Conditions: Esophageal Squamous Cell Carcinoma
Keywords: esophageal squamous cell carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The study aimed to evaluate the efficacy and safety of sitravatinib in combination with tislelizumab as a second- or third-line treatment for participants with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC) who experienced disease progression following prior systemic chemotherapy.

Detailed description:

Arms:
arm 1: Sitravatinib administered orally and tislelizumab administered intravenously arm 2: Sitravatinib administered orally arm 3: Investigators chose between docetaxel or irinotecan

Interventions: intervention 1: Sitravatinib intervention 2: Tislelizumab intervention 3: Docetaxel intervention 4: Irinotecan
Intervention descriptions: intervention 1: 100 mg orally once daily intervention 2: 200 mg intravenously once every 3 weeks intervention 3: 75 milligrams per square meter of body surface area (mg/m2) intravenously on Day 1 of every 21-day cycle intervention 4: 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle

Protocol document:
Prot_000.pdf: 
BGB-A317-Sitravatinib-203 
BeiGene 
Protocol Amendment 2.0 
10 July 2023 
 
CONFIDENTIAL 
Page 1 
 
CLINICAL STUDY PROTOCOL 
TITLE PAGE  
Protocol Title: 
A Phase 2, Randomized, Open-Label Study to Investigate the 
Efficacy and Safety of Sitravatinib in Combination With 
Tislelizumab in Patients With Locally Advanced Unresectable or 
Metastatic Esophageal Squamous Cell Carcinoma That 
Progressed on or After Anti-PD-(L)1 Antibody Therapy 
Protocol Identifier: 
BGB-A317-Sitravatinib-203 
Phase: 
2 
Investigational Medicinal 
Product(s): 
Sitravatinib (BGB-9468), tislelizumab (BGB-A317), docetaxel, 
and irinotecan 
Indication: 
Locally Advanced Unresectable or Metastatic Esophageal 
Squamous Cell Carcinoma 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive, Third Floor 
San Mateo, California 94404, USA 
Sponsor Medical Monitor: 
 
 
 
Original Protocol Version 0.0: 
Protocol Amendment 1.0: 
Protocol Amendment 2.0: 
19 April 2022 
10 August 2022 
10 July 2023 
 
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 affiliates. 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 affiliates. 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 affiliates. 
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FINAL PROTOCOL APPROVAL SHEET  
A Phase 2, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sitravatinib 
in Combination With Tislelizumab in Patients With Locally Advanced Unresectable or 
Metastatic Esophageal Squamous Cell Carcinoma That Progressed on or After Anti-PD-(L)1 
Antibody Therapy 
 
BeiGene, Ltd., Approval: 
 See electronic signature  
Sponsor Medical Monitor 
See electronic signature 
Date 
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INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
A Phase 2, Randomized, Open-Label Study to Investigate the Efficacy and 
Safety of Sitravatinib in Combination With Tislelizumab in Patients With 
Locally Advanced Unresectable or Metastatic Esophageal Squamous Cell 
Carcinoma That Progressed on or After Anti-PD-(L)1 Antibody Therapy 
Protocol Identifier: BGB-A317-Sitravatinib-203 
This protocol is a confidential communication of BeiGene, Ltd., and its affiliates. 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 affiliates. 
Instructions for Investigator: Please SIGN and DATE this signature page prior to implementation of 
this sponsor-approved protocol. PRINT your name, title, and the name and address of the center in 
which the study will be conducted. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: _______________________________ 
Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
SYNOPSIS ....................................................................................................................................13 
LIST OF ABBREVIATIONS AND TERMS ................................................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background Information on Advanced Esophageal Squamous Cell 
Carcinoma ...................................................................................................................22 
1.2. 
Current Treatment of Advanced Esophageal Squamous Cell Carcinoma and 
Unmet Clinical Needs .................................................................................................22 
1.3. 
Background Information on Sitravatinib ....................................................................25 
1.3.1. 
Pharmacology .............................................................................................................26 
1.3.2. 
Toxicology ..................................................................................................................27 
1.3.3. 
Clinical Pharmacology ................................................................................................28 
1.3.4. 
Clinical Experience With Sitravatinib ........................................................................28 
1.3.4.1. 
Safety ..........................................................................................................................29 
1.3.4.2. 
Efficacy .......................................................................................................................36 
1.4. 
Background Information on Tislelizumab ..................................................................38 
1.4.1. 
Prior Clinical Experience With Tislelizumab .............................................................39 
1.4.1.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................39 
1.4.1.2. 
Efficacy Assessment of Tislelizumab .........................................................................39 
1.5. 
Study Rationales .........................................................................................................41 
1.5.1. 
Rationale for Sitravatinib in Combination of Tislelizumab in the Treatment 
of Advanced Esophageal Squamous Cell Carcinoma After Checkpoint 
Inhibitor Failure ..........................................................................................................41 
1.5.1.1. 
Rationale for Sitravatinib Monotherapy or in Combination With 
Tislelizumab in the Treatment of Advanced Esophageal Squamous Cell 
Carcinoma ...................................................................................................................41 
1.5.1.2. 
Rationale for Sitravatinib Monotherapy or in Combination With 
Tislelizumab in the Treatment of Tumors After Checkpoint Inhibitor Failure ..........45 
1.5.2. 
Rationale for Dose Selection ......................................................................................46 
1.5.2.1. 
Rationale for Selection of Sitravatinib Dose ..............................................................46 
1.5.2.2. 
Rationale for Selection of Tislelizumab Dose ............................................................47 
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1.5.3. 
Rationale for Docetaxel and Irinotecan as the Comparators ......................................48 
1.5.4. 
Biomarker Strategy Rationale.....................................................................................48 
1.6. 
Benefit-Risk Assessment ............................................................................................49 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................51 
2.1. 
Study Objectives and Endpoints .................................................................................51 
2.2. 
Definition of Primary Estimand ..................................................................................53 
3. 
STUDY DESIGN .......................................................................................................54 
3.1. 
Summary of Study Design ..........................................................................................54 
3.2. 
Screening Period .........................................................................................................55 
3.3. 
Treatment Period ........................................................................................................55 
3.4. 
Patient Discontinuation From Study Treatment .........................................................57 
3.5. 
End of Treatment ........................................................................................................57 
3.6. 
Safety Follow-up for Immune-Mediated Adverse Events ..........................................58 
3.7. 
Survival Follow-up .....................................................................................................58 
3.8. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........58 
3.9. 
End of Study ...............................................................................................................58 
4. 
STUDY POPULATION .............................................................................................60 
4.1. 
Inclusion Criteria ........................................................................................................60 
4.2. 
Exclusion Criteria .......................................................................................................62 
5. 
STUDY TREATMENT ..............................................................................................67 
5.1. 
Formulation, Packaging, and Handling ......................................................................67 
5.1.1. 
Sitravatinib ..................................................................................................................67 
5.1.2. 
Tislelizumab ...............................................................................................................67 
5.1.3. 
Docetaxel and Irinotecan ............................................................................................67 
5.2. 
Dosage, Administration, and Compliance ..................................................................67 
5.2.1. 
Sitravatinib ..................................................................................................................68 
5.2.2. 
Tislelizumab ...............................................................................................................68 
5.2.3. 
Docetaxel ....................................................................................................................69 
5.2.4. 
Irinotecan ....................................................................................................................70 
5.3. 
Overdose .....................................................................................................................70 
5.3.1. 
Sitravatinib ..................................................................................................................70 
5.3.2. 
Tislelizumab ...............................................................................................................70 
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5.3.3. 
Docetaxel ....................................................................................................................71 
5.3.4. 
Irinotecan ....................................................................................................................71 
5.4. 
Investigational Medicinal Product Accountability .....................................................71 
5.5. 
Dose Modification ......................................................................................................71 
5.5.1. 
Dose Modification for Sitravatinib .............................................................................71 
5.5.2. 
Dose Modification for Tislelizumab ...........................................................................72 
5.5.3. 
Dose Modification for Investigator-Chosen Chemotherapy.......................................73 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................76 
6.1. 
Prior Therapy ..............................................................................................................76 
6.2. 
Concomitant Therapy .................................................................................................76 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................76 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................76 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................76 
6.2.1.3. 
Hepatitis C Treatment .................................................................................................77 
6.2.1.4. 
Radiation Therapy ......................................................................................................77 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................77 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................78 
6.3. 
Potential Interactions Between the Study Treatment and Concomitant 
Medications .................................................................................................................78 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................81 
7.1. 
Screening ....................................................................................................................81 
7.1.1. 
Informed Consent and Screening Log ........................................................................81 
7.1.2. 
Patient Numbering ......................................................................................................81 
7.1.3. 
Demographic Data and Medical History ....................................................................82 
7.1.4. 
Women of Childbearing Potential and Contraception ................................................82 
7.2. 
Enrollment ..................................................................................................................82 
7.2.1. 
Confirmation of Eligibility .........................................................................................82 
7.2.2. 
Enrollment/Randomization .........................................................................................82 
7.3. 
Dispensation of Study Treatment ...............................................................................83 
7.4. 
Safety Assessments .....................................................................................................83 
7.4.1. 
Vital Signs ..................................................................................................................83 
7.4.2. 
Physical Examinations ................................................................................................83 
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7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................83 
7.4.4. 
Laboratory Safety Tests ..............................................................................................83 
7.4.4.1. 
Cardiac Enzyme Monitoring .......................................................................................84 
7.4.5. 
Electrocardiograms .....................................................................................................84 
7.4.6. 
Echocardiogram ..........................................................................................................84 
7.4.7. 
Adverse Events ...........................................................................................................84 
7.4.8. 
Hepatitis B and C Testing ...........................................................................................84 
7.5. 
Tumor and Response Evaluations ..............................................................................85 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................87 
7.7. 
Biomarkers ..................................................................................................................87 
7.7.1. 
Tissue Biomarkers ......................................................................................................87 
7.7.2. 
Blood Biomarkers .......................................................................................................88 
7.8. 
Patient-Reported Outcomes ........................................................................................88 
7.9. 
Visit Windows ............................................................................................................88 
7.10. 
Unscheduled Visits .....................................................................................................89 
8. 
SAFETY MONITORING AND REPORTING .........................................................90 
8.1. 
Risks Associated With Study Treatment ....................................................................90 
8.1.1. 
Risks Associated With Sitravatinib ............................................................................90 
8.1.2. 
Risks Associated With Tislelizumab ..........................................................................90 
8.1.3. 
Risks Associated With Investigator-Chosen Chemotherapy ......................................90 
8.2. 
General Plan to Manage Safety Concerns ..................................................................91 
8.2.1. 
Eligibility Criteria .......................................................................................................91 
8.2.2. 
Safety Monitoring Plan ...............................................................................................91 
8.3. 
Adverse Events ...........................................................................................................92 
8.3.1. 
Definitions and Reporting ...........................................................................................92 
8.3.2. 
Assessment of Severity ...............................................................................................92 
8.3.3. 
Assessment of Causality .............................................................................................93 
8.3.4. 
Follow-up of Adverse Events .....................................................................................94 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................94 
8.4. 
Definition of a Serious Adverse Event .......................................................................95 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................95 
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8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................96 
8.6.1. 
Adverse Event Recording Period ................................................................................96 
8.6.2. 
Reporting Serious Adverse Events .............................................................................96 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................96 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................97 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................97 
8.6.3. 
Eliciting Adverse Events ............................................................................................98 
8.6.4. 
Disease Progression ....................................................................................................98 
8.6.5. 
Deaths .........................................................................................................................98 
8.6.6. 
Pregnancies .................................................................................................................98 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................98 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................99 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................99 
8.7. 
Sitravatinib-Specific Adverse Events .........................................................................99 
8.7.1. 
Non-Hematological Toxicities of Sitravatinib ............................................................99 
8.7.2. 
Hematological Toxicities of Sitravatinib ..................................................................100 
8.7.3. 
Dose Modification Guidelines for Sitravatinib-Specific Adverse Events ................100 
8.7.3.1. 
Management of Hy’s Law Cases ..............................................................................102 
8.7.4. 
Hypertension .............................................................................................................102 
8.7.5. 
Palmar-Plantar Erythrodysesthesia Syndrome .........................................................102 
8.7.6. 
Diarrhoea ..................................................................................................................102 
8.7.7. 
Hemorrhagic Events .................................................................................................103 
8.7.8. 
Thrombotic Events ....................................................................................................103 
8.7.9. 
Thyroid Dysfunction Other Than Immune-Mediated ...............................................103 
8.7.10. 
Decreased Left Ventricular Ejection Fraction ..........................................................103 
8.7.11. 
Proteinuria .................................................................................................................103 
8.7.12. 
Gastrointestinal Perforation/Fistula ..........................................................................103 
8.8. 
Tislelizumab-Related Adverse Events of Special Interest ........................................104 
8.8.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ....................................104 
8.8.2. 
Immune-Mediated Adverse Events ..........................................................................104 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...............106 
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9.1. 
Statistical Analysis ....................................................................................................106 
9.1.1. 
Randomization Methods ...........................................................................................106 
9.1.2. 
Analysis Sets .............................................................................................................106 
9.1.3. 
Patient Disposition ....................................................................................................106 
9.1.4. 
Demographic and Other Baseline Characteristics ....................................................106 
9.1.5. 
Prior and Concomitant Medications .........................................................................107 
9.2. 
Efficacy Analyses .....................................................................................................107 
9.2.1. 
Primary Efficacy Analysis ........................................................................................107 
9.2.1.1. 
Primary Estimand .....................................................................................................107 
9.2.1.2. 
Primary Analysis for Primary Estimand ...................................................................107 
9.2.1.3. 
Handling of Missing Values Not Related to Intercurrent Event ...............................107 
9.2.1.4. 
Sensitivity and Supplementary Analyses for Primary Endpoint/Estimand ..............107 
9.2.2. 
Secondary Efficacy Analysis ....................................................................................108 
9.2.3. 
Exploratory Efficacy Analysis ..................................................................................108 
9.3. 
Safety Analyses ........................................................................................................109 
9.3.1. 
Extent of Exposure ...................................................................................................109 
9.3.2. 
Adverse Events .........................................................................................................109 
9.3.3. 
Laboratory Analyses .................................................................................................109 
9.3.4. 
Vital Signs ................................................................................................................110 
9.3.5. 
Pulmonary Function Test ..........................................................................................110 
9.4. 
Pharmacokinetic Analysis ........................................................................................110 
9.5. 
Immunogenicity Analyses ........................................................................................110 
9.6. 
Other Exploratory Analyses .....................................................................................110 
9.7. 
Sample Size Consideration .......................................................................................110 
9.8. 
Interim Analyses .......................................................................................................111 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................112 
10.1. 
Independent Review Committee ...............................................................................112 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................113 
11.1. 
Access to Information for Monitoring ......................................................................113 
11.2. 
Access to Information for Auditing or Inspections ..................................................113 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................114 
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12.1. 
Regulatory Authority Approval ................................................................................114 
12.2. 
Quality Assurance .....................................................................................................114 
12.3. 
Study Site Inspections...............................................................................................114 
12.4. 
Drug Accountability .................................................................................................114 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................116 
13.1. 
Ethical Standard ........................................................................................................116 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................116 
13.2.1. 
Protocol Amendments ..............................................................................................116 
13.3. 
Informed Consent .....................................................................................................116 
13.4. 
Patient and Data Confidentiality ...............................................................................117 
13.5. 
Financial Disclosure .................................................................................................119 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................120 
14.1. 
Data Collection and Management Responsibilities ..................................................120 
14.1.1. 
Data Entry in the Electronic Case Report Form .......................................................120 
14.1.2. 
Data Collection .........................................................................................................120 
14.1.3. 
Data Management/Coding ........................................................................................120 
14.2. 
Data Integrity and In-House Blinding ......................................................................121 
14.3. 
Study Records Retention ..........................................................................................121 
14.4. 
Protocol Deviations ..................................................................................................122 
14.5. 
Study Report and Publications..................................................................................122 
14.6. 
Study and Study Center Closure ...............................................................................123 
14.7. 
Information Disclosure and Inventions ....................................................................123 
15. 
REFERENCES .........................................................................................................125 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................133 
APPENDIX 2. SCHEDULE OF ASSESSMENT OF PHARMACOKINETIC AND 
ANTIDRUG ANTIBODY ........................................................................................140 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................141 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...................................................................................................................142 
APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES VERSION 1.1 ..................................................................................143 
APPENDIX 6. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................153 
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APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................155 
APPENDIX 8. INFUSION-RELATED REACTIONS, HYPERSENSITIVITY 
REACTIONS AND IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT .................................................................156 
APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION EQUATION ...........................................................................175 
APPENDIX 10. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................176 
APPENDIX 11. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH STUDY DRUGS ...................178 
APPENDIX 12. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE QUESTIONNAIRE 
CORE CANCER (EORTC QLQ-C30) ....................................................................180 
APPENDIX 13. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
QUESTIONNAIRE-OESOPHAGUS CANCER MODULE (EORTC 
QLQ-OES18) ............................................................................................................182 
APPENDIX 14. DEFINITION OF HIGH-FAT AND LOW-FAT MEALS ............................183 
APPENDIX 15. THE DETECTION AND MANAGEMENT OF 
GASTROINTESTINAL PERFORATION/FISTULA .............................................185 
 
