 
Tumour compression 
0 (0.0) 
Metabolism and nutrition disorders 
2 (0.1) 
Cachexia 
1 (0.1) 
Decreased appetite 
1 (0.1) 
Renal and urinary disorders 
2 (0.1) 
Renal failure 
1 (0.1) 
Renal impairment 
1 (0.1) 
Investigations 
1 (0.1) 
Platelet count decreased 
1 (0.1) 
Musculoskeletal and connective tissue disorders 
1 (0.1) 
Muscular weakness 
1 (0.1) 
Psychiatric disorders 
1 (0.1) 
Depression 
1 (0.1) 
Vascular disorders 
1 (0.1) 
Shock haemorrhagic 
1 (0.1) 
Arterial haemorrhage 
0 (0.0) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event; MedDRA, Medical Dictionary for 
Regulatory Activities. 
A patient with multiple occurrences of an AE is counted only once. The number (percentage) for System Organ 
Class represents all counts of patients with relevant Preferred Terms in that class. All AEs are coded using MedDRA 
v24.0.  
Sorted in descending order of the number of patients in System Organ Class then Preferred Terms in ‘Solid Tumor 
Studies’ column.  

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a Solid Tumor Studies include: BGB-A317_Study_001, BGB-A317-102, BGB-A317-204, BGB-A317-208, BGB-
A317-209, BGB-A317-302, and BGB-A317-303.  
 
Of 1992 patients in the solid tumor group of pooled monotherapy studies, 163 (8.2%) died 
≤ 30 days after their last dose of tislelizumab.  The causes of death for these patients were 
adverse events (54 patients, 2.7%), disease under study (52 patients, 2.6%), disease progression 
(50 patients, 2.5%), and other (7 patients, 0.4%). 
1.3.4.2. 
Efficacy Assessment of Tislelizumab  
On 11 March 2022, tislelizumab monotherapy in MSI-H/dMMR metastatic solid tumor was 
approved under conditional approval by the China National Medical Products Administration 
(NMPA) based on the result of Study BGB-A317-209.  
BGB-A317-209 is a single-arm, multi-center, open-label, Phase 2 study to evaluate the efficacy 
and safety of tislelizumab (BGB-A317), an anti-PD-1 monoclonal antibody, as monotherapy in 
patients with previously-treated locally advanced unresectable or metastatic MSI-H or dMMR 
solid tumors. The primary efficacy endpoint of the study is objective response rate (ORR) as 
assessed by the Independent Review Committee (IRC) per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1. 
As of 08 July 2021, 80 patients were enrolled (median age 53 years; range: 19-81 years) and 
received at least one dose of tislelizumab. Most patients had metastatic disease (98.8%), and the 
majority of patients had CRC (61.3%). Of the 75 patients in the Efficacy Analysis Set, ORRIRC was 
46.7% (n = 35; 95% confidence interval [CI] 35.1 to 58.6) in all tumor types (1-sided p < 0.0001), 
including 5 complete responses (CR) and 30 partial responses (PR). ORRIRC was 39.1% (n = 18; 
95% CI 25.1 to 54.6) in colorectal cancer (CRC) patients (N = 46), 55.6% (n = 5; 95% CI 21.2 to 
86.3) in gastric or gastroesophageal junction cancer patients (N = 9), and 60.0% (n = 12; 95% CI 
36.1 to 80.9) in other patients (N =20). Median duration of response (DoR) was not reached, 
median time to response (TTR)IRC was 11.9 weeks (range: 8.4-98.9 weeks) and disease control rate 
(DCR) was 72.0% (95% CI 60.4 to 81.8). Median PFSIRC was not reached (95% CI 7.5 months to 
not estimable [NE]). Median overall survival (OS) in safety analysis set was not reached (95% CI 
28.7 months to NE)( Li et al, 2022).  
1.4. 
Study Rationales  
1.4.1. 
Rationale for Tislelizumab as Neo-adjuvant Treatment of Resectable 
Microsatellite Instability-High or Mismatch Repair Deficient CRC  
The promising antitumor activity of anti-PD-1 antibodies reported for metastatic and localized 
MSI-H/dMMR CRC (see section 1.2).These outcomes have been attributed to the higher 
mutational burden of dMMR tumors, particularly the accumulation of insertions–deletions 
(indels), giving rise to more neoantigens (Overman et al, 2018; Overman et al, 2017; Diaz et al, 
2015; Germano et al, 2017; Mandal et al, 2019). Possibly as a result of their higher neoantigen 
burden, dMMR tumors are also characterized by an increased density of intratumoral T cells 
(Fabrizio et al, 2018; Maby et al, 2015).  
With mass screening, more CRCs were diagnosed at their early-stage and MSI-H is more 
common (10–15%) in early stage CRCs compared to metastatic CRC (see Section 1.1). Treating 

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with immune checkpoint inhibitors (ICI) have showed higher response rates in early-stage 
disease compared with metastatic disease. That may be attributed to a difference in T cell 
infiltration (TCI), a lower degree of systemic immune suppression, the absence of visceral 
metastases and a lower tumor burden (Blank et al, 2018; Forde et al, 2018). These biological 
features suggested that early stage MSI-H/dMMR CRCs might respond well to immune 
checkpoint blockade. 
Furthermore neoadjuvant therapeutic strategies have been successful in many gastro-intestinal 
cancer locations and the pathological response (pCR and marked regression) to neoadjuvant 
treatment in CCs is closely related to recurrence risk (see Section 1.2) and may improve long-
term benefit. However according to FOxTROT study, the presence of MSI-H/dMMR disease 
demonstrated the lack of impact of chemotherapy (see Section 1.2). 
Preliminary data from the ongoing Phase 1 and Phase 2 studies show that tislelizumab has been 
well tolerated in patients with advanced tumors in multiple solid and hematological 
malignancies. The safety profile for single-agent tislelizumab is similar to those observed in 
other PD-1 inhibitors (Tislelizumab Investigator’s Brochure). 
Tislelizumab has been approved in China for the treatment of patients with relapsed or refractory 
classical Hodgkin lymphoma, for the treatment of patients with pretreated locally advanced or 
metastatic urothelial carcinoma with PD-L1 high expression and in combination with Paclitaxel 
and Carboplatin as first-line treatment in patients with locally advanced or metastatic squamous 
NSCLC. Tislelizumab is also being investigated for the treatment of patients with advanced 
cancers, including, but not limited to, NSCLC, esophageal carcinoma, gastric cancer, HCC, and 
MSI-H/dMMR metastatic solid tumor (Tislelizumab Investigator’s Brochure). 
This study is a window of opportunity design, in which patients receive Tislelizumab as neo-
adjuvant therapy between their cancer diagnosis and standard treatment (surgery). Patients are 
CRC treatment naïve. Tumor biopsies before and after the investigational treatment are collected 
for translational research. This study design can enable detailed characteristics of the 
pharmacodynamic effects of Tislelizumab and the tumor biology. It offers a unique opportunity 
to study pharmacodynamic response in the setting of a tumor unperturbed by prior therapy and 
may improve the understanding of pharmacodynamic parameters and help to identify biomarkers 
for better patient selection. 
Given the promising antitumor activity of anti-PD-1 antibodies reported for metastatic and 
localized MSI-H/dMMR CRC and the biological features of localized MSI-H/dMMR CRC, 
Tislelizumab, an efficient PD-1 inhibitor as neo-adjuvant treatment for resectable MSI-H/dMMR 
CRC may bring clinical benefit and warrants further clinical development. 
1.4.2. 
Rationale for Selection of Tislelizumab Dose and Treatment Duration  
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 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 shows no 
relationship between exposure and treatment-emergent imAEs (Wu et al, 2019a; Wu 
et al, 2019b). 

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• Confirmed response rates in patients treated with tislelizumab on a once every 
3 weeks schedule were 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. 
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. 
Three-cycle neo-adjuvant treatment (9 weeks) with tislelizumab is selected as planned treatment 
duration. That is considering the minimum time to have treatment response with ICI therapy and 
to avoid potential surgery delay.  
1.4.3. 
Biomarker Strategy Rationale  
Biomarker analyses will be performed to explore the association of biomarkers with patient 
prognosis, response, and potential resistance to tislelizumab as neo-adjuvant treatment.  
A number of biomarkers have been identified that correspond with response to immunotherapy 
for patients with dMMR CRC in the neo-adjuvant setting by the Niche study (Chalabi et al, 
2020). 
The NICHE study reports potentially predictive biomarkers as well as pharmacodynamic 
biomarkers (post-treatment versus pre-treatment) for response monitoring. 
For potentially predictive biomarkers: Tumor infiltrated immune cell analysis using multiplex 
immunofluorescence have demonstrated the capability of immune cell infiltration in predicting 
response or resistance to anti-PD-1 therapies. PD-L1 expression, TMB and GEP (various 
signatures) have been reported to be correlated to the response to anti-PD-1 therapies(Miller et al, 
2019; Keung et al, 2020; Cristescu R et al, 2019; Marabelle A et al, 2020). No clear conclusions 
could be derived from these biomarkers in NICHE study due to the limited number of patients 
Considering the limited number of patients, the role of these biomarkers in predicting response to 
tislelizumab as neo-adjuvant therapy warrants further exploration. Apart from their potential 
predictive value, GEP and TMB panels can be designed to explore underlying resistance 
mechanism to guide potential combination strategies. In summary, the role of immune cell 
infiltration, PD-L1 expression, TMB/DNA mutation and GEP in predicting response/resistance to 
tislelizumab as neo-adjuvant treatment will be investigated. 

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For pharmacodynamic biomarkers (post-treatment versus pre-treatment) for response monitoring: 
In NICHE study, enhanced CD8+ T cell infiltration and IFNγ score (pooled from the GEP panel) 
were observed post treatment in dMMR CRC patients, indicating the potential role of immune cell 
infiltration and GEP in identifying pharmacodynamic biomarkers for response monitoring. The 
pharmacodynamic change of PD-L1 expression and TMB/DNA mutation were not reported by the 
Niche study, and their role as pharmacodynamic biomarkers can be further explored. 
Consequently, immune cell infiltration, PD-L1, TMB/DNA mutation and GEP can be explored 
in paired tumor samples (pre-treatment and post-treatment) to identify their potential predictive 
value, their potential role in response monitoring, as well as resistance mechanisms in patients 
who receive tislelizumab as neo-adjuvant therapy in MSI-H/dMMR CRC patients. 
1.5. 
Benefit-Risk Assessment  
The promising antitumor activity of anti-PD-1 antibodies in treating MSI-H/dMMR CRC was 
reported (see Section 1.2). These outcomes have been attributed to the higher mutational burden 
and more neoantigens of dMMR tumors (see Section 1.4.1). Possibly as a result of their higher 
neo-antigen burden, dMMR tumors are also characterized by an increased density of 
intratumoral T cells. MSI-H/dMMR is more common in localized cancer (10–15% compared to 
5% of metastatic CRC) (see Section 1.1). Treatment with ICIs has shown higher response rates 
in early-stage disease compared with metastatic disease. This has been attributed to a difference 
in TCI, a lower degree of systemic immune suppression, the absence of visceral metastases and a 
lower tumor burden (see Section 1.4.1) 
MSI-H/dMMR CRC has a favorable prognostic feature in localized (Stage I–III) disease. 
However, there is still an unmet need for therapeutic improvements for patients with high-risk 
early-stage MSI-H/dMMR CRC (see Section 1.2).   
Furthermore, neo-adjuvant therapeutic strategies have been successful in many gastro-intestinal 
cancer locations and the pathological response (pCR and marked regression) to neo-adjuvant 
treatment in CCs is closely related to recurrence risk (Seymour et al, 2019). This treatment 
strategy for early-stage MSI-H/dMMR CRCs may improve long-term benefit. In China, the 
clinical research of ICI for early-stage CRC was scarce.  
Preliminary data from the ongoing Phase 1 and Phase 2 studies show that tislelizumab has been 
well tolerated in patients with advanced tumors in multiple solid and hematological 
malignancies. The safety profile for single-agent tislelizumab is similar to that observed in other 
PD-1 inhibitors. Two pivotal Phase 2 studies demonstrated clinical meaningful benefit. The 
initial data collected in other studies suggest that tislelizumab can result in antitumor activity 
across a variety of tumor types. Antitumor activity has been observed across the dose ranges 
evaluated in patients. Therefore, the benefit-risk profile for tislelizumab monotherapy appears to 
be favorable in oncology population based on preliminary efficacy and safety data Tislelizumab 
Investigator’s Brochure. 

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In summary, for early-stage MSI-H/dMMR CRCs, identifying patients who are at risk of disease 
recurrence, providing neo-adjuvant treatment with ICIs and refine therapeutic strategies for 
early-stage MSI-H/dMMR CRCs, is an urgent unmet need. Given the promising antitumor 
activity of anti-PD-1 antibodies reported for metastatic and localized MSI-H/dMMR CRC, the 
biological features of localized MSI-H/dMMR CRC, introducing tislelizumab, an PD-1 inhibitor 
as neo-adjuvant treatment for resectable MSI-H/dMMR CRC may bring clinical benefit and 
warrants further research. 
1.6. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 

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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
• To evaluate major pathological response (MPR) rate in patients receiving tislelizumab 
as neo-adjuvant treatment. 
2.1.2. 
Secondary Objectives  
• To evaluate pathological complete response (pCR) rate in patients receiving 
tislelizumab as neo-adjuvant treatment. 
• To evaluate event-free survival (EFS) in patients receiving tislelizumab as neo-
adjuvant treatment 
• To explore potential biomarkers that may correlate with clinical responses/resistance 
to tislelizumab as neo-adjuvant treatment. 
• To evaluate the safety and tolerability of neo-adjuvant treatment with tislelizumab in 
patients with early-stage (Stage II-III) Microsatellite Instability-High (MSI-H) or 
Mismatch Repair Deficient (dMMR) colorectal cancer  
2.1.3. 
Exploratory Objectives  
• To evaluate R0 resection rate in patients receiving tislelizumab as neo-adjuvant 
treatment  
• To evaluate perioperative events (including but not limited to treatment related 
surgery delay, postoperative complication) in patients receiving tislelizumab as 
neo-adjuvant treatment. 
2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• MPR rate is defined as the proportion of patients in the EAS with ≤ 10% residual 
viable tumor in the resected primary tumor after completion of neo-adjuvant therapy. 
2.2.2. 
Secondary Endpoints  
• The pCR rate is defined as the proportion of patients in the EAS with absence of 
residual tumor in the resected primary tumor and all resected lymph nodes after 
completion of neo-adjuvant therapy. 
• EFS is defined as the time from first dose until any of the following events, 
whichever occurs first: radiographic disease progression according to RECIST v1.1, 
local or distant recurrence, or death due to any cause in the EAS. The 2-year/3-year 
EFS rate is defined as the proportion of patients free from EFS events at 2 years and 
3 years as estimated using the Kaplan-Meier method.  

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• Potential biomarkers including immune cell infiltration, PD‑L1 expression, tumor 
mutational burden (TMB) and DNA mutation, gene expression profile (GEP) and the 
association of biomarkers with disease status, response/resistance to tislelizumab as 
neo-adjuvant treatment. 
• Incidence and severity of TEAEs, including serious adverse events and imAEs, with 
severity determined according to National Cancer Institute-Common Terminology 
Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) in the safety analysis set 
(SAS). 
2.2.3. 
Exploratory Endpoints  
• Complete resection (R0) rate – defined as the proportion of patients with R0 
resection. 
• To evaluate perioperative events (including but not limited to treatment-related 
surgery delay, postoperative complication) in patients receiving tislelizumab as 
neo-adjuvant treatment. 

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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, multicenter Phase 2 study designed to investigate the preliminary efficacy 
and safety of tislelizumab monotherapy as neo-adjuvant treatment in approximately 38 patients 
with early-stage (Stage II-III) MSI-H or dMMR CRC.  
The study consists of a screening phase (and/or prescreening phase), a treatment phase that 
includes a neo-adjuvant phase, surgery, and a disease follow-up phase.   
The study schema is presented in Figure 1.  
Figure 1: 
Study Schema 
 
 
Abbreviations: MSI-H, microsatellite instability-high; IV, intravenously; N, number of patients; Q3W, once every 3 
weeks. 
For all study procedures see Section 7 and Appendix 1.  
3.2. 
Prescreening Period  
Patients with unknown MSI and MMR status are required to provide blood and tumor tissues for 
central laboratory confirmation of MSI status during the prescreening period (defined as within 
56 days prior to the first dose of the study drug). A separate prescreening informed consent must 
be obtained. Refer to Section 7.1 and Section 7.7 for details. 
3.3. 
Screening Period  
Screening evaluations will be performed within 28 days before first dose. Patients who agree to 
participate in this study will sign the informed consent form (ICF) before undergoing any 
screening procedure. Patients who are suspected to have a serious respiratory concurrent illness 
or who exhibit significant respiratory symptoms unrelated to the underlying cancer will also take 
a pulmonary function test (refer to Section 7.2.4 and Appendix 1 for details). Screening 
evaluations may be repeated as needed within the screening period; the investigator will assess 
preliminary patient eligibility according to the latest screening assessment results. 
Archival tumor tissue must be collected for the purpose of biomarker analysis. In the absence of 
archival tumor tissues, a fresh tumor biopsy at baseline is mandatory (Section 7.7). 