 
LIST OF TABLES  
Table 1: 
Second-Line Chemotherapy for Esophageal Squamous Cell Carcinoma ..................24 
Table 2: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study 516-001 ........................................29 
Table 3: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study MRTX-500 ...................................31 
Table 4: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study BGB-900-103 ...............................33 
Table 5: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 25% of Patients) by Preferred Term for Study BGB-900-104 ...............................35 
Table 6: 
Summary of Studies Evaluating Inhibitor of Receptor Tyrosine Kinase With 
or Without PD-1 for Esophageal Squamous Cell Carcinoma ....................................44 
Table 7: 
Primary Objectives and Endpoints .............................................................................51 
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Table 8: 
Secondary Objectives and Endpoints .........................................................................51 
Table 9: 
Exploratory Objectives and Endpoints .......................................................................52 
Table 10: Selection and Timing of Dose for Each Patient ..........................................................68 
Table 11: Dose Reductions for Sitravatinib ................................................................................72 
Table 12: Dose Reductions for Investigator-Chosen Chemotherapy .........................................74 
Table 13: Docetaxel Dose Modifications for Specific Adverse Events .....................................74 
Table 14: Irinotecan Dose Modifications for Specific Adverse Events .....................................74 
Table 15: Prohibited Concomitant Medications/Procedures by Treatment Component ............77 
Table 16: Restricted Concomitant Medications/Procedures by Treatment Component .............78 
Table 17: Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms ....................................................................................................96 
Table 18: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................97 
Table 19: Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities ..................................................................................................................100 
Table 20: Sitravatinib Dose Modification for Increased Blood Pressure .................................101 
Table 21: Sitravatinib Dose Modification for Increased Hepatic Transaminases ....................101 
Table 22: Sitravatinib Dose Modification for Palmar-Plantar Erythrodysesthesia 
Syndrome ..................................................................................................................101 
Table 23: Examples of Immune-Mediated Adverse Events .....................................................104 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................55 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Medicinal Product(s): Sitravatinib (also known as BGB-9468), tislelizumab (also 
known as BGB-A317), docetaxel, and irinotecan 
Title of Study: A Phase 2, Randomized, Open-Label Study to Investigate the Efficacy and Safety of 
Sitravatinib in Combination With Tislelizumab in Patients With Locally Advanced Unresectable or 
Metastatic Esophageal Squamous Cell Carcinoma That Progressed on or After Anti-PD-(L)1 Antibody 
Therapy 
Protocol Identifier: BGB-A317-Sitravatinib-203 
Phase of Development: 2 
Number of Patients: Approximately 100 
Study Centers: Approximately 25 centers in Mainland China 
Study Objectives and Endpoints: 
Primary: 
Objective 
Endpoint 
To assess the overall response rate (ORR) by the 
investigator per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version (v) 1.1 in the 
Intention-to-Treat (ITT) Population between 
Arm A (sitravatinib plus tislelizumab) and 
Arm C (investigator-chosen chemotherapy) 
ORR as assessed by the investigator, defined as 
the proportion of patients with a confirmed 
complete response (CR) or partial response (PR) 
per RECIST v1.1, in Arms A and C in the ITT 
Analysis Set 
Secondary: 
Objectives 
Endpoints 
To evaluate the duration of response (DOR) as 
assessed by the investigator per RECIST v1.1 in 
Arm A and Arm C 
DOR as assessed by the investigator, defined as 
the time from the first confirmed objective 
response until the first documentation of disease 
progression or death, whichever comes first, in 
Arms A and C in the ITT Analysis Set 
To assess the efficacy between Arm A and 
Arm C through overall survival (OS) 
OS, defined as the time from the date of 
randomization until the date of death from any 
cause, in Arms A and C in the ITT Analysis Set 
To assess the efficacy between Arm A and 
Arm C through disease control rate (DCR), 
clinical benefit rate (CBR), and progression-free 
survival (PFS) as assessed by the investigator 
per RECIST v1.1 
DCR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, 
or stable disease, in Arms A and C in the ITT 
Analysis Set 
CBR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, 
or durable stable disease (stable disease 
≥ 24 weeks), in Arms A and C in the ITT 
Analysis Set 
 
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Objectives 
Endpoints 
 
PFS as assessed by the investigator, defined as 
the time from the date of randomization to the 
date of first documentation of disease 
progression or death, whichever occurs first, in 
Arms A and C in the ITT Analysis Set 
To assess the efficacy of Arm A and Arm B 
(sitravatinib monotherapy) through ORR, DOR, 
DCR, CBR, and PFS as assessed by the 
investigator per RECIST v1.1 
ORR as assessed by the investigator, defined as 
the proportion of patients with a confirmed CR 
or PR per RECIST v1.1, in Arms A and B in the 
ITT Analysis Set 
DOR as assessed by the investigator, defined as 
the time from the first confirmed objective 
response until the first documentation of disease 
progression or death, whichever comes first, in 
Arms A and B in the ITT Analysis Set 
DCR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, 
or stable disease, in Arms A and B in the ITT 
Analysis Set 
CBR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, 
or durable stable disease (stable 
disease ≥ 24 weeks), in Arms A and B in the 
ITT Analysis Set 
PFS as assessed by the investigator, defined as 
the time from the date of randomization to the 
date of first documentation of disease 
progression or death, whichever occurs first, in 
Arms A and B in the ITT Analysis Set 
To assess the safety and tolerability of 
sitravatinib as monotherapy and in combination 
with tislelizumab 
Incidence and severity of adverse events (AEs), 
with severity determined according to National 
Cancer Institute-Common Terminology Criteria 
for Adverse Events NCI-CTCAE v5.0; vital 
signs; and clinical laboratory test results in the 
Safety Analysis Set 
Exploratory: 
Objectives 
Endpoints 
To assess the OS between Arm A and Arm B 
OS, defined as the time from the date of 
randomization until the date of death from any 
cause, in Arms A and B in the ITT Analysis Set 
To perform a sample-based tumor assessment by 
independent review committee (IRC) in 
Arms A, B, and C 
ORR as assessed by the IRC, defined as the 
proportion of patients with a confirmed CR or 
PR per RECIST v1.1, in part of patients in 
Arms A, B, and C 
 
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Objectives 
Endpoints 
To explore potential biomarkers that may 
correlate with clinical responses/resistance to 
sitravatinib plus tislelizumab or sitravatinib 
monotherapy versus chemotherapy 
Potential biomarkers including but not limited to 
PD‑L1 expression, tumor mutational burden 
(TMB)/DNA mutation/microsatellite instability 
(MSI), blood tumor mutational burden 
(bTMB)/circulating tumor DNA (ctDNA) 
monitoring/DNA mutation/MSI, gene 
expression profile (GEP), and tumor-infiltrated 
immune cells as well as the associations of 
biomarkers with disease status and 
response/resistance to sitravatinib plus 
tislelizumab or sitravatinib monotherapy versus 
chemotherapy 
To characterize the pharmacokinetics of 
sitravatinib and its metabolite M10 
Plasma concentrations of sitravatinib and its 
metabolite M10 at specified timepoints 
To characterize the pharmacokinetics and 
immunogenicity of tislelizumab 
Serum concentrations of tislelizumab and the 
incidence of antidrug antibodies (ADAs) 
To assess health-related quality of life (HRQoL) 
HRQoL is defined as the assessment of changes 
in patient-reported outcomes (PRO) of 
esophageal squamous cell carcinoma 
(ESCC)-related symptoms and function from 
baseline 
Study Design: 
This is an open-label, randomized, multicenter, Phase 2 study to investigate the efficacy and safety of 
sitravatinib in combination with tislelizumab given as a second- or third-line treatment in patients with 
locally advanced unresectable or metastatic ESCC whose disease progressed after prior platinum-based 
chemotherapy doublet and anti-PD-(L)1 antibody therapy, with the anti-PD-(L)1 antibody administered 
in combination with or sequentially following the platinum-based chemotherapy. 
The study will be conducted at approximately 25 centers in Mainland China. Approximately 
100 patients with locally advanced unresectable or metastatic ESCC whose disease progressed on or 
after platinum-based chemotherapy doublet and anti-PD-(L)1 antibody therapy will be randomized to 
receive either sitravatinib plus tislelizumab (Arm A), sitravatinib monotherapy (Arm B), or 
investigator-chosen chemotherapy (ICC) (Arm C). Patients must have received ≤ 2 lines of prior 
systemic therapy for locally advanced unresectable or metastatic disease. Other prior 
immunotherapeutic agents specifically targeting T-cell costimulation or checkpoint pathways (eg, 
anti-TIGIT antibody) are allowed if it was administered in combination with an anti-PD-(L)1 antibody. 
The choice of chemotherapy must be determined before randomization at the investigator’s discretion, 
either docetaxel or irinotecan. Randomization will be stratified by programmed cell death protein 
ligand-1 (PD-L1) expression status (assessed by the Ventana PD-L1 [SP263] assay: Tumor Area 
Positivity [TAP] score ≥ 10% versus TAP score < 10%) in a 2:1:2 ratio to receive 1 of treatment 
regimens: 
• 
Arm A: Sitravatinib 100 mg orally once daily plus tislelizumab 200 mg intravenously once 
every 3 weeks 
• 
Arm B: Sitravatinib 100 mg orally once daily 
• 
Arm C: Docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle OR  
irinotecan 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle 
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Switching of chemotherapeutic agent or cross-over between treatment arms will not be allowed during 
the study. 
Efficacy and safety will be assessed between Arm A and Arm C, while efficacy between Arm A and 
Arm B will only be assessed for efficacy contribution analysis of tislelizumab in the combination 
treatment. 
Study treatment will be administered until disease progression as assessed by the investigator per 
RECIST v1.1, unacceptable toxicity, withdrawal of consent, or another treatment discontinuation 
criterion is met, whichever occurs first. 
HRQoL will be assessed via 2 validated PRO instruments: the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Quality 
of Life Questionnaire-Oesophageal Cancer Module (EORTC QLQ-OES18). 
Study Schema: 
 