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3.4. 
Treatment Period  
Neo-adjuvant Phase: 
After completing all screening activities, patients confirmed to be eligible by the investigator will 
receive tislelizumab 200 mg intravenously once every 3 weeks for 3 cycles.  
During the neo-adjuvant phase, patients who are found to have disease progression at scheduled 
tumor assessments (before Cycle 3 and surgery) or at any time during neo-adjuvant treatment, 
and whose tumors are still deemed resectable and non-metastatic, will proceed to receive surgery 
if amenable and will remain eligible for all on-study evaluations based on investigator’s 
judgement. 
Patients who discontinue neo-adjuvant treatment early because of urgent surgery (eg., because of 
intestinal obstruction, intestinal perforation, or intestinal bleeding), disease progression or 
intolerable AEs and who do not proceed to have a complete resection will proceed to receive 
other treatment as determined by the investigator. Further in-clinic study procedures for these 
patients should be discussed with the medical monitor. 
Surgery: 
Upon completion of neo-adjuvant therapy, patients will undergo surgical resection of their 
tumor. Surgical specimens will be assessed for pathological response (MPR and pCR). In 
addition, exploratory biomarker analysis of surgical specimens (primary tumor tissue and 
dissected lymph nodes) will be performed. 
Before surgery, tumor imaging and assessment will be performed within 9 weeks ± 7 days after 
first dose, and the investigator will reassess the patient to reconfirm disease resectability. The 
surgical procedure should be performed within 10 weeks from the first administered dose of 
study treatment. If surgery cannot be performed within this time window (eg, because of a 
prolonged AE), the medical monitor should be consulted. The investigator and the medical 
monitor will determine the acceptable length of this time window. Complete resection (R0) 
should be performed. 
Disease Follow-up Phase: 
Patients will continue adjuvant treatment and perform follow-up which will be determined by the 
investigator according to the stage of disease and benefit-risk assessment in accordance with the 
relevant clinical practice (eg. Cancer NCCN guidelines, CSCO guideline). Patients will continue 
to undergo tumor assessments based on RECIST v1.1, which will be performed every 12 weeks 
(± 14 days) for the first 3 years, and then every 24 weeks (± 28 days) for a total  of 5 years, and 
then once each year (± 28 days) thereafter. Patients will continue with the scheduled tumor 
assessments until the patient experiences disease progression or recurrence according to RECIST 
v 1.1, withdraws consent, is lost to follow up, death, begins a new anticancer therapy (excluding 
adjuvant therapy), or until the study terminates, whichever occurs first. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per NCI-CTCAE v5.0) and laboratory results. Vital signs, physical examinations, ECOG PS 
change, electrocardiogram (ECG) results, and other examinations will also be used for safety 
assessment. Safety assessments are further detailed in Section 7.5 and in the Schedule of 
Assessments (Appendix 1).   

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3.5. 
End-of-Treatment/Safety Follow-up  
The End-of-Treatment Visit (EOT)/Safety Follow-up will be conducted as follows: 
EOT/ Safety Follow-up 1: Patients who received surgery will be asked to return to the clinic for 
the 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 discontinued pre-operative treatment for any reason and 
for whom surgery will not be conducted will be asked to return to the clinic for the EOT/Safety 
Follow-up Visit (to occur within 30 days [± 7 days] after the last dose of study treatment, 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 assessments as 
outlined in Section 7.6. 
In addition, telephone contacts with patients should be conducted to assess imAEs and 
concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer 
therapy) at 60 days and 90 days (± 14 days) after the last dose of study drug, regardless of 
whether the patient starts a new anticancer therapy.  If patients report a suspected imAE at a 
telephone follow-up contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visit. 
3.6. 
Discontinuation From the Study Treatment or From the Study  
3.6.1. 
Patient Discontinuation From Study Treatment  
Patients have the right to withdraw from the study or 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 the study treatment for reasons other than disease 
progression should be followed for assessments of antitumor activity (Section 7.6) and safety 
(Section 7.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue from the study 
treatment for reasons that include, but are not limited to, the following: 
• Treatment Completed 
• Disease progression  
• AEs 
• Patient decision 
• Pregnancy 

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• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she was to continue the study treatment. 
• Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
country) herbal medicine and Chinese (or other country) patent medicines] for the 
treatment of cancer) (Section 6.3). 
• 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 if they are consistently 
noncompliant. 
3.6.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient)  
Patients may discontinue the 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 
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 dies, withdraws consent, completes all study 
assessments, or is lost to follow up. 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. 
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 IRBs/ IECs of the early termination of the study. 

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The sponsor has the right to terminate study participation of an individual clinical study site at 
any time. The site will be informed of the decision in advance. Reasons for terminating a site’s 
study participation may include but are not limited to the following:  
• Excessively slow recruitment 
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• GCP noncompliance  
• Study activity is completed (ie, all patients have completed the study activity and all 
obligations have been fulfilled)  

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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments.  
2. Age ≥ 18 years on the day of signing the ICF.  
3. ECOG PS of 0 or 1.  
4. Pathologically (histologically) confirmed diagnosis of potentially resectable Stage II or 
Stage III (per the Eighth American Joint Committee on Cancer staging system for 
Colon/Rectal Cancer) CRC with MSI-H confirmed by sponsor-designated central 
laboratory or known MSI-H status by local laboratory. Patients should be eligible for an 
R0 resection with curative intent. 
5. Evaluable or measurable disease as assessed by the investigator per RECIST v1.1. 
6. With unknown MSI status by local laboratory, patients must provide blood 
(approximately 2 mL peripheral whole blood) and tumor tissues (archival formalin-fixed 
paraffin-embedded [FFPE] blocks or at least 10 freshly cut unstained slides) for central 
MSI confirmation. Patients must be able to provide paired tumor tissues (pretreatment 
and post-treatment tumor tissues as FFPE blocks or approximately 14 [≥ 10] freshly cut 
unstained slides) for retrospective analysis of other exploratory biomarkers related to 
response/resistance. A fresh biopsy is mandatory in the absence of pre-treatment archival 
tumor tissues.  
7. Adequate organ function as indicated by the following clinical laboratory values 
(obtained within 7 days before first dose): 
a. Patients must not have required a blood transfusion or growth factor support 
≤ 14 days before blood sample collection at screening for any of the following: 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  
ii. 
Platelets ≥ 75 x 109/L  
iii. 
Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol /L (Note: For patient with 
cancer-induced anemia, hemoglobin ≥ 80 g/L or 4.9 mmol/L is eligible 
with appropriate supportive care.)  
iv. 
International normalized ratio or prothrombin time ≤ 1.5 x upper limit of 
normal (ULN) 
v. 
Activated partial thromboplastin time ≤ 1.5 x ULN 
b. Serum creatinine ≤ 1.5 x ULN or estimated Glomerular Filtration Rate 
≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration 
equation (Appendix 9). 

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c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilbert’s syndrome). 
d. AST and ALT ≤ 2.5 x ULN.   
8. Women of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study (see Appendix 8) and for ≥ 120 days after the 
last dose of study drugs, and have a negative urine or serum pregnancy test ≤ 7 days 
before first dose. 
9. Nonsterile men must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of study drugs (see 
Appendix 8): 
a. A sterile man is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
b. Men with known “low sperm counts” (consistent with “subfertility”) are not to be 
considered sterile for purposes of this study. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from this study:  
1. Any prior therapy for current CRC, including chemotherapy or radiotherapy or 
immunotherapy (including but not limited to interferons, interleukin-2, tumor necrosis 
factor interleukin, and thymosin). 
2.  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug 
specifically targeting T-cell costimulation or checkpoint pathways. 
3.  History of severe hypersensitivity reactions to other humanized monoclonal antibodies. 
4. Any active malignancy ≤ 2 years before first dose except for the specific or curatively 
treated relevant cancer under investigation in this study (eg, endometrial cancer with 
lynch syndrome) and any locally recurring cancer that has been curatively treated (eg, 
resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ 
of the cervix or breast). 
5. Active autoimmune diseases or history of autoimmune diseases that may relapse.   
Note: Patients with the following diseases are not excluded and may proceed to further 
screening:  
a. Controlled Type I diabetes. 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only). 
c. Controlled celiac disease. 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia). 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors. 

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6. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
first dose.  
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). 
7. 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.  
8. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 14 days after intervention). 
9. With history of interstitial lung disease, noninfectious pneumonitis or uncontrolled 
diseases including pulmonary fibrosis, acute lung diseases, hypertension, etc. Patients 
with significantly impaired pulmonary function or who require supplemental oxygen at 
baseline must undergo an assessment of pulmonary function at screening. 
10. Infections (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal or antiviral therapy within 14 days before first dose. 
Note: Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) or 
hepatitis C virus (HCV) infection.  
11. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or 
> 2500 copies/mL) at screening. 
Note: 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 
HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients 
receiving antivirals at screening should have been treated for > 14 days before first dose. 
12. Patients with active hepatitis C. 
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody 
test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test 
will be performed only for patients testing positive for HCV antibody. Patients receiving 
antivirals at screening should have been treated for > 14 days before first dose. 
13. A known history of HIV infection. 
14. Any major surgical procedure requiring general anesthesia ≤ 28 days before first dose. 
Patients must have recovered adequately from the toxicity and/or complications from the 
intervention before first dose. 