Abbreviations: CBR, clinical benefit rate; D, Day; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern 
Cooperative Oncology Group Performance Status; ESCC, esophageal squamous cell carcinoma; HRQoL, health-related 
quality of life; INV, investigator; IRC, Independent Review Committee; IV, intravenously; N, number of patients; ORR, 
overall response rate; OS, overall survival; PD-1, programmed cell death protein-1; PD-(L)1, programmed cell death protein 
(ligand)-1; PFS, progression-free survival; PK, pharmacokinetic(s); PO, orally; QD, once daily; R, randomization ratio; TAP, 
Tumor Area Positivity; VEGF(R), vascular endothelial growth factor (receptor). 
Study Assessments: 
A detailed table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. 
The baseline tumor imaging will be performed ≤ 28 days before randomization. During the study 
treatment period, evaluation of tumor response by the investigator per RECIST v1.1 will be performed 
every 6 weeks from Day 1 of Cycle 1 for the first 55 weeks and then every 9 weeks thereafter. 
After initiation of study treatment, all AEs and serious adverse events (SAEs), regardless of 
relationship to study treatment, will be reported until either 30 days after the last dose of study 
treatment or initiation of new anticancer therapy, whichever occurs first. Immune-mediated AEs 
(serious or nonserious) should be recorded until 90 days after the last dose of tislelizumab, regardless 
of initiation of new anticancer therapy. SAEs considered related to the study treatment that are brought 
to the attention of the investigator should be reported regardless of time since the last dose of treatment. 
Duration of Patient Participation: 
Duration of patient participation will vary by patient. Each patient’s visit course will include: 
• 
Screening period will be ≤ 28 days before randomization 
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• 
Treatment period will start on the first day of study drug administration and end on the last 
dose of study drug administration when the patient is discontinued from the study treatment for 
any reason. 
• 
End-of-Treatment (EOT) Visit: Patient who permanently discontinues the study treatment 
(ie, sitravatinib and tislelizumab in Arm A, sitravatinib in Arm B, or ICC in Arm C) for any 
reason will be asked to return to the clinic for an EOT Visit, which is required to be conducted 
within 30 (± 7) days after the last dose of study treatment (unless otherwise specified) or before 
the initiation of subsequent anticancer therapy, whichever occurs first. If the decision to end 
the study treatment is made ≥ 23 days after the last dose of any component of the study 
treatment, the EOT Visit may occur later, but no later than 7 days after the decision. 
• 
Safety follow-up for immune-mediated adverse events (imAEs) period: Patients who 
discontinue tislelizumab in Arm A will be asked to return to the clinic or will be contacted via 
telephone to assess imAEs and concomitant medications (if appropriate, ie, associated with an 
imAE) at 60 (± 14) and 90 (± 14) days after the last dose of tislelizumab, regardless of whether 
they start a subsequent anticancer therapy. If patients report a suspected imAE at a follow-up 
visit or a telephone contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
• 
Survival follow-up period: Survival follow up information will be collected via telephone 
calls, patient medical records, and/or clinic visits approximately every 3 months (± 14 days) 
after the EOT Visit or as directed by the sponsor until death, loss to follow up, withdrawal of 
consent, or study termination by the sponsor. All patients will be followed up for survival and 
subsequent anticancer therapy information unless a patient requests to be withdrawn from 
follow up. 
Study Population: 
Approximately 100 patients in Mainland China with locally advanced unresectable or metastatic ESCC 
that progressed after prior platinum-based chemotherapy doublet and anti-PD-(L)1 antibody therapy, 
with the anti-PD-(L)1 antibody administered in combination with or sequentially following the 
platinum-based chemotherapy. 
Key Eligibility Criteria: 
Adult patients with histologically or cytologically confirmed locally advanced unresectable or 
metastatic ESCC that is not amenable to treatment with curative intent and progressed after prior 
systemic therapy are eligible. Prior treatment must include a platinum-based chemotherapy doublet and 
anti-PD-(L)1 antibody, with the anti-PD-(L)1 therapy administered in combination with or sequentially 
following the platinum-based chemotherapy. Other prior immunotherapeutic agents specifically 
targeting T-cell costimulation or checkpoint pathways (eg, anti-TIGIT antibody) are allowed if it was 
administered in combination with an anti-PD-(L)1 antibody. Patients must have received ≤ 2 lines of 
prior systemic therapy for locally advanced unresectable or metastatic ESCC; have ≥ 1 measurable 
lesion per RECIST v1.1 ≤ 28 days before randomization; and have an Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) score of ≤ 1. Archived or fresh tumor samples should be 
obtained from each patient for assessment of PD-L1 expression status by the Ventana PD-L1 (SP263) 
assay in the central lab during screening period. 
Investigational Product, Dose, and Mode of Administration: 
Arm A: 
Sitravatinib 100 mg orally once daily plus tislelizumab 200 mg intravenously once every 3 weeks 
Arm B: 
Sitravatinib 100 mg orally once daily 
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Reference Therapy, Dose, and Mode of Administration: 
Arm C: 
Single-agent chemotherapy as determined before randomization at the investigator’s discretion: 
Docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle OR  
irinotecan 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle 
Statistical Methods: 
Primary analysis: 
The primary analysis of ORR as assessed by the investigator is descriptive and exploratory; no formal 
testing is designed. 
The crude odds ratio and risk difference of ORR, along with their exact 95% CIs will be calculated 
between Arms A and C. The ORR rate and its Clopper Pearson 95% CI will be calculated for each arm. 
The primary analysis for ORR as assessed by the investigator will be conducted ≥ 4 months 
(approximately 3 tumor assessments) after the enrollment of the last patient. 
Analysis sets: 
• 
The ITT Analysis Set includes all patients randomly assigned to a treatment arm. Patients’ data 
will be analyzed according to their randomized treatment arm. This will be the primary 
analysis population for all efficacy analysis. 
• 
The Safety Analysis Set includes all patients who received at least 1 dose of any component of 
study treatment; it will be the population for the safety analyses. 
• 
The Sitravatinib PK Analysis Set includes all patients who receive ≥ 1 dose of sitravatinib per 
the protocol and for whom any quantifiable postbaseline PK data for sitravatinib are available. 
• 
The M10 PK Analysis Set includes all patients who receive ≥ 1 dose of sitravatinib per the 
protocol and for whom any quantifiable postbaseline PK data for M10 are available. 
• 
The Tislelizumab PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab 
per the protocol and for whom any quantifiable postbaseline PK data for tislelizumab are 
available. 
• 
The ADA Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab and for whom 
both baseline and ≥ 1 postbaseline ADA result are available. 
Sample size considerations: 
This exploratory study is not powered for the hypothesis testing between treatment arms but rather to 
obtain preliminary efficacy and safety data for sitravatinib in combination with tislelizumab and 
sitravatinib monotherapy for patients with locally advanced unresectable or metastatic ESCC that 
progressed on or after anti-PD-(L)1 antibody therapy. This study will enroll approximately 100 patients 
into 3 arms, with approximately 40, 20, and 40 patients in Arms A, B, and C, respectively. The efficacy 
of tislelizumab in combination with sitravatinib versus chemotherapy will be demonstrated by 
descriptive analysis of ORR, PFS, OS, DCR, CBR, and DOR as assessed by the investigator in the 
assessment between Arms A and C. The contribution of adding tislelizumab to sitravatinib 
monotherapy will be demonstrated by similarly descriptive analysis in the assessment of Arms A and 
B. With a sample size of 40 patients in Arm A (sitravatinib in combination with tislelizumab), the 
binomial probabilities of detecting ≥ 1 treatment-emergent adverse event (TEAE) with a frequency of 
5% and 1% are approximately 0.87 and 0.33, respectively. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-9468 
sitravatinib 
BGB-A317 
tislelizumab 
BOR 
best overall response 
BP 
blood pressure 
BSA 
body surface area 
bTMB 
blood tumor mutational burden 
CPI 
checkpoint inhibitor 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DOR 
duration of response 
EC 
esophageal cancer 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End-of-Treatment 
ESCC 
esophageal squamous cell carcinoma 
FDG 
fluorodeoxyglucose 
G/GEJ 
gastric/gastroesophageal junction 
GCP 
good clinical practice 
GEP 
gene expression profile 
HBV 
hepatitis B virus 
HCC 
hepatocellular cancer 
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICC 
investigator-chosen chemotherapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRT 
interactive response technology 
ITT 
Intent-to-Treat (Analysis Set) 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD-L1 
programmed cell death protein ligand-1 
PD-(L)1 
programmed cell death protein (ligand)-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
TAP 
Tumor Area Positivity 
TEAE 
treatment-emergent adverse event 
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Abbreviation 
Definition 
TMB 
tumor mutational burden 
TME 
tumor microenvironment 
ULN 
upper limit of normal 
V 
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1. 
INTRODUCTION  
1.1. 
Background Information on Advanced Esophageal Squamous Cell 
Carcinoma  
Esophageal cancer (EC) is the eighth most common cancer in terms of incidence and the sixth 
most common cause of cancer-related death worldwide, with 604,100 new cases and 
544,076 deaths observed in 2020 (GLOBOCAN 2020a). Eastern Asia exhibits the highest 
regional incidence for both men and women among the globe, which reflects on a large disease 
burden in China (GLOBOCAN 2020b). In China, EC is the sixth most common cancer and the 
fourth most common cause of cancer-related deaths. It was estimated that > 324,422 new EC 
cases were diagnosed and approximately 301,135 deaths occurred in China in 2020, accounting 
for 53.7% of the incidence and 55.3% of the mortality of global cases (GLOBOCAN 2020c). 
Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma are the two main 
histologic types of EC. Because of differences in tumor localization and comorbidities, response 
to molecularly targeted therapy, and prognosis, ESCC and esophageal adenocarcinoma are 
usually considered as two distinct diseases that require different therapeutic strategies (Arnold et 
al 2015; Siewert and Ott 2007; Cancer Genome Atlas Research Network et al 2017; Salem et al 
2018). ESCC is the dominant histological subtype of EC worldwide, accounting for 
approximately 90% of EC cases (Abnet et al 2018). Regions of high incidence include Eastern to 
Central Asia, along the Rift Valley in East Africa, and into South Africa. ESCC is more common 
in the elderly (aged ≥ 60 years) and has a mean male to female ratio of 3:1 (Lagergren et al 
2017). The main risk factors include tobacco, alcohol, ingestion of hot liquid, and poor 
nutritional status (Tran et al 2005; Engel et al 2003). 
Advanced ESCC is a rapidly progressing and symptomatic disease with poor clinical outcomes. 
The 5-year survival rate is only 5.2% for patients with distant metastases (SEER 2022). 
1.2. 
Current Treatment of Advanced Esophageal Squamous Cell 
Carcinoma and Unmet Clinical Needs  
International treatment guidelines are consistent in the approach to the treatment of ESCC, and 
the management is dependent on the characteristics of the patient (including PS and overall 
health status) and those of the tumor, mainly the Tumor Node Metastasis (TNM) stage 
(NCCN 2022; Muro et al 2019; Lordick et al 2016). 
In newly diagnosed ESCC, neoadjuvant chemoradiation in combination with surgery is 
recommended for patients with localized resectable tumors, and definitive chemoradiation 
therapy is recommended for patients who decline surgery, are poor surgical candidates, or have 
locally advanced unresectable tumors. However, more than 30% of patients with ESCC are 
diagnosed at an advanced or metastatic stage (Abraham et al 2020) and are ineligible for curative 
interventions. Moreover, in one-third to one-half of patients treated with curative intent, the 
disease progressed, with approximately 5% to 20% of disease progression or death occurring 
within 6 months of the curative treatment (Shapiro et al 2015; Conroy et al 2014; Crosby et al 
2017). Ultimately, most patients with ESCC will require palliative systemic treatment. 
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Patients with advanced ESCC (metastatic, unresectable, or recurrent after curative treatment) are 
recommended to receive first-line palliative chemotherapy (Lordick et al 2016). Platinum-based 
chemotherapy doublets, which include either platinum agents (cisplatin, oxaliplatin, or 
carboplatin) plus fluoropyrimidine (5-fluorouracil [5-FU] or capecitabine) or taxanes (paclitaxel 
or docetaxel) are recommended (NCCN 2022; Lordick et al 2016; Muro et al 2019). First-line 
palliation has an overall response rate (ORR) of 30% to 58% and a median overall survival (OS) 
of 10.0 to 13.2 months (Kato et al 2020; Liu et al 2016; Lee et al 2015). 
Immune checkpoint inhibitors (CPIs) targeting the PD-(L)1 pathway have revolutionized the 
therapeutic landscape of advanced ESCC in recent years. Multiple multicenter, randomized 
Phase 3 studies have demonstrated that anti-PD-1 antibodies in combination with chemotherapy 
(cisplatin plus 5-FU or paclitaxel) as the first-line systemic treatment significantly prolongs the 
OS in patients with ESCC compared with chemotherapy alone (cisplatin plus 5-FU or paclitaxel) 
(Sun et al 2021; Luo et al 2021). Based on the positive readout of Keynote-590, pembrolizumab 
in combination with chemotherapy was approved in China in September 2021 for the treatment 
of locally advanced unresectable or metastatic EC in the first-line treatment setting (National 
Medical Products Administration [NMPA] Acceptance No.: JXSS2000051). In December 2021, 
another PD-1 inhibitor, camrelizumab was also approved by the NMPA to be used in 
combination with chemotherapy as the first-line treatment of ESCC (NMPA Acceptance No.: 
CXSS2100031) based on the results of ESCORT-1st. In addition to Keynote-590 and 
ESCORT-1st, multiple studies including Checkmate-648 (Doki et al 2022), ORIENT-15, and 
JUPITOR-06 demonstrate positive results for anti-PD-(L)1 antibodies in combination with 
chemotherapy as the first-line treatment for ESCC, which likely brings alternative options of 
anti-PD-(L)1 antibodies to the treatment setting in the near future. As the first chemotherapy-free 
regimen that had positive readout, nivolumab in combination with ipilimumab as the first-line 
treatment was superior than chemotherapy alone in prolonging survival in patient with ESCC 
regardless of programmed cell death protein ligand-1 (PD-L1) expression status (Doki et al 
2022), which adds another PD-(L)1-based treatment option for the population. Furthermore, 
several Phase 3 studies including RATIONALE-306, HLX10-007-EC301, SKYSCRAPER-08, 
and GEMSTONE-304 are ongoing, which are all anti-PD-(L)1 antibodies (with or without an 
anti-TIGIT antibody) in combination with chemotherapy as first-line ESCC treatment setting. 
Second-line or subsequent therapy for ESCC are dependent on patients’ physical performance 
status and the prior therapy received. For patients whose disease progressed on the first-line 
chemotherapy, clinical benefits of anti-PD-(L)1 antibody monotherapy outweigh those of 
chemotherapy, which is demonstrated by prolonging patients’ OS with a significantly more 
tolerable safety profile. Pembrolizumab monotherapy was approved for the treatment of 
recurrent locally advanced or metastatic ESCC that expresses PD-L1 (Combined Positive Score 
[CPS] ≥ 10) and progressed after ≥ 1 prior line of systemic therapy by the United States Food 
and Drug Administration (US FDA) in 2019 (Keytruda USPI 2020; Kojima et al 2020) and by 
the NMPA in 2020. Based on the results of ESCORT, camrelizumab monotherapy was approved 
by the NMPA in June 2020 for patients with advanced ESCC whose disease progressed after 
first-line chemotherapy or who were intolerant to the first-line chemotherapy, regardless of the 
PD-L1 expression status of ESCC (Huang et al 2020). Although nivolumab has not yet been 
approved by the NMPA, Chinese Society of Clinical Oncology (CSCO) guideline lists 
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nivolumab as a second-line treatment option for similar population based on efficacy results 
from ATTRACTION-3 (Kato et al 2019; CSCO 2021). 
PD-(L)1 antibody in combination with chemotherapy as the first-line therapy and PD-(L)1 
antibody monotherapy as the second-line therapy have become standard of care for patients with 
advanced ESCC. Even without epidemiological data to support, it is expected that CPI resistance 
in ESCC will inevitably develop in a large number of patients. Treatment options for ESCC are 
limited after exhausting platinum-based or fluoropyrimidine-based doublet chemotherapy and 
checkpoint therapy. Several single-agent chemotherapeutic regimens have been recommended by 
guidelines for treating ESCC after prior CPI failure, including docetaxel, paclitaxel, or irinotecan 
(NCCN 2022). Although the efficacy of single-agent chemotherapy after prior CPI treatment 
remains unclear for patients with ESCC, these therapeutic agents generally display poor OS 
outcomes (typically < 6 months) after prior chemotherapy failure (Shirakawa et al 2014; Mizota 
et al 2011; Song and Zhang 2014; Burkart et al 2007) (Table 1) and are associated with 
significant toxicity, which results in substantial morbidity and mortality with frequent dose 
interruptions, delays, or reductions. 
• Docetaxel is associated with Grade 3 or 4 neutropenia (32.6% to 48.8%), febrile 
neutropenia (6.1% to 20.9%), and anaemia (2.3% to 9.1%), as well as Grade 3 or 4 
anorexia (3.0% to 4.7%) and pneumonia (4.5%) (Shirakawa et al 2014; Mizota et al 
2011). 
• Paclitaxel is associated with Grade 3 or 4 neutropenia (52.8%), leukopenia (45.3%), 
anorexia (9.4%), fatigue (9.4%), constipation (7.5%), pneumonia (7.5%), and sensory 
neuropathy (5.7%). Sensory neuropathy of any grade is observed in 81.1% of patients 
treated with paclitaxel and is often debilitating (Kato et al 2011). 
• Irinotecan often results in neutropenia (21.4%), anaemia (28.6%), and diarrhoea 
(21.4%) (Burkart et al 2007). 
Table 1: 
Second-Line Chemotherapy for Esophageal Squamous Cell Carcinoma 
Agent 
Study design 
and patient 
population 
Sample size by 
histology (n) 
Regimen 
Median 
OS 
(mo) 
Median 
PFS 
(mo) 
Paclitaxel 
(Shirakawa et al 2014) 
Retrospective 
study in 
Japanese 
patients 
ESCC (n = 31) 
100 mg/m2 weekly 
for 6 weeks 
followed by a 
1-week rest 
6.1 
2.5 
Paclitaxel 
(Mizota et al 2011) 
Retrospective 
study in 
Japanese 
patients 
ESCC (n = 35) 
EAC (n = 3) 
80 to 100 mg/m2 
Days 1, 8, and 15 
for a 28-day 
treatment cycle 
7.2 a 
3.5 a 
Paclitaxel 
(Ilson et al 2007) 
Multicenter, 
collaborative 
study in US 
patients 
ESCC (n = 32) 
EAC (n = 63) 
80 mg/m2 weekly 
9.0 a 
3.1 a 
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Agent 
Study design 
and patient 
population 
Sample size by 
histology (n) 
Regimen 
Median 
OS 
(mo) 
Median 
PFS 
(mo) 
Docetaxel 
(Shirakawa et al 2014) 
Retrospective 
study in 
Japanese 
patients 
ESCC (n = 132) 
70 mg/m2 Q3W 
5.5 
2.3 
Docetaxel 
(Mizota et al 2011) 
Retrospective 
study in 
Japanese 
patients 
ESCC (n = 84) 
EAC (n = 2) 
60 to 70 mg/m2 
Q3W 
6.1 a 
2.1 a 
Docetaxel  
(Song and Zhang 
2014) 
Retrospective 
study in Chinese 
patients 
ESCC (n = 41) 
Not specified 
5.2 
3.2 
Docetaxel 
(Albertsson et al 
2007) 
Prospective 
study in 
Scandinavian 
patients 
ESCC (n = 39) 
EAC (n = 13)  
Docetaxel alone: 
100 mg/m2 Q3W 
NA b 
NA b 
Irinotecan 
(Burkart et al 2007) 
Single-arm, 
Phase 2 study in 
German patients 
ESCC (n = 7) 
EAC (n = 7) 
100 mg/m2 weekly 
x 3 every 4 weeks 
5 a 
2 a 
Abbreviations: CR, complete response; EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell 
carcinoma; mo, month(s); NA, not available; OS, overall survival; PFS, progression-free survival; PR, partial 
response; Q3W, once every 3 weeks; US, United States. 
a Combined ESCC and EAC histology (and first- and second-line combined, Ilson et al 2007) 
b Study I: CR, 5%; PR, 26% 
Overall, clinical benefits of the single-agent chemotherapy regimens as second- or third-line 
options for patients with advanced ESCC after treatment failure with a prior anti-PD-(L)1 
antibody and chemotherapy are diminished by modest treatment effect with significant toxicities 
such as myelosuppression and neuropathy (docetaxel, paclitaxel, and irinotecan) as well as 
diarrhoea (irinotecan). Dismal prognosis for patients with previously treated, locally advanced 
unresectable or metastatic ESCC highlights the large unmet medical need for novel therapies 
with survival benefit and better safety and tolerability profile. 
1.3. 
Background Information on Sitravatinib  
Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that 
mediate cell-to-cell communication (Hubbard and Miller 2007). They are a subclass of 
cell-surface growth-factor receptors with an intrinsic, ligand-controlled tyrosine-kinase activity. 
These single-pass transmembrane receptors that bind polypeptide ligands (mainly growth 
factors) play key roles in processes such as cell growth, differentiation, metabolism, and motility. 
In cancer, constitutive and aberrant activations of components of those pathways result in 
increased proliferation, survival, and metastasis. Therefore, these signaling pathways became 
prime targets for cancer therapy. 
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Sitravatinib (also known as BGB-9468) is an orally bioavailable RTK inhibitor with potential 
antineoplastic activity. It is a potent inhibitor of multiple RTKs, including AXL, MER, MET, 
KIT, FLT3, RET, VEGFR1, VEGFR2, VEGFR3, PDGFRα, DDR2, TRKA, and TRKB. 
Sitravatinib targets are genetically altered in a variety of cancers and act as oncogenic drivers, 
promoting cancer development and progression. In addition to targeting genetically altered 
oncogenic drivers, sitravatinib targets are expressed in a number of immune cell types and 
promote an immunosuppressive tumor microenvironment (TME), thus providing a rationale for 
combining with PD-1 CPI therapy. Along with the immunostimulatory effects, the 
immunomodulatory effects of sitravatinib mediated through VEGFR and KIT inhibition may 
further condition the TME in favor of antitumor activity. Preclinical data for sitravatinib indicate 
that it can increase PD-L1 expression in tumor cells, in vitro and in vivo. Pilot studies in 
syngeneic mouse tumor models also suggest that sitravatinib increases the proliferation and 
fraction of systemic/spleen CD4+ and CD8+ T lymphocytes and reduces the number of systemic 
myeloid-derived suppressor cells (MDSCs). 
1.3.1. 
Pharmacology  
Sitravatinib was demonstrated to be a potent inhibitor of the catalytic activity of a subset of 
closely related recombinant human RTKs with IC50 values ranging from 0.5 to 76 nmol/L. 
Sitravatinib showed potent activity in RTK-target dependent cell-based assays with IC50 values 
ranging from < 10 to 181 nmol/L. Consistent with this antitumor and antiangiogenic mechanism 
of action, sitravatinib demonstrated antitumor efficacy over a broad spectrum of human tumor 
xenograft models. In addition, concurrent treatment with sitravatinib greatly enhanced the 
activity of anti-PD-1 therapy in the CT26 syngeneic mouse tumor model. 
In vitro, sitravatinib is a substrate of P-glycoprotein (P-gp) but is not a substrate of breast cancer 
resistance protein (BCRP), Organic Anion Transporter (OAT) 1 or 3, Organic Cation Transporter 
(OCT) 2, Organic Transporting Polypeptide (OATP) 1B1 or 1B3, or Multi-Antimicrobial 
Extrusion Protein (MATE) 1 or 2K. Sitravatinib inhibited the efflux transporters P-gp and 
BCRP, and Bile Salt Export Pump (BSEP) mediated transport with IC50 values of 0.838 μM, 
1.51 μM, and 5.06 μM, respectively. Sitravatinib demonstrated direct inhibition of cytochrome 
P450 (CYP) 2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, with IC50 values of 2.9 μM, 
11 μM, 10 μM, 1.9 μM, 11 μM, and 0.81 μM, respectively. 
Sitravatinib was more extensively metabolized in dogs than in mice, rats, and humans in vitro. In 
vitro results from the hERG assay demonstrate an IC50 of 0.6 μM (0.38 μg/mL) on the potassium 
current, which is approximately 227-fold higher than the mean free Cmax at steady-state 
(0.00265 μM) in patients, suggesting a low risk for QTc prolongation. In vivo results 
demonstrated that there were no adverse effects on the cardiovascular system in telemetered 
dogs, including no effect on the QTc interval, when sitravatinib was administered as a 
single-dose to dogs at doses up to 4 mg/kg (mean 6-hour concentration of 0.072 μg/mL). Minor 
increases in vascular pressures were observed during the dog cardiovascular study. 
Assessment of the neurological functional observation battery and respiratory evaluations (tidal 
volume, respiration rate, and minute volume) did not reveal any sitravatinib-related effects at 
doses up to 25 mg/kg in rats (Day 1 mean Cmax = 4.9 μg/mL). 
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Please refer to the Sitravatinib Investigator’s Brochure for additional details regarding 
nonclinical studies of sitravatinib. 
1.3.2. 
Toxicology  
In the 4-week repeated-dose toxicology study in beagle dogs, sitravatinib was tolerated at doses 
up to 3 mg/kg/day, the highest dose tested (Study TX-MGCD516-006). No unscheduled deaths 
occurred in the study; however, 1 dog in the 3 mg/kg/day group was taken off dosing on Day 8 
due to decreased body weight, emesis, loose feces, and dehydration. The remaining dogs in this 
dose group also exhibited decreased body weight and food consumption throughout the 
remainder of the dosing period. Upon necropsy, there were no treatment-related gross findings, 
clinical pathology changes, or microscopic findings attributed to sitravatinib at any dose level. 
Given the marked loss of body weight and decreased food consumption at 3 mg/kg/day, the 
no-observed-adverse-effect level (NOAEL) was considered 1 mg/kg/day. 
In the 13-week repeated-dose study in dogs (Study TX-MGCD516-014), sitravatinib was 
tolerated at doses up to 2 mg/kg/day, the highest dose tested. There were no test article-related 
unscheduled deaths and no adverse sitravatinib-related ophthalmic or clinical pathology 
parameter changes. Target organ effects were limited to necrotizing vascular/perivascular 
inflammation in the serosa of the oviduct and uterus of the 2 mg/kg/day group females. These 
reproductive organ effects in females were not present after the 4-week recovery period, 
demonstrating complete reversal of these effects. Based on the adverse effects in the 
reproductive organs of female dogs given 2 mg/kg/day of sitravatinib, the NOAEL was 
considered to be 2 mg/kg/day in males and 0.6 mg/kg/day in females. 
In rats, VEGF-related target organs were identified, including the adrenal gland, Brunner’s 
glands in the duodenum, lymphoid tissues, ovary, kidney (increased basophilic tubules), liver, 
pancreas, tongue, bone, and teeth. All effects, except those in the kidney, bile duct, and pancreas, 
either recovered or showed partial recovery. Daily oral administration of sitravatinib to Crl:CD 
(Sprague Dawley) rats at a dose level of 25 mg/kg/day was not tolerated and resulted in adverse 
clinical observations, changes in body weight and food consumption, mortality, and early 
termination. Based on the severity of the sitravatinib-related toxicity at 25 mg/kg/day and 
mortality (though reduced) in animals given ≥ 10 mg/kg/day, the NOAEL was determined as 
2.5 mg/kg/day. 
Administration of sitravatinib in the 4-week repeated-dose rat study (TX-MGCD516-007) led to 
early deaths at 10 and 25 mg/kg/day. The cause of death and morbidity at these dose levels 
consisted of adrenal hemorrhage and necrosis. Based on the severity of the sitravatinib-related 
toxicity at ≥ 10 mg/kg/day, the NOAEL was 2.5 mg/kg/day. 
Sitravatinib was evaluated in a standard battery of Good Laboratory Practice genotoxicity studies 
(Ames, chromosome aberrations and in vivo rat micronucleus assays) and was considered 
negative for mutagenicity and clastogenicity. 
Refer to the Sitravatinib Investigator’s Brochure for more detailed information on the toxicology 
of sitravatinib. 
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1.3.3. 
Clinical Pharmacology  
The pharmacokinetics (PK) profile of single-agent treatment with the sitravatinib free-base 
formulation has been evaluated in Study 516-001 after single- and repeated-dose administration 
in patients with advanced solid tumor malignancies. Plasma samples for PK analyses were 
collected over a 168-hour period following single-dose administration (Lead-In Period) and over 
a 24-hour period following repeated-dose administration. Plasma drug concentrations were 
determined using a validated, sensitive, liquid chromatography with tandem mass spectrometry 
(LC-MS/MS) assay. The PK of sitravatinib was evaluated using noncompartmental analysis 
methods. 
After single-dose administration, sitravatinib reached peak concentration in a median time (tmax) 
of approximately 3.02 to 8.87 hours. Exposure parameters (maximum concentration [Cmax] and 
area under the concentration-time curve [AUC]) were approximately dose proportional with 
single doses up to 200 mg. The arithmetic mean elimination half-life ranged from 42.1 to 
51.5 hours. After multiple oral administration, steady-state appeared to have been reached by 
Day 8 and Cmax and AUCτ accumulation ratios at steady-state ranged from 1.82 to 6.89 and 2.13 
to 8.34, respectively. 
Sitravatinib underwent multiple biotransformation reactions following single oral administration 
to healthy male volunteers, with metabolism mediated via oxidation, and oxidative O- and 
N-dealkylation, as well as secondary sulfation, demethylation, dehydrogenation, deamination, 
and reduction. Sitravatinib was the most abundant circulating component in human plasma, 
accounting for > 56% of the total drug-related exposure. M10 was the only major metabolite, 
accounting for approximately 19% of the total drug-related exposure. M10 was evaluated in 
nonclinical studies, and the data suggested M10 was pharmacologically active against 
sitravatinib RTK targets. 
Pharmacodynamic assessments of sitravatinib are ongoing; however, preliminary analysis shows 
a concentration-dependent modulation of VEGF-A, soluble VEGF-R2, and soluble MET 
ectodomain (sMET) levels in patients’ plasma samples. The mean prediction (95% CI) percent 
change from baseline in biomarker modulation with exposure was as follows: 300% increase for 
VEGFA, 50% decrease for sVEGFR-R2, and 35% increase for sMET, consistent with VEGFR 
and MET inhibition. Mean Ctrough at Day 15 of Cycle 1, for the 120 mg of sitravatinib free-base 
formulation once a day dose level in Study MRTX-500 was 62.4 ng/mL. At these sitravatinib 
plasma exposure levels, near-optimal modulation of biomarker levels are expected. 
Refer to the Sitravatinib Investigator’s Brochure for more detailed information on clinical 
pharmacology of sitravatinib. 
1.3.4. 
Clinical Experience With Sitravatinib  
Sitravatinib monotherapy and sitravatinib in combination with nivolumab or tislelizumab (also 
known as BGB-A317; an anti-PD-1 monoclonal antibody) are being evaluated in ongoing 