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15. Prior allogeneic stem-cell transplantation or organ transplantation. 
16. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living ≤ 28 days before first dose.  
b. Pulmonary embolism ≤ 28 days before first dose. 
c. Any history of acute myocardial infarction ≤ 6 months before first dose. 
d. Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 6) ≤ 6 months before first dose.  
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before first 
dose.  
f. Any history of cerebrovascular accident ≤ 6 months before first dose. 
g. Uncontrolled hypertension that cannot be managed by standard antihypertension 
medications ≤ 28 days before first dose. 
h. Any episode of syncope or seizure ≤ 28 days before first dose. 
17. Has received a live vaccine ≤ 4 weeks before first dose. 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
18. 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. 
19. Women who are pregnant or are breastfeeding.  
20. Concurrent participation in another therapeutic clinical study.  
Note: Concurrent participation in observational or noninterventional studies is allowed. 
In addition, patients who have completed active treatment in a clinical study and are in 
the follow-up period can be enrolled in this study. 

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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
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 single-use vials with a 
Flurotec-coated butyl rubber stopper and an aluminum cap. Each vial is packaged into a single 
carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions as specified on the label. Shaking 
should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the Tislelizumab Investigator’s Brochure for other details 
regarding tislelizumab. 
5.2. 
Dosage, Administration, and Compliance  
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks) 
for 3 cycles before surgery.  
Tislelizumab will be administered by intravenous infusion through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on 
filter.  Specific instructions for product preparation and administration are provided in the 
Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents.  For Cycle 3, a ≥ 30-minute monitoring period is required in an area with 
resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion.  Tislelizumab must not be concurrently administered with any 
other drug (refer to Section 6). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 7. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Surgery  
A surgeon with experience in locally advanced resectable CRC 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 

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within 14 days of surgery and in accordance with local institutional practice. Pre-operative 
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 in accordance with the relevant local guidance 
and/or clinical practice within 10 weeks after the first dose of neo-adjuvant study treatment 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.  
The performed surgical procedure should be documented and reported in the eCRF. If, after 
neo-adjuvant 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. 
5.4. 
Incorrect Administration or Overdose  
Any overdose of tislelizumab (defined as ≥ 600 mg in a 24-hour period) should be recorded in 
the patient’s chart and on the appropriate eCRF. AEs associated with an overdose or incorrect 
administration of study drug will be recorded on the AE eCRF. Any SAEs associated with an 
overdose or incorrect administration are required to be reported within 24 hours of awareness via 
the SAE reporting process as described Section 8.6. Supportive care measures should be 
administered as appropriate. 
5.5. 
Investigational Medicinal Product Accountability  
The investigational medicinal product required for completion of this study (tislelizumab) will be 
provided by the sponsor. The investigational site will acknowledge the receipt of the 
investigational medicinal product. Any damaged shipments will be replaced.  
Accurate records of all investigational medicinal products received, dispensed, returned, and 
disposed should be recorded on the site’s Drug Inventory Log. Refer to the Pharmacy Manual for 
details of investigational medicinal product management.  
5.6. 
Dose Delay or Modification  
Every effort should be made to administer the study drugs on the same day according to the 
planned dose and schedule. In the event of significant toxicities, dosing may be delayed and/or 
interrupted based on the guidelines provided below. Reasons for dose interruptions or delays, the 
supportive measures taken, and the outcome will be documented in the patient's chart and 
recorded in the eCRF. 
For AEs that are assessed as related to tislelizumab, the following general guidance should be 
followed unless otherwise specified: 
• ≤ Grade 2: Maintain dose level. 
• Grade 3: Omit dose until resolved to ≤ Grade 1 or baseline except for alopecia or AEs 
that, in the opinion of the investigator, are not considered a safety risk for the patient. 

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• Grade 4: Permanent discontinuation from study. Exceptions may be considered after 
consultation with the medical monitor. 
5.6.1. 
Dose Interruptions or Delay for Study Drugs  
A dose interruption is an interruption of an infusion. A dose delay is a deviation from prescribed 
dosing schedule (ie, the drug is withheld beyond visit window). 
Every effort should be made to administer the study drug according to the planned dose and 
schedule.  In the event of significant toxicities, dosing may be delayed and/or interrupted based 
on the guidelines below.  Reasons for dose interruptions or delays, the supportive measures 
taken, and the outcome will be documented in the patient's chart and recorded in the eCRF. 
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 the administration of study drug can resume within ≤ 10 days, it should be 
administered in the current cycle.  If the study drug needs to be withheld for > 10 days, it should 
be omitted from the current cycle and administration should continue at the start of the next 
cycle.   
Management guidelines for imAEs and infusion-related reactions in patients treated with 
tislelizumab are presented Section 8.7 and Appendix 7, respectively. 
5.6.2. 
Dose Reductions for Study Drugs  
There will be no dose reductions allowed for tislelizumab.  

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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 cancer, including chemotherapy and radiotherapy, and prior treatment with anti-PD-1, 
anti-PD-L1, PD-L2 or anti-CTLA-4 (Section 4.2), or any other antibody or drug specifically 
targeting T-cell costimulation or checkpoint pathways. All prior and concomitant medications 
(eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) given to patients within 30 days before the first dose and 30 days after the last dose 
of study treatment (as of the safety follow-up visit) should be recorded on the CRF.  
6.2. 
Permitted Concomitant Medications/Procedures  
Unless noted otherwise, 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, hematopoietic growth factors, red blood cell/platelet 
transfusions) and in a patient’s interest are allowed. Anemia is frequently observed in colorectal 
cancer patients (Wilson et al, 2017). For patients with cancer-induced anemia at baseline or with 
worsened cancer-induced anemia during the study period, appropriate management of 
cancer-induced anemia is recommended per the NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines 2022) for cancer- and chemotherapy-induced anemia or local clinical 
practice guidance. 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. 
All concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter, herbal supplements, and intravenous medications and fluids.  
6.2.1. 
Systemic Corticosteroids  
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 7) and must be administered at nonimmunosuppressive doses (≤ 10 mg/day of 
prednisone or equivalent) before the next administration of the study drugs. The short-term use 
of steroids as prophylactic treatments (eg, for patients with contrast allergies to diagnostic 
imaging contrast dyes) is permitted.   
6.2.2. 
Hepatitis B Treatment  
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator as aligned with local 
guidance. Such medications must be documented in the patient’s chart and recorded in the eCRF. 
Patients receiving antivirals at screening should be treated for > 2 weeks before enrollment and 
continue treatment during the study and for 6 months after study drug discontinuation. 
6.2.3. 
Hepatitis C Treatment  
Patients with detectable HCV RNA who are receiving treatment at screening should remain on 
continuous, effective antiviral therapy during the study. Investigators can consider treatment with 

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antiviral agents following the international or local guidelines as appropriate. However, 
interferon-based therapy for HCV is not permitted on study. Patients who are given antiviral 
therapy must initiate treatment > 2 weeks before enrollment and continue treatment during the 
study and for 6 months after study drug treatment discontinuation. 
6.3. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited: 
• Other than the adjuvant therapy, any concurrent anticancer therapy (ie, chemotherapy, 
hormonal therapy, immunotherapy, or standard or investigational agents including 
Chinese [or other country] herbal medicine and Chinese [or other country] patent 
medicines for the treatment of cancer [regardless of cancer type]) ≤ 14 days (or 
≤ 5 half-lives, if applicable, whichever is shorter) before first dose and during the 
study. 
• Live vaccines within 28 days before first dose and up to 60 days after the last dose of 
study drugs. 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or which 
are known to potentially interfere with liver or other major organ functions 
(eg, hypericin) ≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is longer) before 
first dose and during the study. Patients must notify the investigator of all herbal 
remedies used during the study.   
6.4. 
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. 
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
The potential for drug-drug interaction between tislelizumab and small-molecule drug products 
is very low, given that 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 recycled into other proteins. 