studies. Please refer to the Sitravatinib Investigator’s Brochure for more detailed information on 
sitravatinib and the currently ongoing studies. 
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1.3.4.1. 
Safety  
Across the sitravatinib development program, a total of 1546 subjects/patients have received 
≥ 1 dose of any study treatment with sitravatinib, including 215 patients in 8 pharmacokinetic 
studies of sitravatinib and 1331 patients with advanced/metastatic solid malignancies in 9 clinical 
studies. Of the 1279 patients with solid malignancies included in the safety analysis of 
sitravatinib, 220 patients have received treatment with sitravatinib as a single agent, an estimated 
723 patients have received sitravatinib in combination with nivolumab, 20 patients have received 
sitravatinib in combination with nivolumab and ipilimumab, 16 patients have received 
sitravatinib in combination with pembrolizumab and enfortumab, and 300 patients have received 
sitravatinib in combination with the PD-1 inhibitor tislelizumab. 
1.3.4.1.1. Safety Assessment of Monotherapy Study  
Study 516-001 is a multicenter Phase 1/1b first-in-human clinical study evaluating the safety, 
PK, metabolism, pharmacodynamics, and clinical activity of single-agent sitravatinib in patients 
with advanced solid tumor malignancies. The study determined that the 200 mg dose exceeded 
the maximum tolerated dose (MTD) and 150 mg once daily was initially considered the viable 
Phase 1b starting dose, which was subsequently decreased to 120 mg once daily based on the 
ongoing assessment of tolerability. The Phase 1b expansion included patients having tumors with 
selected histological diagnoses (renal cell carcinoma and castrate-resistant prostate cancer) or 
with histological diagnosis and/or tumor molecular markers (genetic alterations in sitravatinib 
RTK targets, or loss of function mutations in CBL, the negative regulators of AXL, MET, and 
PDGFR/KIT signaling). As of 17 November 2022, among the 193 patients with available safety 
data, 190 patients (98%) had experienced ≥ 1 adverse event (AE) regardless of causality, and 
174 patients (90%) had experienced ≥ 1 treatment-related AE. Treatment-related AEs reported in 
≥ 10% of patients are provided in Table 2. 
Treatment-related Grade 3 events reported in ≥ 5% of patients were hypertension (21%), 
diarrhoea (10%), fatigue (7%), and palmar-plantar erythrodysaesthesia syndrome (6%). 
Treatment-related Grade 4 events were reported in 3 patients and included lipase increased in 
2 patients and febrile neutropenia in 1 patient. 
Table 2: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study 516-001  
Adverse event 
Preferred Term, n (%)  
Patients (N = 193), n (%) 
Any treatment-related TEAE 
174 (90.2) 
 Diarrhoea 
98 (50.8) 
 Fatigue 
83 (43.0) 
 Hypertension 
78 (40.4) 
 Nausea 
58 (30.1) 
 Decreased appetite 
51 (26.4) 
 Vomiting 
46 (23.8) 
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Adverse event 
Preferred Term, n (%)  
Patients (N = 193), n (%) 
 Palmar-plantar erythrodysaesthesia syndrome 
39 (20.2) 
 Aspartate aminotransferase increased 
36 (18.7) 
 Alanine aminotransferase increased 
35 (18.1) 
 Hypothyroidism 
33 (17.1) 
 Stomatitis 
28 (14.5) 
 Weight decreased 
28 (14.5) 
 Dysphonia 
27 (14.0) 
 Abdominal pain 
22 (11.4) 
 Constipation 
22 (11.4) 
 Proteinuria 
22 (11.4) 
 Dry mouth 
21 (10.9) 
 Rash 
21 (10.9) 
 Dizziness 
20 (10.4) 
Abbreviation: TEAE, treatment emergent adverse event. 
Serious Adverse Events: Overall, 79 patients (41%) have experienced ≥ 1 serious adverse event 
(SAE), regardless of causality, and treatment-related SAEs were reported in 30 patients (16%). 
Treatment-related SAEs reported in ≥ 2 patients (≥ 1%) included diarrhoea in 6 patients (3%), 
nausea and vomiting in 5 patients each (3%), fatigue in 4 patients (2%), hypertension in 
3 patients (2%), and headache, left ventricular dysfunction, pancreatitis, and pulmonary 
embolism in 2 patients each (1%). A treatment-related Grade 5 SAR of cardiac arrest was 
reported in 1 patient. 
Treatment Discontinuation and Deaths: Of the 193 treated patients, 189 patients (98%) have 
discontinued receiving study treatment, in most cases due to objective disease progression 
(90 patients [47%]), AE (31 patients [16%]), or patient withdrawal (31 patients [16%]). A total 
of 164 patients (85%) have discontinued the study, with the primary reasons being death (112 
[58%]) and withdrawal by patient (35 [18%]). 
1.3.4.1.2. Safety Assessment of Combination Study  
MRTX-500: Sitravatinib in Combination With Nivolumab in Patients With Advanced 
Non-Small Cell Lung Cancer 
Study MRTX-500 is an open-label, parallel group Phase 2 evaluation of sitravatinib in the 
combination with nivolumab in patients with locally advanced, unresectable or metastatic 
nonsquamous non-small cell lung cancer (NSCLC). Patients who have experienced progressive 
disease on or after treatment with a CPI (CIT-experienced) as well as those who have 
experienced progressive disease after treatment with platinum-based doublet chemotherapy 
(CIT-naive) are enrolled. The sitravatinib treatment arm began with a lead-in evaluation of 
sitravatinib 120 mg once daily in combination with nivolumab administered by intravenous 
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infusion, 240 mg once every 2 weeks or 480 mg once every 4 weeks. No protocol-defined 
dose-limiting toxicities (DLTs) were reported in the first 6 evaluable patients treated with the 
sitravatinib free base at the starting dose of 120 mg once daily in combination with nivolumab. 
Based on the experience of patients enrolled into this study and in Study 516-001 (Mirati 2018), 
120 mg once daily was selected as the Phase 2 dose of sitravatinib in combination with 
nivolumab at 240 mg once every 2 weeks or 480 mg once every 4 weeks. 
As of 26 June 2022, among the 156 patients (excludes the PK substudies) with available safety 
data, 155 patients (99%) had experienced ≥ 1 AE regardless of causality; 146 patients (94%) had 
experienced treatment-related AEs; 145 patients (93%) had experienced sitravatinib-related AEs; 
and 115 patients (74%) had experienced nivolumab-related AEs. Treatment-related AEs reported 
in ≥ 10% of patients are provided in Table 3. 
Sitravatinib-related Grade ≥ 3 events were reported in 86 patients (55%). Sitravatinib-related 
Grade 3 AEs were reported for 78 patients (50%), and the most common events (in > 5% of 
patients) by Preferred Term were hypertension (17%), diarrhoea (12%), and fatigue and weight 
decreased (5% each). Nivolumab-related Grade ≥3 events were reported for 39 patients (25%). 
Nivolumab-related Grade 3 events were reported for 35 patients (22%); only the event of 
diarrhoea occurred in > 5% of patients (8 patients, 5%). 
Treatment-related Grade 4 events were reported for 7 patients (5%) overall, including 7 patients 
(5%) with sitravatinib-related Grade 4 events and 4 patients (3%) with nivolumab-related 
Grade 4 events. Grade 4 events related to sitravatinib included lipase increased, lymphocyte 
count decreased, acute kidney injury, hyperuricemia, pneumonitis, bacillus bacteraemia, 
duodenal ulcer, gastric ulcer perforation, hypertensive crisis, and haemorrhagic shock (in 
1 patient each). Grade 4 events related to nivolumab included lipase increased, lymphocyte count 
decreased, pneumonitis, duodenal ulcer, and haemorrhagic shock (in 1 patient each). The 
Grade 4 events of haemorrhagic shock, duodenal ulcer, and bacillus bacteraemia occurred in the 
same patient.  
Table 3: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study MRTX-500  
Adverse event 
Preferred Term, n (%) 
Patients (N = 156) 
Sitravatinib related 
Nivolumab 
related 
Any 
treatment 
related 
Any treatment-related TEAE 
145 (92.9) 
115 (73.7)  
146 (93.6) 
Diarrhoea 
82 (52.6) 
38 (24.4) 
85 (54.5) 
Fatigue 
66 (42.3) 
45 (28.8) 
72 (46.2) 
Nausea 
62 (39.7) 
23 (14.7) 
62 (39.7) 
Decreased appetite 
54 (34.6) 
20 (12.8) 
54 (34.6) 
Weight decreased 
44 (28.2) 
15 (9.6) 
44 (28.2) 
Hypertension 
46 (29.5) 
2 (1.3) 
46 (29.5) 
Vomiting 
41 (26.3) 
18 (11.5) 
41 (26.3) 
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Adverse event 
Preferred Term, n (%) 
Patients (N = 156) 
Sitravatinib related 
Nivolumab 
related 
Any 
treatment 
related 
Hypothyroidism 
15 (9.6) 
36 (23.1) 
40 (25.6) 
Dysphonia 
31 (19.9) 
3 (1.9) 
31 (19.9) 
Palmar-plantar erythrodysaesthesia syndrome 
27 (17.3) 
1 (0.6) 
27 (17.3) 
Aspartate aminotransferase increased 
25 (16.0) 
17 (10.9) 
26 (16.7) 
Stomatitis 
23 (14.7) 
5 (3.2) 
24 (15.4) 
Alanine aminotransferase increased 
23 (14.7) 
17 (10.9) 
23 (14.7) 
Dry mouth 
16 (10.3) 
5 (3.2) 
17 (10.9) 
Dysgeusia 
17 (10.9) 
3 (1.9) 
17 (10.9) 
Dehydration 
15 (9.6) 
6 (3.8) 
16 (10.3) 
Proteinuria 
15 (9.6) 
4 (2.6) 
16 (10.3) 
Abbreviation: TEAE, treatment emergent adverse event. 
Note: The order of adverse events is descending by incidence of “any treatment related” adverse events. 
Serious Adverse Events: Among the 156 patients receiving study treatment, 79 patients (51%) 
experienced ≥ 1 SAE, regardless of causality. Treatment-related SAEs were reported in 
42 patients (27%) overall, including sitravatinib-related SAEs in 34 patients (22%) and 
nivolumab-related SAEs in 19 patients (12%). Sitravatinib-related SAEs occurring in 
> 2 patients included diarrhoea (7 patients [5%]), pulmonary embolism (4 patients [3%]), and 
deep vein thrombosis (2 patients [1%]). Nivolumab-related SAEs occurring in ≥ 2 patients 
included diarrhoea and pneumonitis (3 patients [2%] each), as well as colitis, pancreatitis, and 
hypoxia (in 2 patients [1%] each). Treatment-related Grade 5 AEs were reported for 1 patient 
(1%) overall and included cardiac arrest (related to sitravatinib). 
Treatment Discontinuation and Deaths: On the sitravatinib treatment arms, all patients have 
discontinued treatment with sitravatinib and nivolumab, except for 3 patients who enrolled in the 
continuation protocol, Study 516-014. Among these sitravatinib treatment patients, most patients 
had discontinued treatment due to objective disease progression (49%) or an AE (24%). On the 
sitravatinib treatment arms, a total of 141 patients have died, with the primary cause of death 
being the primary disease under study (120 of 141 patients [85%]). One death was attributed to 
study treatment toxicity (Grade 5 event of cardiac arrest related to sitravatinib). 
BGB-900-103: Sitravatinib in Combination With Tislelizumab in Patients With Advanced 
Solid Tumors 
Study BGB-900-103 is an open-label, multicenter, Phase 1b study sponsored by BeiGene, Ltd 
(BeiGene). The study is designed to evaluate sitravatinib in combination with tislelizumab in 
patients with advanced or metastatic malignancies, including squamous and nonsquamous 
NSCLC, renal cell cancer (RCC), or epithelial ovarian cancer. Patients receive sitravatinib 
120 mg orally once a day in combination with tislelizumab 200 mg intravenously once every 
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3 weeks. Refer to the Sitravatinib Investigator’s Brochure for an overview of the study design, 
study status, and study population. 
As of 26 June 2022, all 216 patients who received study treatment experienced at least 1 AE 
regardless of causality. A total of 211 patients (98%) experienced treatment-related AEs overall, 
including 204 patients (94%) experiencing sitravatinib-related AEs and 165 patients (76%) 
experiencing tislelizumab-related AEs. Treatment-related AEs reported in ≥ 10% of patients 
overall are presented in Table 4. 
Treatment-related Grade 3 events were reported in 96 patients (44%), and those reported in 
≥ 5 patients were hypertension (35 patients [16%]), alanine aminotransferase (ALT) increased 
(11 patients [5%]), diarrhoea (8 patients [4%]), and palmar-plantar erythrodysaesthesia syndrome 
(7 patients [3%]), and fatigue, stomatitis, malaise, and hypokalaemia (in 5 patients [2%] each). 
Treatment-related Grade 4 events were reported for 7 patients (3%), and treatment-related 
Grade 5 AEs were reported for 5 patients (death [2 patients, 1%]), and cardiac failure 
(respiratory failure), ischaemic stroke, and multiple organ dysfunction syndrome (1 patient [1%] 
each). 
Table 4: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 10% of Patients) by Preferred Term for Study BGB-900-103 
Adverse event 
Preferred Term, n (%) 
Patients (N = 216) 
Sitravatinib related 
Tislelizumab 
related 
Any 
treatment 
related 
Any treatment-related AE 
204 (94.4) 
165 (76.4) 
211 (97.7) 
Diarrhoea 
96 (44.4) 
36 (16.7) 
101 (46.8) 
Alanine aminotransferase increased 
84 (38.9) 
65 (30.1) 
96 (44.4) 
Aspartate aminotransferase increased 
83 (38.4) 
65 (30.1) 
92 (42.6) 
Hypertension 
76 (35.2) 
7 (3.2) 
77 (35.6) 
Hypothyroidism 
14 (6.5) 
64 (29.6) 
66 (30.6) 
Palmar-plantar erythrodysaesthesia syndrome 
62 (28.7) 
4 (1.9) 
62 (28.7) 
Decreased appetite 
56 (25.9) 
14 (6.5) 
57 (26.4) 
Nausea 
52 (24.1) 
15 (6.9) 
54 (25.0) 
Vomiting 
40 (18.5) 
5 (2.3) 
41 (19.0) 
Weight decreased 
41 (19.0) 
9 (4.2) 
41 (19.0) 
Proteinuria 
40 (18.5) 
7 (3.2) 
40 (18.5) 
Blood creatine phosphokinase increased 
23 (10.6) 
30 (13.9) 
39 (18.1) 
Fatigue 
32 (14.8) 
12 (5.6) 
35 (16.2) 
Rash 
25 (11.6) 
21 (9.7) 
35 (16.2) 
Dysphonia 
27 (12.5) 
4 (1.9) 
29 (13.4) 
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Adverse event 
Preferred Term, n (%) 
Patients (N = 216) 
Sitravatinib related 
Tislelizumab 
related 
Any 
treatment 
related 
Blood creatine phosphokinase MB increased 
23 (10.6) 
14 (6.5) 
26 (12.0) 
Blood lactate dehydrogenase increased 
21 (9.7) 
19 (8.8) 
26 (12.0) 
Stomatitis 
23 (10.6) 
1 (0.5) 
24 (11.1) 
Blood bilirubin increased 
23 (10.6) 
10 (4.6) 
23 (10.6) 
Blood thyroid stimulating hormone increased 
4 (1.9) 
23 (10.6) 
23 (10.6) 
Platelet count decreased 
19 (8.8) 
17 (7.9) 
22 (10.2) 
Abbreviation: AE, adverse event. 
Note: The order of adverse events is descending by incidence of “any treatment related” adverse events. 
Serious Adverse Events: Among the 216 patients with available safety data, 119 patients (55%) 
experienced ≥ 1 SAE, regardless of causality. Treatment-related SAEs were reported in 
70 patients (32%), and included diarrhoea in 8 patients (4%), pneumonia in 5 patients (2%) 
hepatic function abnormal in 4 patients (2%), and hypertension and immune-mediated lung 
disease in 3 patients each (1%). All other treatment-related SAEs occurred in ≤ 2 patients 
overall. 
Treatment Discontinuation and Deaths: Of the 216 patients receiving study treatment, 
201 patients (93%) have discontinued sitravatinib and 199 patients (92%) have discontinued 
tislelizumab treatment. The most common reasons for discontinuation from sitravatinib were 
progressive disease (125 patients [58%]), an AE (49 patients [23%]), and withdrawal by patient 
(18 patients [8%]). The most common reasons for discontinuation from tislelizumab were 
progressive disease (138 patients [64%]), an AE (32 patients [15%]), and withdrawal by patient 
(21 patients [10%]). A total of 143 deaths have been reported, and the primary cause of death 
was progressive disease (118 of 143 patients [83%]). 
BGB-900-104: Sitravatinib Alone and in Combination With Tislelizumab in Patients With 
Hepatocellular Cancer or Gastric/Gastroesophageal Junction Cancer 
Study BGB-900-104 is an open-label, multicenter, Phase 1/2 study sponsored by BeiGene. The 
study is designed to evaluate single-agent sitravatinib and sitravatinib in combination with 
tislelizumab in patients with advanced or metastatic hepatocellular cancer (HCC) or 
gastric/gastroesophageal junction (G/GEJ) cancer. The primary objective is to evaluate the safety 
of sitravatinib as monotherapy and in combination with tislelizumab and to determine the RP2D 
of sitravatinib as monotherapy and when administered in combination with tislelizumab 200 mg 
intravenously once every 3 weeks in the Phase 1 dose-escalation phase starting with a dose of 
80 mg once a day. Secondary objectives include the assessment of the preliminary antitumor 
activity of sitravatinib administered either as a single agent or in combination with tislelizumab 
and PK. Refer to the Sitravatinib Investigator’s Brochure for an overview of the study design, 
study status, and study population. 
As of 26 June 2022, 108 of the 111 treated patients (97%) experienced ≥ 1 AE, regardless of 
causality. Sitravatinib-related AEs were reported in all patients receiving sitravatinib 
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monotherapy and in 75 patients (89%) receiving sitravatinib in combination with tislelizumab. 
Tislelizumab-related AEs were reported in 69 patients (82%) receiving sitravatinib in 
combination with tislelizumab. Treatment-related AEs reported in ≥ 25% of either treatment 
group are presented in Table 5. 
Treatment-related Grade 3 events were reported in 14 patients (52%) in the sitravatinib 
monotherapy group and in 31 patients (37%) within the combination group.  
Treatment-related Grade 3 events by Preferred Term reported in > 2 patients in the sitravatinib 
monotherapy group were hypertension (4 patients [15%]), palmar-plantar erythrodysaesthesia 
syndrome (3 patients [11%]), and diarrhoea, ALT increased, and aspartate aminotransferase 
(AST) increased (2 patients each [7%]). Hypertension, palmar-plantar erythrodysaesthesia 
syndrome, and platelet count decreased (5 patients [6%] each); gamma-glutamyltransferase 
increased and proteinuria (in 4 patients [5%] each); and diarrhoea, blood creatine phosphokinase 
increased, abdominal pain upper, anaemia, and rash (2 patients [2%] each) were reported in the 
combination group. 
Treatment-related Grade 4 events were reported for 2 patients (hypokalaemia and haemoptysis in 
1 patient [1%] each), and treatment-related Grade 5 events were reported for 5 patients (death 
[3 patients, 4%], and hepatic encephalopathy and respiratory failure [1 patient each, 1%]); all 
occurred in the combination group. 
Table 5: 
Summary of Treatment-Related, Treatment-Emergent Adverse Events 
(≥ 25% of Patients) by Preferred Term for Study BGB-900-104 
Adverse event 
Preferred Term, n (%) 
Patients (N) 
Sitravatinib monotherapy 
(N = 27) 
Sitravatinib + tislelizumab 
(N = 84) 
Any treatment-related AE a 
27 (100.0) 
75 (89.3) 
Proteinuriab 
14 (51.9) 
38 (45.2) 
Aspartate aminotransferase increased 
13 (48.1) 
35 (41.7) 
Alanine aminotransferase increased 
13 (48.1) 
34 (40.5) 
Palmar-plantar erythrodysaesthesia 
syndrome 
19 (70.4) 
30 (35.7) 
Hypertension 
7 (25.9) 
28 (33.3) 
Diarrhoea 
16 (59.3) 
25 (29.8) 
Platelet count decreased 
12 (44.4) 
21 (25.0) 
Abbreviation: AE = adverse event. 
a Includes all treatment-related adverse events (sitravatinib and tislelizumab combined). 
b Two Preferred Terms, proteinuria and albuminuria, were combined into one term as “Proteinuria.” 
Serious Adverse Events: SAEs were reported for 41 patients (37%) overall, regardless of 
causality. Sitravatinib-related SAEs were reported for 23 patients (21%), and tislelizumab-related 
SAEs were reported for 14 patients (17%). Sitravatinib-related SAEs in ≥ 2 patients included 
death (3 patients [4%]), hemoptysis and hepatic encephalopathy (2 patients each [2%]) in the 
combination group. Tislelizumab-related SAEs in ≥ 2 patients included death in 2 patients (2%). 
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Treatment Discontinuation and Deaths: Among the 111 patients treated with sitravatinib, 
105 patients (95%) have discontinued sitravatinib treatment, in most cases due to progressive 
disease (64 patients [58%]), withdrawal by patient (21 patients [19%]), or an AE (10 patients 
[9%]). Among the 84 patients treated with tislelizumab, 80 patients (95%) have discontinued 
tislelizumab treatment, in most cases due  to progressive disease (48 patients [57%]), withdrawal 
by patient (16 patients [19%]), or an AE (7 patients [8%]). A total of 58 deaths were reported for 
this study; 44 of 58 deaths (76%) were due to progressive disease. 
1.3.4.2. 
Efficacy  
1.3.4.2.1. Efficacy Assessment of Sitravatinib Monotherapy  
Efficacy results are available from the Phase 1/1b Study 516-001 (Werner et al 2017). In this 
Phase 1b dose expansion study, sitravatinib was evaluated in different patient populations: 
• Tumors harboring genetic alterations resulting in dysregulation of sitravatinib’s RTK 
targets: 
− NSCLC with activating genetic alteration in RET, KDR, PDGFRA, KIT, NTRK, 
DDR2, MET, AXL, or with loss of function mutation with CBL 
− Any solid tumor malignancy with genetic alteration of sitravatinib RTK targets or 
CBL 
• Metastatic renal cell carcinoma (mRCC) refractory to VEGF pathway inhibitors 
(simultaneously targeting MET and VEGFR) 
• Castration resistant prostate cancer (CRPC) with bone metastases 
As of 18 April 2018, 29 patients were enrolled in the Phase 1b mRCC study, after failure of prior 
anti-angiogenic therapy. Sitravatinib monotherapy showed 20% confirmed ORR among 
20 evaluable patients. Prolonged stable disease for at least 24 weeks was observed in 6 additional 
patients. 
As of 04 September 2018, 16 patients were enrolled in the Phase 1b CBL loss of function cohort. 
Among 8 clinical activity evaluable patients (received ≥ 1 cycle of sitravatinib for more than 
80% of assigned total dose and ≥ 1 on-study disease assessment), sitravatinib monotherapy 
demonstrated antitumor activity in 2 patients (1 patient with NSCLC and 1 patient with 
melanoma). 
1.3.4.2.2. Efficacy Assessment of Sitravatinib in Combination With PD-1 Blocking Agent  
MRTX-500: Sitravatinib in Combination With Nivolumab in Patients With Advanced 
Non-Small Cell Lung Cancer 
Early signs of clinical activity from the Phase 2 MRTX-500 study have been observed in patients 
with nonsquamous NSCLC, whose disease has progressed following prior anti-PD-(L)1 therapy. 
As of the cutoff date of 01 June 2021, the median OS was 14.9 months (95% CI: 9.3 to 
21.1 months) in patients with nonsquamous NSCLC who had clinical benefit from prior CPI 
therapy and received the sitravatinib plus nivolumab as second- or third-line treatment in the 
study (N = 68) (Leal et al 2021). Among the 68 patients, the ORR was 18% (12 responders of 
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68 patients) including 2 complete responses (CRs) (3%) and 10 partial responses (PRs) (15%), 
with a median duration of response (DOR) of 12.8 months; the median progression-free survival 
(PFS) was 5.7 months (95% CI: 4.9 to 7.6 months) (Leal et al 2021). The combination of 
sitravatinib with nivolumab is a rational approach to restore or enhance the clinical activity of 
treatment with a CPI in patients with immunotherapy resistant NSCLC. 
BGB-900-103: Sitravatinib in Combination With Tislelizumab in Patients With Advanced 
Solid Tumors 
Study BGB-900-103 is an open-label, multicenter, nonrandomized, multicohort, Phase 1b study 
to evaluate the safety, tolerability, PK, and preliminary antitumor activity of sitravatinib in 
combination with tislelizumab in patients with advanced solid tumors (NCT03666143). 
Cohort A and Cohort F of the study enrolled patients with nonsquamous and squamous 
metastatic NSCLC, respectively, with the disease refractory/resistant to anti-PD-(L)1 therapy. 
From December 2018 to June 2020, a total of 47 patients with NSCLC, nonsquamous (n = 24) 
and squamous (n = 23), were enrolled. As of the data cutoff date of 13 October 2020, the 
confirmed ORR was 13.6% and the disease control rate (DCR) was 86.4%. The median DOR 
was 6.90 months (95% CI: 3.06 months to not evaluable [NE]). The median PFS was 5.2 months 
(95% CI: 4.1 to 5.9 months). As of the data cutoff date, the median OS was 10.1 months 
(95% CI: 6.1 to 18.1 months), with a median follow-up duration of 12.4 months. The OS data 
were not mature (Gao et al 2021). 
As of 29 March 2021, 63 patients with platinum-resistant ovarian cancer were enrolled to 
Cohort E. Fifty-nine patients were included in the Efficacy Evaluable Population. The confirmed 
ORR was 28.8% and the DCR was 79.7%. The median DOR was 5.6 months (95% CI: 2.8 to 
22.3 months). The median PFS was 4.1 months (95% CI: 3.5 to 5.1 months). The median OS 
was 11.8 months (95% CI: 6.7 to 17.2 months), with a median follow-up duration of 8.9 months. 
However, the OS data were immature. When tumor samples were deemed as PD-L1 positive at a 
cut-off of ≥ 1% on tumor cells (TC) or ≥ 10% on immune cells (IC), no clear associations were 
observed between PD-L1 expression and ORR, PFS, or OS in the Efficacy Evaluable Population 
(Goh et al 2021). 
Cohort G of the study enrolled 25 patients with anti-PD-(L)1 antibody refractory/resistant 
unresectable or metastatic melanoma and all enrolled patients were included in the Efficacy 
Evaluable Population. As of 29 March 2021, the confirmed ORR was 36.0% and the DCR was 
88.0%. The median DOR was still NE (95% CI: 2.8% to 22.3%). The median PFS was 
6.7 months (95% CI: 4.1 months to NE). With a median follow-up duration of 10.1 months, the 
median OS was not yet mature (Cui et al 2021). 
In total, 220 patients with NSCLC were screened and 122 patients were enrolled in the study 
between 03 January 2019 and 10 February 2021. Of these 122 patients (the total NSCLC 
population), 115 patients were included in the five cohorts, with each cohort including 
22 to 24 patients (Cohort A: n = 24; Cohort B: n = 22; Cohort F: n = 23; Cohort H: n = 22; 
Cohort I: n = 24) (Zhao et al 2023). 
Median follow-up was 10.9 months (range: 0.4 to 30.6 months). Treatment-related adverse 
events (TRAEs) occurred in 98.4% of the patients, with ≥ Grade 3 TRAEs occurring in 51.6% of 
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patients. TRAEs led to discontinuation of either drug in 23.0% of the patients. The ORRs for the 
5 cohorts were the following: 
• Cohort A: 2 of 23 patients (8.7% [95% CI: 1.1% to 28.0%]) 
• Cohort B: 5 of 21 patients (23.8% [95% CI: 8.2% to 47.2%]) 
• Cohort F: 4 of 22 patients (18.2% [95% CI: 5.2% to 40.3%]) 
• Cohort H: 12 of 21 patients (57.1% [95% CI: 34.0% to 78.2%]) 
• Cohort I: 7 of 23 patients (30.4% [95% CI: 13.2% to 52.9%]) 
Median DOR was not reached in Cohort A and ranged from 6.9 to 17.9 months across other 
cohorts. Disease control was achieved in 78.3% to 90.9% of the patients. Median PFS ranged 
from 4.2 months (Cohort A) to 11.1 months (Cohort H) (Zhao et al 2023). 
BGB-900-104: Sitravatinib Alone and in Combination With Tislelizumab in Patients With 
Hepatocellular Cancer or Gastric/Gastroesophageal Junction Cancer 
Study BGB-900-104 is an open-label, multicenter, Phase 1/2 study to evaluate the safety and 
preliminary antitumor activity of sitravatinib in combination with tislelizumab in patients with 
advanced or metastatic HCC or G/GEJ cancer (NCT03941873). As of 12 July 2021, 43 patients 
with HCC and 24 patients with G/GEJ cancer were enrolled. In patients with HCC, the 
confirmed ORR was 10.0% and the DCR was 85%. The median DOR was 5.4 months (95% CI: 
4.1 to 5.7 months). The median PFS was 4.8 months (95% CI: 3.2 to 6.9 months). With a median 
study follow-up of 8.6 months, the median OS was NE (95% CI: 8.6 months to NE). In patients 
with G/GEJ cancer, the confirmed ORR was 12.5% and the DCR was 66.7%. The median DOR 
was NE (95% CI: 3.5 months to NE). The median PFS was 3.4 months (95% CI: 2.0 months to 
NE). With a median study follow-up of 5.2 months, the median OS was NE (95% CI: 4.7 months 
to NE) (Zhang et al 2022; Chen et al 2022). 
1.4. 
Background Information on Tislelizumab  
Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against 
programmed cell death protein-1 (PD-1) under clinical development for the treatment of several 
human malignancies. Tislelizumab is being investigated either as monotherapy or in combination 
with other therapies. 
PD-1 is mainly expressed in activated T cells, including cluster of differentiation (CD)8+ 
cytotoxic T lymphocytes and CD4+ T-helper lymphocytes (McDermott and Atkins 2013). The 
PD-1 signaling cascade negatively regulates the T cell and attenuates T-cell proliferation and 
functional activities, leading to T-cell exhaustion. PD-1 expression is markedly upregulated on 
tumor-infiltrating lymphocytes, while the expression of PD-1 ligand (PD-L1) is significantly 
increased on tumor cells and tumor-associated immune cells in the presence of stimulating 
cytokines such as interferon-gamma (IFN-γ) and interferon-alpha in the TME (Riley 2009), 
which is observed in many types of human solid tumors. This body of evidence provides the 
basis for cancer immunotherapeutic intervention via the approach of antagonizing PD-1. 
Refer to the most recent edition of the Tislelizumab Investigator’s Brochure for additional 
background on tislelizumab. 
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1.4.1. 
Prior Clinical Experience With Tislelizumab  
As of 20 July 2022, 18 studies with tislelizumab are ongoing, and 7 studies have been completed 
(Tislelizumab Investigator’s Brochure). Of the 18 ongoing studies, 10 studies have data 
available: 5 monotherapy studies and 5 chemotherapy combination therapy studies. 
For more detailed information on the safety and efficacy of tislelizumab when given as 
monotherapy or in combination with chemotherapy, refer to the most recent edition of the 
Tislelizumab Investigator’s Brochure. 
1.4.1.1. 
Pooled Safety Assessment of Monotherapy Studies  
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety 
assessment separate from combination therapy. Data from patients with solid tumors were 
analyzed separately from patients with hematologic malignancies. 
As of 20 July 2022, data are available from 1992 patients treated in 7 pooled solid tumor 
monotherapy studies (Tislelizumab Investigator’s Brochure). The median treatment exposure 
duration was 4.07 months (range: 0.10 to 55.46 months), and the median study follow-up 
duration was 11.65 months (range: 0.07 to 58.91 months). The median age of the patients was 
60 years, and 72.1% were male. 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 1925 patients 
(96.6%) experienced ≥ 1 treatment-emergent adverse event (TEAE). The most commonly 
occurring (≥ 15%) TEAEs by Preferred Term were anaemia (25.3%) AST increased (18.4%), 
ALT increased (17.1%), decreased appetite (16.7%), and cough (15.3%). Of the 1992 patients, 
712 patients (35.7%) experienced ≥ 1 treatment-emergent SAE. The most commonly occurring 
SAEs were pneumonia (4.8%), pneumonitis (1.4%), dysphagia (1.2%), pyrexia (1.1%), and 
pleural effusion (1.0%). 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 55 patients (2.8%) 
experienced ≥ 1 infusion-related reactions of any grade. 
Most monotherapy studies pooled have undergone an adjudication processing for identifying 
imAE (see Tislelizumab Investigator’s Brochure). Of the 1912 patients in the adjudicated solid 
tumor group of pooled monotherapy studies, 312 patients (16.3%) experienced 
≥ 1 immune-mediated adverse event (imAE) of any grade. The most commonly occurring imAEs 
of any grade were hypothyroidism (6.3%), pneumonitis (2.1%), hyperthyroidism (0.9%), rash 
(0.9%), ALT increased (0.7%), and immune-mediated lung disease (0.7%). The categories of 
imAEs experienced by ≥ 1% of patients were immune-mediated hypothyroidism (6.6%), 
immune-mediated pneumonitis (3.8%), immune-mediated hepatitis (1.9%), immune-mediated 
skin adverse reaction (1.8%), and immune-mediated colitis (1.0%). 
For more detailed information on the safety of tislelizumab when given as monotherapy or in 
combination with chemotherapy, refer to the most recent edition of the Tislelizumab 
Investigator’s Brochure. 
1.4.1.2. 
Efficacy Assessment of Tislelizumab  
Efficacy data from Studies BGB-A317-102, BGB-A317-205, and BGB-A317-302 that enrolled 
patients with ESCC are summarized below. 
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1.4.1.2.1. BGB-A317-102  
Study BGB-A317-102 is a Phase 1/2 study investigating the safety, tolerability, PK, and 
preliminary antitumor activities of tislelizumab in Chinese patients with advanced solid tumors. 
Phase 1 includes a dose-verification substudy and a substudy of PK evaluation of the products 
derived from 2 manufacturing processes and scales. Phase 2 is an indication-expansion study. 
The efficacy endpoints include ORR, DCR, and clinical benefit rate as assessed by the 