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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 (which must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Prescreening  
Patients with unknown MMR and MSI status must undergo examination or confirmation of MSI 
status by a central laboratory within 56 days prior to the first dose of study drug. The details for 
collection, storage, shipment, and analysis of tissue block are detailed in the laboratory manual. 
At prescreening period, the following criteria are a prerequisite for the confirmation of MSI 
status by central laboratory:  
• Pathologically (histologically) confirmed diagnosis of potentially resectable Stage II or Stage 
III (per the Eighth American Joint Committee on Cancer staging system for Colon/Rectal 
Cancer) CRC without any prior therapy for current CRC, including chemotherapy or 
radiotherapy or immunotherapy 
• Mandatory availability for shipment of blood and tumor tissue to qualified central laboratory 
for analysis. Approximately 2 mL peripheral whole blood together with tumor tissues 
(archival FFPE blocks or at least 10 freshly cut unstained slides) are required. Information on 
previous histopathology reports and previous molecular analysis (if applicable) is required to 
accompany the tissue samples. In the absence of sufficient archival tumor tissues, a fresh 
biopsy of a tumor lesion at baseline is mandatory.   
• Written informed consent for collection, storage and analysis of tissue block must be 
obtained from the patient according to International Council for Harmonisation (ICH)/GCP, 
and national/local regulations.  
7.2. 
Screening  
Screening evaluations will be performed ≤ 28 days before first dose. Patients who agree to 
participate will sign the ICF before undergoing any screening procedures. 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 will assess patient eligibility 
according to the latest screening assessment results.  
For patients who have been confirmed to have MSI-H by central laboratory during the 
prescreening period, the central confirmation of MSI status is not required during the screening 
period.  
Results of standard-of-care tests or examinations performed before obtaining informed consent 
and ≤ 28 days before first dose may be used for the purposes of screening rather than repeating 
the standard-of-care tests unless otherwise indicated. 

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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 the sections about safety assessments (Section 7.5), tumor and response 
evaluations (Section 7.6), and biomarkers (Section 7.7).  
Rescreening under limited conditions may be allowed after consultation with the sponsor: Eg, 
when a patient’s laboratory results narrowly miss a laboratory criterion, and are correctable and 
not due to rapidly deteriorating condition or disease progression. Rescreening is allowed only 
once. 
7.2.1. 
Informed Consent and Screening Log  
Voluntary written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. The ICFs for enrolled patients and for patients who 
are screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before first dose. The investigator will maintain a screening log to record 
details of all patients screened to confirm eligibility or record reasons for screening failure, as 
applicable. 
7.2.2. 
Demographic Data and Medical History  
Demographic data will include age or date of birth, gender, and self-reported race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before first dose.  
7.2.3. 
Women of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 8 for contraception guidelines and definitions of “Women of Childbearing 
Potential” and “No Childbearing Potential.”  
7.2.4. 
Pulmonary Function Tests  
Patients who are suspected of having or known to have serious/severe respiratory conditions, or 
who exhibit significant respiratory symptoms unrelated to the underlying cancer, or who have a 
history of thoracic radiotherapy will undergo pulmonary function testing which may include, but 
is not limited to, spirometry and assessment of diffusion capacity done during the screening 
period to assist the determination of suitability for the study. 
Tests may be repeated as clinically indicated while on study (refer to Appendix 1 for details). 

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7.3. 
Enrollment  
7.3.1. 
Confirmation of Eligibility  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined.  No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
7.3.2. 
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 re-assigned to any 
other patient.  Rescreened patients will sign a new ICF and receive a new identification number. 
7.4. 
Study Drug Dispensation  
Tislelizumab will be dispensed and administered as described in Section 5.2. 
7.5. 
Safety Assessments  
7.5.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate and blood pressure 
(systolic and diastolic). Pulse rate and blood pressure will be collected while the patient is in a 
seated position after resting for 10 minutes. If coinciding with study drugs administration, the 
patient’s vital signs are required to be recorded within 60 minutes before, during, and 
approximately 30 minutes after the first 2 cycles of study drug administration. For subsequent 
cycles, vital signs will be collected within 60 minutes before the infusion of study drug, and if 
clinically indicated, during and approximately 30 minutes after the infusion of study drug. 
Height should only be measured and recorded during screening. Weight will be measured before 
study drug administration in every cycle. 
7.5.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including the 
evaluations of 1) head, eyes, ears, nose, throat; and 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 will be 

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recorded as AEs on the eCRF. Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements. 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS(Appendix 3) will be assessed during the study per timepoints as indicated in 
Appendix 1. 
7.5.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of clinical chemistry, hematology, coagulation, and 
urinalysis will be conducted as outlined in in Appendix 2, per the timepoints shown in 
Appendix 1.  
If laboratory tests at screening are not performed ≤ 7 days before study drug administration on 
Day 1 of Cycle 1, these tests should be repeated and reviewed before study drug administration. 
After Cycle 1, these laboratory tests are to be performed and 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 should use results from the same local laboratories for assessing eligibility, safety 
monitoring, and dosing decision for each patient.   
7.5.4.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune CPIs, serum 
creatinine kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all tislelizumab 
studies to protect the study patients 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).  
If CK-MB fractionation is not available, serum troponin (troponin I and/or T) measurements will 
be performed instead per local guidelines, and used consistently throughout the study.  
7.5.5. 
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. 
7.5.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6.  
7.5.7. 
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], 

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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. 
7.6. 
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. 
Before surgery, patients will undergo computed tomography (CT) scans (with oral/intravenous 
contrast, unless contraindicated) or magnetic resonance imaging (MRI) of the neck, chest, pelvis, 
and abdomen within 9 weeks ± 7 days after first dose  to reconfirm resectability. Other known or 
suspected sites of disease must be included in the imaging assessments (bone, brain, etc). 
After surgery, disease follow-up tumor assessment will be performed by CT or MRI (including 
neck, chest, pelvis, and abdomen) every 12 weeks (± 14 d ays) for the first 3 years, then every 
24 weeks (± 28 days) for a total of 5 years, and then once each year (± 28 days) thereafter based 
on RECIST v1.1. Patients will continue with the scheduled tumor assessments until the patient 
experiences disease progression or recurrence according to RECIST v 1.1, withdraws consent, is 
lost to follow up, death, begins a new anticancer therapy (excluding adjuvant therapy), or until 
the study terminates, whichever occurs first. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation.  The same radiographic procedure used to 
assess disease sites at Screening is required to be used throughout the study (eg, the same 
contrast protocol for CT scans). 
• Screening evaluations will be performed within 28 days before first dose. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT scan of the chest plus a 
contrast-enhanced MRI (if possible) of the abdomen should be performed.  
• If a CT scan for tumor assessment is performed on a 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).   
7.7. 
Biomarkers  
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling and the Schedule of Assessments (Appendix 1) 
for timepoints. 
During the prescreening period, patients with unknown MSI and MMR status are required to 
provide blood and tumor tissues for central laboratory confirmation of MSI status. 
Approximately 2 mL peripheral whole blood together with tumor tissues (archival FFPE blocks 
or at least 10 freshly cut unstained slides) are required for central laboratory confirmation of MSI 
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Patients with known MSI-H status by local laboratory must undergo central laboratory 
assessment of MSI-H during or after the screening period if tumor samples are obtainable. For 
patients with known dMMR status determined by local laboratory, central laboratory 
confirmation of MSI-H status will be performed during screening period for enrollment. 
Approximately 2 mL peripheral whole blood together with tumor tissues (archival FFPE blocks 
or at least 10 freshly cut unstained slides) are required for central laboratory 
assessment/confirmation of MSI-H. Available paired tumor tissues (pretreatment and post-
treatment tumor tissues as FFPE blocks or approximately 14 [≥ 10] freshly cut unstained slides) 
need to be sent for retrospective analysis of other exploratory biomarkers related to response and 
resistance for all patients in a BeiGene-designated central or test laboratory. These exploratory 
biomarkers include immune cell infiltration, PD-L1, TMB/DNA mutation, and GEP for all 
enrolled patients.  
A fresh tumor biopsy at a tumor lesion is mandatory if there are no available pre-treatment 
archival tumor samples. Written patient consent is required for fresh tumor biopsies. 
For fresh biopsies, acceptable samples include core needle biopsies for nonsuperficial tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. Tumor tissue should be of good quality based on total and viable tumor content. 
Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable. Approximately 2 mL of peripheral whole blood will be required for collection to 
work as the MSI test control.  
7.8. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted 
(Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed before any study treatment 
infusion/dose unless otherwise noted. Laboratory results are required to be reviewed before 
dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of Cycle 1 during pre-operative treatment phase.  
7.9. 
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 PS, AE review, concomitant 
medications and procedure reviews, radiographic assessments, physical examination of liver, 
spleen, and lymph nodes, assessment of disease-related constitutional symptoms, and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation.  
If an unscheduled visit is necessary to assess toxicity or evaluate suspected disease progression, 
then diagnostic tests may be performed based on the investigator’s assessment as appropriate, 
and the results of these tests should be entered on the unscheduled visit eCRF. 

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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated With Study Drugs  
8.1.1. 
Risks Associated With Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or exacerbation 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. 
8.2. 
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, with a history of autoimmune 
diseases that may relapse, who have undergone allogenic stem-cell or organ transplantation or 
who have received a live viral vaccine ≤ 28 days before first dose are excluded from the study. 
Refer to Section 4.2 for the full list of exclusion criteria.  
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. 
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 5), physical examinations, laboratory measurements 
(hematology, clinical 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 autoimmune conditions or infection. 
At the start of each cycle, the study drug will be administered only after clinical laboratory 
results have been reviewed. Administration of study drug will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (for additional information, see Section 5.2).  