investigator per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1. 
There were 300 patients treated in the study and all treated patients were included in the Safety 
Analysis Set (Shen et al 2020). Of the 26 patients in the ESCC cohort, no patients (0%) had a 
CR. A total of 2 patients (8.0%) had a confirmed PR. Additionally, 7 patients (27%) had a best 
overall response (BOR) of stable disease. A total of 13 patients (50%) had a BOR of progressive 
disease in this cohort, and the assessment for 4 patients (15%) was unknown. 
1.4.1.2.2. BGB-A317-205  
Study BGB-A317-205 is a Phase 2, multicohort study to investigate the safety, PK, and 
preliminary antitumor activity of tislelizumab in combination with chemotherapy as first-line 
treatment in adults with inoperable, locally advanced or metastatic esophageal, gastric, or 
gastroesophageal junction carcinoma. The efficacy endpoints include ORR and DCR as assessed 
by the investigator per RECIST v1.1. 
There were 30 patients treated in the study and all treated patients were included in the Safety 
Analysis Set (Xu et al 2020). Of the 15 patients in the ESCC cohort, no patients (0.0%) had a 
CR. A total of 7 patients (46.7%) had a confirmed PR. Additionally, 5 patients (33.3%) had a 
BOR of stable disease. Three patients (20.0%) did not have a postbaseline tumor assessment. 
1.4.1.2.3. BGB-A317-302  
Study BGB-A317-302 is a Phase 3, randomized, open-label, multicohort study to compare the 
efficacy and safety of tislelizumab versus investigator-chosen chemotherapy (ICC) (paclitaxel, 
docetaxel, or irinotecan) in patients with unresectable recurrent locally advanced or metastatic 
ESCC after prior systemic therapy. The efficacy endpoints include OS, PFS, ORR, and DOR as 
assessed by the investigator per RECIST v1.1. 
A total of 512 patients were randomized in a 1:1 ratio to receive tislelizumab or ICC 
(256 patients each), and all of those patients were included in the Intent-to-Treat (ITT) Analysis 
Set (Shen et al 2021). As of the data cutoff date of 01 December 2020, the median duration of 
follow-up was 8.49 months in the Tislelizumab Arm and 5.80 months in the ICC Arm. 
Tislelizumab monotherapy demonstrated a statistically significant and clinically meaningful 
improvement in the primary endpoint of OS versus ICC with a stratified hazard ratio (HR) of 
0.70. The median OS was 8.6 months (95% CI: 7.5 to 10.4 months) in the Tislelizumab Arm and 
6.3 months (95% CI: 5.3 to 7.0 months) in the ICC Arm. A statistically significant and clinically 
meaningful OS benefit was also observed in patients with PD-L1 score ≥ 10% with a stratified 
HR of 0.54; the median OS improvement was 3.5 months (10.3 months in the Tislelizumab Arm 
versus 6.8 months in the ICC Arm). Treatment with tislelizumab resulted in a clinically relevant 
increase in the ORR (20.3% versus 9.8%) and more durable response (median DOR: 7.1 months 
versus 4.0 months) compared with ICC in the ITT Analysis Set. 
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For more detailed information on the efficacy of tislelizumab when given as monotherapy in 
patients with ESCC, refer to the most recent edition of the Tislelizumab Investigator’s Brochure. 
1.5. 
Study Rationales  
1.5.1. 
Rationale for Sitravatinib in Combination of Tislelizumab in the Treatment of 
Advanced Esophageal Squamous Cell Carcinoma After Checkpoint Inhibitor 
Failure  
1.5.1.1. 
Rationale for Sitravatinib Monotherapy or in Combination With Tislelizumab in 
the Treatment of Advanced Esophageal Squamous Cell Carcinoma  
The activity of tislelizumab in ESCC has been demonstrated in Studies BGB-A317-102 and 
BGB-A317-302 as monotherapy and in BGB-A317-205 in combination with chemotherapy, for 
patients treated in the second-line and first-line setting, respectively (Section 1.4.1.2). 
Although anti-PD-1 therapy have made unprecedented success in prolonging ESCC patients’ 
survival, many patients with advanced ESCC are still unresponsive or refractory to these 
therapies. Combination therapy with other novel agents represents one inevitable trend of cancer 
immunotherapy. These combination therapies are justified on the ground that the combination of 
2 different therapies integrates different immunological and biological mechanisms for 
enhancing the antitumor activity. Moreover, clinical studies suggest that targeted therapy plays a 
role in enhancing certain links in cancer-immunity cycle (eg, tumor antigenicity and 
activation/transport/infiltration of T cells), which exerts synergistic and enhancing effects on 
immunotherapy. For example, sunitinib, targeting the mitogen-activated protein kinase (MAPK) 
and vascular endothelial growth factor (VEGF), not only has a direct impact on tumor cell 
growth and tumor angiogenesis, but also on tumor antigenicity and intratumoral T-cell 
infiltration. Antitumor activity of RTK inhibitor and PD-1 antibody combination works beyond 
direct cytostatic effects on tumor cells, which provides a scientific base for evaluating the 
clinical benefits of the combination treatment. 
In addition to modifying tumor TME which enhances effect of immunotherapy, RTK inhibitor 
itself also has potential antineoplastic activity. The activity of sitravatinib monotherapy has been 
examined in Study 516-001, a Phase 1/1b study (NCT02219711) enrolling patients with different 
solid tumor types, and Study BGB-900-104, a BeiGene-sponsored Phase 1/2 study enrolling 
patients with HCC and G/GEJ cancer. 
Multiple Phase 1 or 2 clinical studies, either initiated by the sponsor or investigator, are ongoing 
to investigate the antitumor activity of RTK inhibitor monotherapy or RTK inhibitor and PD-1 
antibody combination in patients with ESCC. Available data have shown promising antitumor 
activity (Table 6), which indirectly support sitravatinib monotherapy or in combination with 
tislelizumab that may provide clinical benefit in patients with ESCC: 
• Study CAP-02 is single-arm, Phase 2 study in China to investigate the efficacy and 
safety of camrelizumab in combination with apatinib (a selective inhibitor of 
VEGFR2) as second-line treatment after prior chemotherapy failure for patients with 
advanced ESCC (Meng et al 2022). As of 20 June 2021, 52 patients with ESCC after 
failure of first-line chemotherapy were enrolled. The confirmed ORR was 34.6% 
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(18 of 52 patients) (95% CI: 22.0% to 49.1%) and the DCR was 78.8% (95% CI: 
65.3% to 88.9%). Among the 52 enrolled patients, 4 patients (8.0%) had a BOR of 
complete response (CR). The median OS and median PFS was 15.8 months (95% CI: 
8.4 to 16.2 months) and 6.8 months (95% CI: 3.8 to 10.4 months), respectively. No 
clear association between PD-L1 expression level and clinical response was observed. 
• Study ALOT-EC3 is a prospective and observational study in the real-world setting to 
explore the efficacy of various kinds of anti-PD-1 antibody in combination with 
anlotinib in second- and later-lines treatment of ESCC. Anlotinib is a RTK inhibitor 
that targets VEGFR 1, 2, and 3; FGFR 1 to 4; PDGFR ɑ and β; RET; and c-KIT. As 
of 01 September 2021, in a total of 40 patients, 27 patients who received 
camrelizumab, 10 patients who received sintilimab, and 3 patients who received other 
brands of anti-PD-1 antibody were included in the analysis. The DCR was 87.5% 
(35 of 40 patients) and 12 patients (30.8%) had a BOR of CR or PR. The data of OS 
and PFS were not mature as of 01 September 2021 due to the short follow-up period 
(Hong et al 2022). 
• Study NCT03603756 is an investigator-initiated Phase 2 study to investigate 
camrelizumab and apatinib in combination with chemotherapy (liposomal paclitaxel 
and nedaplatin) in patients with ESCC as first-line treatment. The preliminary data 
were encouraging: 80% of patients had a confirmed response and 96.7% of patients 
had their disease under control. The median OS and PFS were 19.4 months and 
6.9 months, respectively (Zhang et al 2020). 
• Study ALTER-1102 is a randomized, placebo-controlled, double-blind Phase 2 study 
in China in patients with advanced ESCC whose disease was previously treated with 
chemotherapy. A total of 165 patients were enrolled and randomized to receive 
anlotinib monotherapy or placebo (Huang et al 2021). During a median follow-up of 
11.8 months, the ORR was almost doubled numerically in the anlotinib group 
compared with the placebo group (7.3% versus 3.6%; p = 0.498). The DCR was 
significantly higher in the anlotinib group than that in the placebo group (64% versus 
18%; p < 0.001), with a higher proportion of patients achieving stable disease in the 
anlotinib group (57% versus 15%). The PFS was almost doubled in the anlotinib 
group (3.02 months versus 1.41 months, HR = 0.46 [0.32 to 0.66]; p < 0.001). 
However, prolonged OS was not observed with anlotinib monotherapy (6.11 months 
versus 7.20 months, HR = 1.18 [0.79 to 1.75]; p = 0.426). 
• Study ESO-Shanghai 11 is an investigator-initiated, single-arm, Phase 2 study in 
China to investigate the efficacy of apatinib as a second- and later-line treatment in 
patients with ESCC (Chu et al 2021). The ORR was 7.5% and the DCR was 65%. 
Median PFS was 3.8 months and OS was 5.8 months. 
Based on the positive readouts of Studies CAP-02 and NCT03603756, camrelizumab in 
combination with apatinib as well as camrelizumab and apatinib in combination with 
chemotherapy (liposomal paclitaxel and nedaplatin) have been recommended by CSCO as the 
Level III recommendation for patients with ESCC as second-line and first-line treatment options, 
respectively (CSCO 2021). In addition, anlotinib monotherapy and apatinib monotherapy have 
been recommended by CSCO as the Level II and Level III recommendation, respectively, for 
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patients with ESCC as a second-line treatment option, based on the findings from 
Studies ALTER-1102 and ESO-Shanghai 11 (CSCO 2021). 
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Table 6: 
Summary of Studies Evaluating Inhibitor of Receptor Tyrosine Kinase With or Without PD-1 for Esophageal 
Squamous Cell Carcinoma  
Study 
Study phase 
Region Treatment 
setting 
Treatment 
regimen (n) 
ORR 
(%) 
DCR 
(%) 
mOS (mo) 
HR (95% CI) 
mPFS (mo) 
HR (95% CI) 
DOR 
(mo) 
ALTER-1102 
(Huang et al 2021) 
Phase 2 
China 
2L, after 
chemotherapy 
failure 
Anlotinib (110) 
versus 
placebo (55) 
7.3%  
versus 
3.6% 
64%  
versus 
18% 
6.11  
versus  
7.20 
HR = 1.18 
(0.79 to 1.75) 
3.02 
versus  
1.41 
HR = 0.46 
(0.32 to 0.66) 
5.8 in the 
Anlotinib 
Arm 
ESO-Shanghai 11 
(Chu et al 2021) 
Phase 2, IIT 
China 
2L/2L+, after 
chemotherapy 
failure 
Apatinib (40) 
7.5% 
65.0% 
5.8 
3.8 
Not 
reported 
CAP-02  
(Meng et al 2022) 
Phase 2, IIT 
China 
2L, after 
chemotherapy 
failure 
Camrelizumab + 
apatinib (52) 
34.6% 
78.8% 
15.8  
(8.4 to 16.2) 
6.8 
Not 
reached 
(3.1 to not 
reached) 
ALOT-EC3 
(Hong et al 2022) 
Prospective, 
observational 
China 
2L/2L+, after 
chemotherapy 
failure 
Anlotinib + 
PD-1 (40) 
(Camre = 27,  
Sinti = 10,  
Other = 3) 
30.0% 
87.5% 
Not reported 
Not reported 
Not 
reported 
NCT03603756 
(Zhang et al 2020) 
Phase 2, IIT 
China 
1L 
Camrelizumab + 
liposomal 
paclitaxel + 
nedaplatin + 
apatinib (30) 
80% 
96.7% 
19.4 
6.9 
9.8 
Abbreviations: Camre, camrelizumab; DCR, disease control rate; DOR, duration of response; HR, hazard ratio; IIT, investigator-initiated trial; L, line; m, 
median; mo, month; ORR, overall response rate; OS, overall survival; PD-1, programmed cell death protein-1; PFS, progression-free survival; Sinti, sintilimab.
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1.5.1.2. 
Rationale for Sitravatinib Monotherapy or in Combination With Tislelizumab in 
the Treatment of Tumors After Checkpoint Inhibitor Failure  
Cancer cells face selective pressures while being treated, and mutations occurring in individual 
cancer cells represent continuous evolution of the original cancer. Almost all malignancies 
develop resistance to anticancer therapies eventually. This is also the case for treatment with 
checkpoint blockade agents where acquired resistance occurs in a large portion of treated 
patients who achieved an initial meaningful response. This phenomenon of acquired resistance 
helps cancer cells adapt to the environment and survive immune attacks and is a reminder of the 
therapeutic challenges that need to be overcome (Syn et al 2017). One of the mechanisms is an 
immunosuppressive TME. It includes a collection of various cell types that have switched sides 
and protect the cancer cells from immune system attacks. Various RTKs have been implicated in 
creating and maintaining an immunosuppressive TME. 
Combining an immunotherapeutic PD-1 CPI with an RTK inhibitor that has both 
immunomodulatory and antitumor properties could enhance the antitumor efficacy observed with 
either agent alone. By targeting the specific RTK receptors, an immunosuppressive TME is 
converted to an immune-supportive TME, which makes the cancers more likely to respond to 
CPI treatment. The use of RTK blocking agents to treat cancer is well established based on 
robust clinical efficacy achieved with well-tolerated inhibitors directed toward oncogenic 
tyrosine kinases. In addition, selected targeted therapies have been shown to modulate the 
immunogenic status of tumors, improve tumor perfusion by reducing intratumoral pressure, and 
modulate subsets of immune cells, thereby increasing the frequency and function of effector 
immune elements while decreasing the number and function of immune suppressor cells. 
As a potent spectrum-selective RTK inhibitor, sitravatinib inhibits several closely related RTKs, 
including members of the TAM family (TYRO3, AXL, and MER), as well as VEGFR2 and KIT. 
This inhibition weakens the cancer’s defenses in the TME. First, the antitumor activity of 
sitravatinib may promote the release of tumor antigens. Second, inhibition of the split kinase 
receptors VEGFR-2 and KIT may decrease the number of regulatory T cells (Tregs) and 
MDSCs, thus promoting the expansion and migration of antitumor cytotoxic T cells and their 
infiltration into tumor tissue. Third, sitravatinib may reverse the immunosuppressive effects 
within the TME that are mediated by the TAM receptors through inhibition of MERTK, resulting 
in an increased number of M1- versus M2-polarized macrophages and release of IL-12, IL-6, and 
tumor necrosis factor. These downstream effects enhance CD8+ T cell-activation, and through 
the inhibition of AXL, promote increased antigen presentation through termination of the 
toll-like receptor-dependent inflammatory response in dendritic cells. 
Treatment options after prior immunotherapy in patients with advanced solid tumors remain a 
significant unmet medical need. Combination therapy with agents that target the molecular and 
cellular mechanisms of resistance to CPI therapy is a rational approach to improving outcomes in 
patients. Targeting RTKs has been shown to stimulate the immune system and cause synergistic 
effects that stimulate tumor shrinkage. Although there is no direct evidence supporting the 
activity of sitravatinib in combination with tislelizumab in ESCC after prior CPI failure, several 
studies have demonstrated encouraging efficacy results of this new combination therapy in 
patients with NSCLC: 
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• Phase 1b Study BGB-900-103 demonstrated promising anticancer activity for the 
combination treatment of sitravatinib with tislelizumab in patients with NSCLC. As of 
13 October 2020, 24 patients with nonsquamous NSCLC and 23 patients with squamous 
NSCLC whose disease progressed on prior anti-PD-(L)1 therapy were enrolled. Among 
all the 47 patients, 6 patients (12.8%) had a confirmed ORR (95% CI: 5.17% to 27.35%), 
and 6 patients (13.6%) achieved a PR. The median DOR was 6.90 months (95% CI: 
3.06 months to NE). The median OS and PFS were 10.09 months (95% CI: 6.05 to 
18.14 months) and 5.19 months (95% CI: 4.07 to 5.85 months), respectively. A clear 
association between PD-L1 expression status and clinical response was not identified 
(Gao et al 2021). 
 