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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 the 
study drug, whether considered related to the study drug or not.  
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or an association with a significantly worse 
outcome  
• New conditions detected or diagnosed after administration of study drug even though 
the condition might have been present before the start of the study drug 
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 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 diagnostic 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 the 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 before submission to the sponsor.  
8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon NCI-CTCAE v5.0. 
Toxicities that are not specified in 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 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  

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• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drugs and the 
occurrence of each AE or SAE, using their best clinical judgement. Alternative causes, such as 
natural history of the underlying disease, concomitant therapy, other risk factors, and the 
temporal relationship of the AE or SAE to the study drugs should be considered and investigated. 
The investigator should consult the Tislelizumab Investigator’s Brochure in the determination of 
his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before 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 change his/her opinion of causality after 
considering follow-up information, amending the SAE report accordingly.  
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drugs (ie, there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment, 
including:  
• Temporal relationship of the AE to the administration of study treatment/study 
procedure  
• Whether an alternative etiology has been identified  
• Mechanism of action of the study drugs  
• Biological plausibility  
An AE should be considered “related” to study drugs 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  

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• 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, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-ray, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgement of the investigator. In general, these are the laboratory test abnormalities or 
other abnormal assessments that:  
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation.  
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 × ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF.  

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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.”  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose:  
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE, 
which hypothetically might have caused death, if it were more severe.  
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.  
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 

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8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the study drug’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 Tislelizumab Investigator’s Brochure.. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Reporting Period  
After the ICF has been signed but before the administration of the study drug, only SAEs should 
be reported to the sponsor. 
After initiation of the study drug, all AEs and SAEs, regardless of relationship to the study drug, 
will be reported until either 30 days after last dose of the study drug, or initiation of new 
anticancer therapy, whichever occurs first. All imAEs (serious or nonserious) should be reported 
until 90 days after the last dose of the study drug, regardless of initiation of new anticancer 
therapy. All SAEs considered related to the study drug that are brought to the attention of the 
investigator should be reported regardless of time since the last dose of treatment.  
AEs and SAEs should be recorded according to the details in Table 4. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.4.2. 
Table 4: 
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 dose, initiation of new 
anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Nonserious AEs due to 
progressive disease 
Do not record (see Section 8.6.4) 
All nonserious AEs, 
except those due to 
progressive disease 
First dose of study drug 
Up to 30 days after last dose, initiation of new 
anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study drug 
Up to 90 days after last dose (regardless of 
initiation of new anticancer therapy), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
 a All SAEs considered related to the study drug that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment. 

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8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 5. 
Table 5: 
Time Frames 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  
Abbreviations: SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames.  
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for receipt of SAE reports. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 

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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 8.6.2).   
8.6.5. 
Deaths  
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event (eg, “death,” 
“death of unknown cause,” or “death unexplained”). 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving study drugs 
or within 120 days after the last dose of study drugs, a pregnancy report form is required to be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported.  
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
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.  

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To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information document: 
• 
Tislelizumab Investigator’s Brochure 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (Section 8.7.3) should be classified as imAEs and identified 
as such in the eCRF AE page until Day 90 after the last dose of the study drug. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs 
which are commonly seen with immune CPIs in Appendix 7. 
An extensive list of potential imAEs is presented in Section 8.7.3, Table 7. 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. Each individual 
sign and symptom of an infusion-related reaction should be recorded as a separate AE in the 
eCRF and identified as an infusion-related reaction. Refer to the eCRF completion guidelines for 
details. 
8.7. 
Management of Adverse Events of Special Interest  
As a routine precaution, patients must be monitored for ≥ 60 minutes after infusion of 
tislelizumab on Day 1 of Cycle 1 and Cycle 2 in an area with resuscitation equipment and 
emergency agents. For Cycle 3, 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 in the following subsections. 
8.7.1. 
Infusion-Related Reactions  
Patients should be closely monitored for infusion-related reactions. Immediate access to an 
Intensive Care Unit 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 the study drug are 
provided in Table 6. 

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Table 6: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due to 
Study Drugs 
NCI-CTCAE Grade 
Treatment Modification for Study Drugs 
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.  
 
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 reactions has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described in the 
text following this table.   
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 in the 
text following this table. 
The patient should be withdrawn from study drug 
treatment. 
Grade 4 - life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described in the 
text following this table. 
The patient should be withdrawn from study drug 
treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions. 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 the study drug. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per type of the reaction. This includes but is not limited to an 
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, the patient should receive either oral premedication with an 
antihistamine (eg, diphenhydramine or equivalent) or an antipyretic (eg, paracetamol or 
equivalent), and the patient should be closely monitored for clinical signs and symptoms of an 
infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and 
oxygen. 

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8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If a 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 as outlined in the Working Group of the Resuscitation Council (United Kingdom) Soar 
et al, 2008). Patients should be instructed to report any delayed reactions to the investigator 
immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction, the infusion must be stopped 
immediately, and the patient must be discontinued from the study. Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes after administration of 
the drug/antigen, and are characterized by respiratory distress, laryngeal edema, and/or intense 
bronchospasm, vascular collapse or shock without antecedent respiratory difficulty, cutaneous 
manifestations such as pruritus and urticaria with/without edema, and/or 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 and should then be placed on monitor immediately. An 
Intensive Care Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs infusion. 
Alternative treatments for fever (ie, paracetamol) may be administered to patients at the 
discretion of the investigator. 
8.7.3. 
Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but are not limited to serologic, immunologic, 
and histologic (biopsy) data. If alternative causes have been ruled out, the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy and is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 7. All conditions 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 et al, 2018), and common immune-mediated toxicities 
are detailed in Appendix 7. For any AEs not included in Appendix 7, please refer to the ASCO 
Clinical Practice Guideline (Brahmer et al, 2018) for further guidance on diagnostic evaluation 
and management of immune-mediated toxicities.  

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Table 7: 
Immune-Mediated Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet 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, the study drug should be 
discontinued after consultation with the sponsor. Patients who experience a recurrence of any 
event at the same or higher severity grade with rechallenge should permanently discontinue 
treatment. 

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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the 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  
No hypothesis testing or p-value will be provided for the below statistical analyses since the 
study is of exploratory purpose. 
9.1.1. 
Analysis Sets  
The Safety Analysis Set (SAS) includes all enrolled patients who received ≥ 1 dose of study 
drug; it will be the analysis set for the safety analyses.  
The Efficacy Analysis Set (EAS) includes all enrolled patients who receive neo-adjuvant 
treatment followed by surgery. This will be the primary analysis set for the efficacy analyses.  
9.1.2. 
Patient Disposition  
The number of patients treated, and the number of patients who discontinued from the study drug 
and/or study will be counted. The primary reason for study drug and/or study discontinuation 
will be summarized according to the categories in 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 WHO Drug Dictionary drug codes. 
Concomitant medications will be further coded to the appropriate Anatomical Therapeutic 
Chemical code indicating therapeutic classification. Prior and concomitant medications will be 
summarized and listed by drug and drug class in the clinical study report (CSR) for this protocol. 
Prior medications will be defined as medications that stopped before the day of the first dose of 
the study drug. Concomitant medications will be defined as medications that 1) started before the 
first dose of the study drug and were continuing at the time of the first dose of the study drug or 
2) started on or after the date of the first dose of the study drug and up to 30 days after the 
patient’s last dose (as of the Safety Follow-up Visit). In addition, telephone contacts with 
patients should be conducted to assess imAEs and concomitant medications (if appropriate, ie, 
associated with an imAE or is a new anticancer therapy) at 60 days, and 90 days (± 14 days) after 
the last dose of study treatment, regardless of whether the patient starts a new anticancer therapy. 

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If patients report a suspected immune-mediated AE at a telephone follow-up contact, the 
investigator should arrange an unscheduled visit if further assessment is indicated. 
9.2. 
Efficacy Analyses  
9.2.1. 
Primary Efficacy Analysis  
The primary efficacy endpoint is MPR rate defined as the proportion of patients in the EAS with 
≤ 10% residual viable tumor in the resected primary tumor after completion of neo-adjuvant 
therapy. The MPR rate will be summarized descriptively, and Clopper-Pearson 95% CI will be 
calculated to evaluate the precision of MPR estimate. The analysis of MPR rate will occur after 
all the patients in the efficacy analysis set have been assessed for pathological response. 
9.2.2. 
Secondary Efficacy Analyses  
The pCR rate is defined as the proportion of patients in the EAS with absence of residual tumor 
in the resected primary tumor and all resected lymph nodes after completion of neo-adjuvant 
therapy followed by surgery assessed by investigator. The pCR rate will be summarized 
descriptively, and a Clopper-Pearson 95% CI will also be calculated. 
EFS is defined as the time from the time of first dose until any of the following events in the 
EAS, whichever occurs first: radiographic disease progression according to RECIST v1.1, local 
or distant recurrence, or death due to any cause. The median and other quartiles of EFS will be 
estimated using the Kaplan-Meier method. The 2-sided 95% CIs will be constructed with the 
generalized Brookmeyer and Crowley method (Brookmeyer et al, 1982).  The 2-year/3-year EFS 
rate is defined as the proportion of patients free from EFS events at 2 years and 3 years after the 
first dose. EFS rates will be estimated by the Kaplan-Meier method with 95% CI estimated using 
Greenwood’s formula (Greenwood et al, 1926). Patients who die without a progression/disease 
recurrence will be considered to have experienced an event on the date of their death. Patients 
who did not report progression/recurrence of disease or who die will be censored on the date of 
their last evaluable tumor assessment. Patients who started any subsequent anticancer therapy 
(excluding adjuvant therapy) without a prior reported progression/recurrence will be censored at 
the last evaluable tumor assessment before initiation of the subsequent anticancer therapy.   
9.3. 
Biomarker Analysis  
Potential biomarkers including immune cell infiltration, PD‑L1 expression, tumor mutational 
burden (TMB) and DNA mutation, gene expression profile (GEP) and the association of 
biomarkers with disease status and response/resistance to tislelizumab as neo-adjuvant treatment 
will be analyzed. 
9.4. 
Safety Analyses  
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry, urinalysis), vital signs, ECGs, and 
physical examinations will also be used to assess the safety profile. Descriptive statistics will be 
used to analyze all safety data in the SAS.  

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9.4.1. 
Extent of Exposure  
Extent of exposure to the study drug will be summarized descriptively as the number of cycles 
received (the number and percentage of patients), duration of exposure (days), cumulative total 
dose received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose interruption, dose delay, and drug 
discontinuation because of AEs will be summarized for the study drug.  Reasons for dose 
modifications and discontinuation will be summarized, as well. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.4.2. 
Adverse Events  
The AE verbatim descriptions (the investigator’s description from the eCRF) will be classified 
into standardized medical terminology using the MedDRA. AEs will be coded to MedDRA 
(Version 20.0 or higher) by lowest level term, preferred term (PT), and primary system organ 
class (SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of the study drug and up to 30 days after study drug 
discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever 
occurs first. Only those AEs that were treatment emergent will be included in summary tables of 
TEAEs. Immune-mediated AEs will be identified from all AEs that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the first dose of tislelizumab and 
up to 90 days from the last dose of tislelizumab, regardless of whether the patient starts a new 
anticancer therapy. If an imAE occurs outside of the above-mentioned TEAE window, it will not 
be classified as a TEAE. 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 
SOC and PT. A patient will be counted only once by the highest severity grade per NCI-CTCAE 
v5.0 within an SOC and PT, even if the patient experienced > 1 TEAE within a specific SOC and 
PT.  
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug. 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, 
TEAEs of ≥ Grade 3 severity, imAEs, treatment-related TEAEs and TEAEs that led to treatment 
discontinuation, dose interruption, or dose delay will be summarized. 
9.4.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, coagulation, and urinalysis) values will be 
evaluated for each laboratory parameter as appropriate. Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range. Reference (normal) 
ranges for laboratory parameters will be included in the CSR for this protocol. Descriptive 
summary statistics for laboratory parameters and their changes from baseline will be calculated. 
Laboratory values will be summarized by visit and by worst postbaseline change. 

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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, calcium, glucose, magnesium, 
potassium, and sodium) will be summarized separately. 
9.4.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (blood pressure [systolic and diastolic], pulse rate, 
temperature and weight) and their changes from baseline will be presented by visit for all visits. 
Vital signs will be listed by patient and visit.  
9.5. 
Sample Size Consideration  
Sample size is based on clinical considerations. Thirty evaluable patients (who received 
neo-adjuvant treatment followed by surgery) will be enrolled and will provide a reasonably 
robust estimate and precision (95% CI) of the primary endpoint MPR rate. Table 8 summarizes 
the 95% CI of MPR rate under different assumptions of MPR estimate. With a 20% drop out 
rate, a total of 38 patients will be enrolled in this study. 
Table 8:    95% CI of MPR rate under different assumptions of MPR estimate  
MPR estimate 
95% CI 
MPR=30% 
（14.7%，49.4%） 
MPR=40% 
（22.7%，59.4%） 
MPR=50% 
（31.3%，68.7%） 
MPR=60% 
（40.6%，77.3%） 
9.6. 
Interim Analyses  
No interim analysis is planned. 

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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 conduction of 
the study will 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 ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation to verify the data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
10.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of the sponsor 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 the 
sponsor 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 either obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements or file the 
protocol to the appropriate regulatory agency before the study is initiated at a study center in that 
country/region. 
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 (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
the study drug (quantity and condition), patient drug dispensation records, and returned or 
destroyed study drug. Dispensation records will document quantities received from the sponsor’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 the requirements of the sponsor 
specified in the Pharmacy Manual. At appropriate timepoints during the conduct of the study or 
at the end of the study after the final drug inventory reconciliation by the medical 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 the sponsor’s requirements 
specified in the Pharmacy Manual for disposal, arrangements will be made between the site and 
the sponsor 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 GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will also comply with the requirements 
of the ICH E2A guideline. 
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 IRB/IEC 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 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 health 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. 
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.  

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The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study.  
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must 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 investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally.  Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study.  
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (e.g, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  

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• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives.  
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc.). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) designated 
by sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws.  If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of the United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (China NMPA), and all other national and local 
health authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs 
for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter.  This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor.  The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 

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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 that 
financial interests and arrangements of the clinical investigators with the sponsor that could 
affect reliability of data submitted to health authorities are identified and disclosed by the 
sponsor. Investigators are responsible for providing information about their financial interests 
before participation in the study and to update this information if any relevant changes occur 
during the study and for 1 year after completion of the study (ie, last patient, last visit). 

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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 investigator or designee must provide an e-signature in the 
EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor 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 the sponsor at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by lowest level term, PT, and primary SOC. 
Concomitant medications will be coded using the World Health Organization 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 ≥ 1 of the following 2 categories: 1) the investigator’s study file and 2) the 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, 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 but not be limited to the 
following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECG tracings, electroencephalograms, X-ray images, pathology and 
special assessment reports, consultant letters, screening and enrollment logs, etc.  
After 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 that there is an acceptable backup of these reproductions and that an acceptable 
quality-control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to archival at an off-site facility or transfer of ownership of or responsibility for 
the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 

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At the conclusion of this study, biological samples may be retained as outlined in the agreement 
with the contract research organization managing the biological samples, for a period of up to 
10 years or as allowed by the IRB/IEC, whichever is shorter. 
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 that they will apply 
due diligence to avoid protocol deviations and shall report all protocol deviations to the 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 CSR will be prepared and provided to the regulatory agency(ies). The sponsor will ensure that 
the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). 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. For 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 or stricter local 
criteria (International Committee of Medical Journal Editors, 2020). 
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. 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 in 
advance of the publication/presentation. 
13.6. 
Completion of the 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/provide all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drugs 

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• Review of study records for completeness 
• Collection of all study documents for the study master file filing according to GCP 
and local regulation 
• Shipment of samples (including but not limited to those for biomarkers) to the assay 
laboratory for central laboratory analysis according to protocol and laboratory 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 reasons. 
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 and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action.  If 
required by applicable regulations, the investigator must inform the IEC/IRB promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor.  In 
addition, arrangements will be made for all unused study drug in accordance with the applicable 
sponsor procedures for the study. 
Financial compensation to 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, titles, 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. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel.  
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor.  

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These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information 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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Cancer Institute Common Terminology Criteria for Adverse Events; OCT, optical coherence tomography; SAE, serious adverse event; TSH, thyroid stimulating 
hormone; v, version. 
a. 
Patients with unknown MSI and MMR status are required to provide blood and tumor tissues for central confirmation of MSI status during the prescreening 
period (defined as within 56 days prior to the first dose of the study drug). A separate prescreening informed consent must be obtained for central 
assessment of microsatellite instability for patients with unknown MMR and MSI status during the prescreening period. Written informed consent is 
required prior to performing any study-specific tests or procedures during the screening period.  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.  
b. 
The presurgical visit and associated assessments should occur within 14 days of surgery and in accordance with local institutional practices. The surgical 
procedure should be performed within 10 weeks from the first administered dose of study treatment as best as possible. If surgery cannot be performed 
within this time window (eg, because of a prolonged AE), the medical monitor should be consulted.  (see Section 3.4 . 
c. 
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 
completed (Section 3.5).  If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the End of Treatment Visit, tests 
need not be repeated.   
d. 
Includes age or year of birth, gender, and self-reported race/ethnicity; history of clinically significant disease, surgery, or cancer history; reproductive status 
(ie, of childbearing potential or no childbearing potential); history of alcohol consumption and tobacco (ie, former or current or never), and all medications 
(eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used within 30 days before the first dose).  
Information on radiographic studies performed prior to study entry may be collected for review by the investigator.  
e. 
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 approximately 30 minutes after the first 2 cycles 
of tislelizumab infusion.  For subsequent infusions, vital signs will be collected within 60 minutes before infusion and, if clinically indicated, during and 
30 minutes after the infusion. Height should only be measured and recorded during screening. Weight will be measured before study drug administration in 
every cycle. 
f.  
During the Screening Visit, a complete physical examination will be conducted. At subsequent visits (and as clinically indicated), limited, 
symptom-directed physical examinations will be performed.  
g. 
The ECG recordings will be obtained during screening, the Safety Follow-up Visit, and as clinically indicated at other timepoints.  Patients should be 
resting in a semi-recumbent supine position for at least 10 minutes prior to each ECG collection. 
h. 
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 the first dose of study drugs, all AEs and 
SAEs, regardless of their assessed relationship to study drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of 
new anticancer therapy, whichever occurs first. In addition, telephone contacts with patients should be conducted to assess immune-mediated AEs and 
concomitant medications (if appropriate, ie, associated with an immune-mediated AE or is a new anticancer therapy) at 60 days, and 90 days (± 14 days) 
after the last dose of study treatment, regardless of whether the patient starts a new anticancer therapy. Immune-mediated AEs (serious or nonserious) will 
be reported until 90 days after the last dose of study treatment, regardless of whether the patient starts a new anticancer therapy. The investigator should 
report any SAEs that are assessed as related to tislelizumab treatment, at any time after treatment discontinuation. 
i.  
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.  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. 

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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.   
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 a central laboratory or the local study site laboratory.  If the tests at Screening are not performed 
within 7 days of first dose, these tests should be repeated and reviewed before dosing. Thyroid function tests will be performed at Screening, during 
neo-adjuvant treatment, presurgical visit, and at the 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. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the underlying 
cancer, or with a history of thoracic radiotherapy will undergo pulmonary function testing which may include, but is not limited to, spirometry and 
assessment of diffusion of oxygenation, at a minimum pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity done 
during the screening period to assist the determination of suitability on the study. Tests may be repeated as clinically indicated while on study. 
n. 
Patients with unknown MSI and MMR status are required to provide blood and tumor tissues for central laboratory confirmation of MSI status during the 
prescreening period. Approximately 2 mL peripheral whole blood together with tumor tissues (archival FFPE blocks or at least 10 freshly cut unstained 
slides) are required for central laboratory confirmation of MSI status. Patients with known MSI-H status by local laboratory must undergo central laboratory 
assessment of MSI-H during or after the screening period if tumor samples are obtainable. For patients with known dMMR status determined by local 
laboratory, central laboratory confirmation of MSI-H status will be performed during screening period for enrollment. Approximately 2 mL peripheral 
whole blood together with tumor tissues (archival FFPE blocks or at least 10 freshly cut unstained slides) are required for central laboratory 
assessment/confirmation of MSI-H. Available archival pre-treatment FFPE blocks or approximately 14 [≥ 10] freshly cut unstained slides need to be sent 
for retrospective analysis of other exploratory biomarkers related to response and resistance in sponsor designated central or test laboratory. A fresh tumor 
biopsy at a tumor lesion is mandatory if there are no available archival tumor samples. Written patient consent is required for fresh tumor biopsies. For fresh 
biopsies, acceptable samples include core needle biopsies for nonsuperficial tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions. Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell 
pellets from pleural effusion, and lavage samples are not acceptable. Approximately 2 mL of peripheral whole blood will be required for collection to work 
as the MSI test control.  
o. 
Post-treatment 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 mIHC, PD-L1, TMB/DNA mutation, and GEP) (Section 7.7) 
p. 
Tumor imaging will be performed within 28 days before first dose as the baseline data and within 9 weeks ± 7 days after first dose  to re-confirm the 
resectability before surgery. See also Section 7.6. 
q. 
After surgery, disease follow-up tumor assessment will be performed by CT or MRI (including neck, chest, pelvis, and abdomen) every 12 weeks (± 14 
days) for 3 years, and then every 24 weeks (± 28 days) for a total of 5 years, and then once each year (± 28 days) thereafter based on RECIST v1.1. Patients 
will continue with the scheduled tumor assessments until the patient experiences disease progression or recurrence according to RECIST v 1.1, withdraws 
consent, is lost to follow up, death, begins a new anticancer therapy (excluding adjuvant therapy), or until the study terminates, whichever occurs first. See 
also Section 7.6. 
r. 
Tislelizumab will be given intravenously once every 3 weeks (3 cycles in total).  The initial infusion will be delivered over 60 minutes.  If well tolerated, 
subsequent infusions can be administered over 30 minutes. Patients must be monitored for 60 minutes after infusion of tislelizumab on first and second 
cycle of tislelizumab administration, for third cycle of tislelizumab administration, at least a 30-minute monitoring period is required.

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

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APPENDIX 3. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
> 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair > 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
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  
The text below was obtained from the following reference: Eisenhauer et al, 2009. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1).  Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  
Note: Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan and MRI (no less than double the slice thickness and a minimum 
of 10 mm) 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or 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 non-measurable) since they 
are, by definition, simple cysts 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 

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

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• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain).  When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note: the appearance 
of one or more new lesions is also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 

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

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• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion).  
• Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy”.  If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point.  While 
it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must 
be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or CR.  For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on trial has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 

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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on 
a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment taking into account any requirement for confirmation.  On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and nontarget disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “best overall response”. 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all time points (for example, a patient who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a BOR of PR).  
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline.  If the minimum time is not met when SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments.  For example, a 
patient who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  The same patient lost to follow-up after the first SD 
assessment would be considered inevaluable. 

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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero.” 
In trials where confirmation of response is required, repeated "NE" time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 

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For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results.  However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
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. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease.  
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome  
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Koyanagi-Harada disease 

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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If 
any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al, 1994 
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. 
The 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 administration 
and the adverse event? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of Possible Immune-mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT.  Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific.  Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered.  Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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. 

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Recommended Diagnostic Tests in the Management of Possible Immune-mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, 
including the following: CBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan.  If a patient 
experiences bleeding, pain or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.   
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering).  Review medications (eg, statins, antibiotics) and alcohol history.  
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies.  Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism.  Consult with a hepatologist 
and consider liver biopsy.  
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy.  Refer to nephrology for further management 
assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology 
referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CBC, complete blood count; 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; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
Treatment of Immune-mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, 
with patients is required. 

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• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice and contact the study medical monitor. 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor. 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]). 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy. 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks.  Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.   
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
µg/kg/da y).  Add oral prednisolone 
0.5 mg/kg/day for thyroid pain.  
Thyrotoxic patients require treatment 
with a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or life-
threatening symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  
Initiate pulse IV methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation.  Convert to 
oral prednisolone and taper over at 
least 1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 2 
months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day.  Taper over at least 4 
weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no perforation, 
sepsis, TB, hepatitis, NYHA grade 
III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/ sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 
2 
Rash covers 10%-30% 
of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch.  Consider a 
short course of oral steroids. 
Continue study 
treatment. 

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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: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment)  
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:   
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day.  When LFTs improve 
to Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day.  Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed IV methylprednisolone 
• 
If on IV, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection.  Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy.  If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 4 
weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-      
13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week.  Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose 
value > 500 
mg/dL; > 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the study medical 
monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
Management as per local guideline.  
Consider referring patient to a 
Continue treatment or, 
if symptoms continue 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care.  Consider IV corticosteroids if 
not contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia.  If symptoms do not 
improve add immunosuppressant 
therapy.  Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
 

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Autoimmune 
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Grade 
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Clinical Judgement) 
Study Drug 
Management 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; INR, 
international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; NYHA, 
New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating 
hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 

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APPENDIX 8. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment). 
− NOTE: Total sexual abstinence should only be used as a contraceptive method if 
it is in line with the patient’s usual and preferred lifestyle.  Periodic abstinence 
(eg, calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with a highly effective form of birth control, listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 

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− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/mL 
and all alternative medical causes for the lack of spontaneous menses for ≥ 12 
months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Recommendations related to contraception and pregnancy testing in clinical trials. 
15 September 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 

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APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Levey 
et al, 2009) equation and the Modification of Diet in Renal Disease Study equation.  National 
Kidney Disease Education Program calculators rely on creatinine determinations which are 
isotope dilution mass spectrometry traceable.  All laboratories should be using creatinine 
methods calibrated to be isotope dilution mass spectrometry traceable. 
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL.  
This equation is recommended when estimated GFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × mi n (Scr/κ, 1)α × max(S cr/κ, 1)-1.209 × 0.993 Age × 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-evalu
ation/glomerular-filtration-rate-calculators