Phase 2 Study MRTX-500 demonstrated encouraging preliminary OS data with 
sitravatinib in combination with nivolumab in patients with NSCLC that progressed on 
or after CPI. As of June 2021, in the subset of patients with prior clinical benefit who 
received the combination in the second- or third-line treatment setting, the confirmed 
ORR was 18% which included 2 CRs (3%) and 10 PRs (15%). The median OS was 
14.9 months (95% CI: 9.3 to 21.1 months) and the median DOR was 12.8 months. The 
1- and 2-year OS rates were 56% and 32%, respectively (Leal et al 2021). 
Two global Phase 3 studies, SAPPHIRE (NCT03906071) and BGB-A317-Sitravatinib-301, 
which evaluate sitravatinib in combination with nivolumab or tislelizumab in patients with 
NSCLC whose disease progressed on or after CPI therapy, are ongoing. 
In summary, selective RTKs inhibit key molecular and cellular pathways strongly implicated in 
CPI resistance and therefore represent reasonable strategies to enhance or restore antitumor 
immunity when combined with anti-PD-(L)1 monoclonal antibodies. It has been established that 
the TME of ESCC is dominant with exhausted T and NK cells, regulatory T cells (Tregs), 
alternatively activated macrophages, tolerogenic dendritic cells, and MDSCs (Zheng et al 2020; 
Dinh et al 2021; Chen et al 2021), suggesting ESCC is a potential tumor type where combination 
therapy of immunotherapy and RTK inhibitors would have synergistic effect. Therefore, 
tislelizumab, which belongs to the same class of PD-1 blocking antibodies, may elicit 
comparable antitumor activity when combined with sitravatinib for patients with ESCC. 
1.5.2. 
Rationale for Dose Selection  
1.5.2.1. 
Rationale for Selection of Sitravatinib Dose  
Available nonclinical and safety and PK data from ongoing studies were analyzed to determine 
the recommended dose of sitravatinib. Nonclinical toxicology studies as well as clinical safety 
data from the Phase 1/1b and Phase 2 studies suggest that AEs that are associated with 
sitravatinib are similar to those observed with other small-molecule inhibitors of the VEGFR 
pathway. 
Sitravatinib administered at 150 mg once a day was originally determined to be the MTD and 
RP2D in Study 516-001. Based on the long-term tolerability observed in patients who were 
enrolled in Study 516-001 and treated with 120 mg or 150 mg once a day, as well as the 
experience of patients who were enrolled in Study MRTX-500 and treated with 120 mg once a 
day in combination with nivolumab, 120 mg once a day was selected as the RP2D using the 
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sitravatinib free base capsule formulation. The 120-mg-once-a-day dose level is predicted to be 
adequate to achieve the plasma exposure required for inhibition of VEGF and TAM receptors 
necessary to attain antitumor efficacy with the combination therapy. 
In Studies BGB-900-103 and BGB-900-104, the RP2D of sitravatinib in combination with 
tislelizumab was further evaluated in patients with advanced or metastatic malignancies, 
including squamous and nonsquamous NSCLC, platinum-resistant ovarian cancer, HCC, or 
G/GEJ cancer. As of 26 June 2021, a total of 327 patients were enrolled in the 2 studies, and the 
tolerability that was observed in these patients further supported the previously established RP2D 
of sitravatinib free base at 120 mg, either as monotherapy or in combination with tislelizumab, 
across tumor types. Based on the preliminary population PK analysis with the limited data of 
77 patients, race and tumor type were not significant covariants on the PK profile of sitravatinib. 
With the purpose of optimizing product characteristics and manufacturing efficiency, a 100 mg 
sitravatinib malate salt capsule formulation was developed and compared with 120 mg of the free 
base formulation. In Study 516-006, the inferential statistical analysis showed that the ratio and 
90% CI of the geometric least squares means of AUC0-∞, AUC0-t, and Cmax were within the 
bioequivalence range of 80% to 125%, demonstrating that the 120 mg sitravatinib free base and 
100 mg malate capsule formulations produce exposures that are equivalent. In 
Study BGB-Sitravatinib-101, the relative bioavailability between the malate formulation 
manufactured by BeiGene and the free-base formulation was assessed in healthy volunteers. The 
results showed that the exposures (geometric means of AUC0-∞, AUC0-t, and Cmax) after a single 
dose of 100-mg malate formulation were numerically lower than those observed with the 120-mg 
free-base formulation, with a difference of approximately 12%. This difference was not expected 
to be clinically meaningful as the PK exposures for the 120-mg free-base formulation were more 
varied and contained that of the 100-mg malate salt formulation. 
Based on the available data described above, 100 mg once daily of sitravatinib malate salt 
capsule formulation is considered safe and is the recommended dose in patients with ESCC. 
1.5.2.2. 
Rationale for Selection of Tislelizumab Dose  
The dosage of 200 mg intravenously once every 3 weeks was selected based on safety, efficacy, 
and PK assessments in the first-in-human Study BGB-A317_Study_001. A wide range of 
dosages were investigated in this study, including 2 mg/kg or 5 mg/kg on schedules of once 
every 2 weeks or once every 3 weeks. For the once every 3 weeks schedule, a fixed dose of 
200 mg was also investigated, and was ultimately selected for the following reasons: 
• All dosages tested, including 200 mg once every 3 weeks, were tolerated. The MTD 
was not reached with dosages up to 10 mg/kg once every 2 weeks. The observed 
serum concentration after 200 mg dosing was within the range seen after 2 mg/kg and 
5 mg/kg dosing. 
• Preliminary clinical activity was observed at this dosage. 
• Exposure-response relationships were flat for ORR and safety endpoints across a 
variety of tumor types (data from Studies BGB-A317_Study_001, BGB-A317-102, 
and BGB-A317-203). In addition, no clinically significant covariates were identified 
in population PK analysis. 
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• Compared with doses based on patient weight, a fixed dose simplifies dose 
administration and reduces the chance of medical errors. 
• Compared with a once-every-2-weeks schedule, a once-every-3-weeks schedule 
allows for more convenient integration with common chemotherapeutic regimens and 
increases patient convenience. 
In summary, the observed clinical benefits with a manageable safety profile in patients with 
advanced tumors supports tislelizumab 200 mg intravenously once every 3 weeks. The efficacy 
and safety of tislelizumab at the proposed dose have been subsequently studied in clinical 
studies, including patients with ESCC. 
1.5.3. 
Rationale for Docetaxel and Irinotecan as the Comparators  
There is no global consensus on standard of care for patients with ESCC who were previously 
treated with anti-PD-(L)1 antibody. Chemotherapy is typically administered, while the choice of 
agent differs by geography and is often tailored to the patient’s needs. Generally, a single-agent 
regimen of docetaxel, paclitaxel, or irinotecan is preferable to combination chemotherapy for 
safety considerations (NCCN 2022). 
Although these agents were widely used, there are no demonstrated clinically significant 
differences in response rates, PFS, or OS between them. In China, irinotecan is often chosen for 
second-line treatment of ESCC, while taxanes is widely used (approximately 70%) for first-line 
treatment in Chinese patients. 
This study is designed to allow the choice of chemotherapy, based on the investigators’ 
discretion, to represent the actual medical practice. Inclusion of both docetaxel and paclitaxel as 
ICC options are less clinically relevant because cross-resistance has been observed between the 
2 agents. Therefore, docetaxel and irinotecan are selected as the comparators in the study. This 
design complies with international guidelines and provides flexibility to accommodate 
differences in treatment management between hospitals and physicians and the potential 
influence of patient characteristics on the treatment choice. In addition, the choice of comparator 
in the study is not expected to influence the survival outcome in the population, which is 
supported by studies showing similar results across the 2 agents chosen for the comparator arms 
(Shirakawa et al 2014; Mizota et al 2011; Song and Zhang 2014; Albertsson et al 2007; 
Burkart et al 2007) (Table 1). 
1.5.4. 
Biomarker Strategy Rationale  
Biomarker analyses will be performed to explore the association of biomarkers with patient 
prognosis, response, and potential resistance to sitravatinib in combination with tislelizumab. 
The planned biomarker analyses include but are not limited to PD-L1 expression status, tumor 
mutational burden (TMB)/DNA mutation/microsatellite instability (MSI), blood tumor 
mutational burden (bTMB)/circulating tumor DNA (ctDNA) monitoring/DNA mutation/MSI, 
gene expression profile (GEP), and tumor-infiltrated immune cells. 
PD-L1 is expressed in tumor cells and tumor infiltrating immune cells, and its expression level 
was shown to correlate with clinical efficacy of tislelizumab treatment in 
Study RATIONALE-302, in which a larger magnitude median OS improvement was observed in 
patients with PD-L1 score ≥ 10% compared with investigator-chosen standard chemotherapy 
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(Shen et al 2021). In the present study, PD-L1 expression status will be assessed centrally by the 
Ventana PD-L1 (SP263) assay and its predictive role will be analyzed in patients treated with 
sitravatinib plus tislelizumab. 
Highly mutated tumors can produce many neoantigens and these may increase T-cell reactivity. 
For this reason, high TMB may be associated with improved response to treatment with immune 
checkpoint blockade, including anti-PD-1 agents. Study KEYNOTE-158 demonstrated that, 
irrespective of tumor type, higher ORR with pembrolizumab treatment was observed in 
TMB-high patients (≥ 10 mutations per megabase) compared with that in TMB-low patients 
(29% versus 6%) (Marabelle et al 2020). MSI-H tumors are characterized by lymphocytic 
infiltration, somatic hypermutation, and increased neoantigen formation, rendering the tumor 
susceptible to immunotherapy as well (Dudley et al 2016). Therefore, TMB level, MSI status, 
along with any specific genetic alterations, merit further exploration for the association with 
clinical outcomes to sitravatinib in combination with tislelizumab. When assessed with large 
panels, good correlations between bTMB and TMB have been observed. In several clinical 
studies, bTMB has been explored as a potential predictive biomarker because the sample 
collection procedure is less invasive. Moreover, results from Studies POPLAR, OAK, and 
MYSTIC suggested that bTMB could predict clinical benefit with anti-PD-(L)1 therapy. 
Circulating tumor DNA (ctDNA) monitoring can be derived from bTMB panel. It has been 
shown that the baseline and dynamics during treatment of ctDNA monitoring could predict 
response/resistance to immunotherapies (Study GO30140). In summary, the role of 
TMB/MSI/DNA mutation and bTMB/ctDNA monitoring/MSI/DNA mutation in predicting 
response/resistance to sitravatinib in combination with tislelizumab will be explored. 
Tumor-infiltrating lymphocyte abundance and location, along with immune-mediated gene 
expression profile, are associated with responses to immunotherapies including anti-PD-1 
antibodies in different cancers (Cristescu et al 2018; Jiang et al 2018; Vilain et al 
2017).  Therefore, the relationship between clinical response to tislelizumab and tumor-
infiltrating lymphocytes and/or GEP will be studied to explore potential predictive biomarkers.  
Consequently, PD-L1, TMB/MSI/DNA mutation, bTMB/ctDNA monitoring/MSI/DNA 
mutation, GEP, and tumor-infiltrated immune cells can be explored in tumor or blood samples to 
identify their potential predictive value, as well as resistance mechanisms in patients who receive 
tislelizumab plus sitravatinib. 
1.6. 
Benefit-Risk Assessment  
Currently, patients with locally advanced unresectable or metastatic ESCC represent a patient 
population with a high unmet medical need. No standard of care has been established as 
second- or later-line treatment for patients with ESCC whose disease progressed on or after CPI 
treatment. Single cytostatic agents have been used for decades with modest treatment effect and 
significant toxicities. 
Immunotherapy with CPIs has demonstrated responses in patients with advanced ESCC. 
Combination of CPI and a small-molecule inhibitor targeting the VEGFR pathway may improve 
the clinical efficacy of immunotherapies and overcome resistance to CPI therapy. Based on 
available data of sitravatinib and tislelizumab and available literatures of other PD-(L)1 
inhibitors and other small-molecule inhibitors targeting the VEGFR pathway, the combination of 
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sitravatinib and tislelizumab may elicit greater antitumor activity with a manageable safety 
profile. 
In all, 1546 patients have been treated with sitravatinib either as monotherapy or in combination 
with other drugs. Safety data from nonclinical toxicology studies, as well as clinical safety data 
from the Phase 1/1b and Phase 2 studies, suggest that AEs associated with sitravatinib are similar 
to those observed with other small-molecule inhibitors targeting the VEGFR pathway. For 
further discussion on safety profile of sitravatinib, refer to the most recent edition of the 
Sitravatinib Investigator’s Brochure. 
A total of 2173 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) (Tislelizumab Investigator’s Brochure). The safety profile is largely consistent 
with the known class effects of anti-PD-1 antibodies and includes mostly mild or moderate AEs. 
Grade 3 to 4 imAEs have been observed and they have been generally reversible and manageable 
with study treatment interruption and/or steroid treatment. Fatal imAEs were rare. For further 
discussion on safety profile of tislelizumab, refer to the most recent edition of the Tislelizumab 
Investigator’s Brochure. 
As shown in Appendix 1, this study includes a comprehensive plan to monitor patient safety. The 
subsequent safety data will be continuously analyzed by the sponsor’s study team and in 
consultation with the investigator(s) as needed. Refer to Section 7.4 and Section 8 for 
information regarding additional safeguards and considerations related to potential risk. 
Given the unmet medical need and limited treatment options in this indication, the benefit-risk 
assessment for this study is considered favorable. To assess the potential benefit and safety of 
sitravatinib in combination with tislelizumab over single-agent chemotherapy, a randomized 
study will be conducted. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives and Endpoints  
Table 7: 
Primary Objectives and Endpoints 
Objective 
Endpoint 
To assess the overall response rate (ORR) by the 
investigator per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version (v) 1.1 in the 
Intention-to-Treat (ITT) Population between 
Arm A (sitravatinib plus tislelizumab) and Arm C 
(investigator-chosen chemotherapy) 
ORR as assessed by the investigator, defined as 
the proportion of patients with a confirmed 
complete response (CR) or partial response (PR) 
per RECIST v1.1, in Arms A and C in the ITT 
Analysis Set 
Table 8: 
Secondary Objectives and Endpoints 
Objectives 
Endpoints 
To evaluate the duration of response (DOR) as 
assessed by the investigator per RECIST v1.1 in 
Arm A and Arm C 
DOR as assessed by the investigator, defined as 
the time from the first confirmed objective 
response until the first documentation of disease 
progression or death, whichever comes first, in 
Arms A and C in the ITT Analysis Set 
To assess the efficacy between Arm A and Arm C 
through overall survival (OS) 
OS, defined as the time from the date of 
randomization until the date of death from any 
cause, in Arms A and C in the ITT Analysis Set 
To assess the efficacy between Arm A and Arm C 
through disease control rate (DCR), clinical 
benefit rate (CBR), and progression-free survival 
(PFS) as assessed by the investigator per 
RECIST v1.1 
DCR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, or 
stable disease, in Arms A and C in the ITT 
Analysis Set 
CBR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, or 
durable stable disease (stable disease ≥ 24 weeks), 
in Arms A and C in the ITT Analysis Set 
PFS as assessed by the investigator, defined as the 
time from the date of randomization to the date of 
first documentation of disease progression or 
death, whichever occurs first, in Arms A and C in 
the ITT Analysis Set 
To assess the efficacy of Arm A and Arm B 
(sitravatinib monotherapy) through ORR, DOR, 
DCR, CBR, and PFS as assessed by the 
investigator per RECIST v1.1 
ORR as assessed by the investigator, defined as 
the proportion of patients with a confirmed CR or 
PR per RECIST v1.1, in Arms A and B in the ITT 
Analysis Set 
DOR as assessed by the investigator, defined as 
the time from the first confirmed objective 
response until the first documentation of disease 
progression or death, whichever comes first, in 
Arms A and B in the ITT Analysis Set 
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Objectives 
Endpoints 
DCR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, or 
stable disease, in Arms A and B in the ITT 
Analysis Set 
CBR as assessed by the investigator, defined as 
the proportion of patients who achieve CR, PR, or 
durable stable disease (stable disease ≥ 24 weeks), 
in Arms A and B in the ITT Analysis Set 
PFS as assessed by the investigator, defined as the 
time from the date of randomization to the date of 
first documentation of disease progression or 
death, whichever occurs first, in Arms A and B in 
the ITT Analysis Set 
To assess the safety and tolerability of sitravatinib 
as monotherapy and in combination with 
tislelizumab 
Incidence and severity of adverse events (AEs), 
with severity determined according to National 
Cancer Institute-Common Terminology Criteria 
for Adverse Events NCI-CTCAE v5.0; vital signs; 
and clinical laboratory test results in the Safety 
Analysis Set 
Table 9: 
Exploratory Objectives and Endpoints 
Objectives 
Endpoints 
To assess the OS between Arm A and Arm B 
OS, defined as the time from the date of 
randomization until the date of death from any 
cause, in Arms A and B in the ITT Analysis Set 
To perform a sample-based tumor assessment by 
independent review committee (IRC) in Arms A, 
B, and C 
ORR as assessed by the IRC, defined as the 
proportion of patients with a confirmed CR or PR 
per RECIST v1.1, in part of patients in Arms A, 
B, and C 
To explore potential biomarkers that may 
correlate with clinical responses/resistance to 
sitravatinib plus tislelizumab or sitravatinib 
monotherapy versus chemotherapy 
Potential biomarkers including but not limited to 
PD‑L1 expression, tumor mutational burden 
(TMB)/DNA mutation/microsatellite instability 
(MSI), blood tumor mutational burden 
(bTMB)/circulating tumor DNA (ctDNA) 
monitoring/DNA mutation/MSI, gene expression 
profile (GEP), and tumor-infiltrated immune cells 
as well as the associations of biomarkers with 
disease status and response/resistance to 
sitravatinib plus tislelizumab or sitravatinib 
monotherapy versus chemotherapy 
To characterize the pharmacokinetics of 
sitravatinib and its metabolite M10 
Plasma concentrations of sitravatinib and its 
metabolite M10 at specified timepoints 
To characterize the pharmacokinetics and 
immunogenicity of tislelizumab 
Serum concentrations of tislelizumab and the 
incidence of ADAs 
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Objectives 
Endpoints 
To assess health-related quality of life (HRQoL) 
HRQoL is defined as the assessment of changes in 
patient-reported outcomes (PRO) of esophageal 
squamous cell carcinoma (ESCC)-related 
symptoms and function from baseline 
2.2. 
Definition of Primary Estimand  
The primary scientific question of interest is: 
Will sitravatinib in combination with tislelizumab given as a second- or third-line treatment 
increase the ORR over chemotherapy in patients with locally advanced unresectable or 
metastatic ESCC whose disease progressed on or after platinum-based chemotherapy doublet 
and anti-PD-(L)1 antibody therapy, before the patients receive any new anticancer therapy or 
before disease progression? 
The primary estimand is described by the following attributes: 
1. Treatment of interest: 
The experimental treatment is sitravatinib 100 mg orally once daily plus tislelizumab 
200 mg intravenously once every 3 weeks. The study control treatment for comparison is 
docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle or irinotecan 
125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle. 
2. Population: 
Patients with locally advanced unresectable or metastatic ESCC whose disease 
progressed after prior platinum-based chemotherapy doublet and anti-PD-(L)1 antibody 
therapy, with the anti-PD-(L)1 antibody administered in combination with or sequentially 
following the platinum-based chemotherapy. 
3. Primary variable: 
The primary variable is ORR, as assessed by the investigator, which is defined as the 
proportion of patients with a confirmed CR or PR before disease progression per 
RECIST v1.1. 
4. Handling of remaining intercurrent events: 
• New anticancer therapy started before disease progression: patients starting any new 
anticancer therapy without achieving a confirmed CR or PR before will be considered 
as nonresponders (composite strategy). 
• Discontinuation of treatment before disease progression: response assessment after 
discontinuation of treatment will be counted and used for analysis (treatment policy 
strategy). 
5. Population-level summary: 
The ORR difference between the sitravatinib plus tislelizumab arm and the ICC arm 
measured by crude odds ratio and risk difference. 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, randomized, multicenter, Phase 2 study to investigate the efficacy and 
safety of sitravatinib in combination with tislelizumab given as a second- or third-line treatment 
in patients with locally advanced unresectable or metastatic ESCC whose disease progressed 
after prior systemic chemotherapy, which is platinum-based chemotherapy doublet and 
anti-PD-(L)1 antibody therapy, with the anti-PD-(L)1 antibody administered in combination with 
or sequentially following the platinum-based chemotherapy. 
The study will be conducted at approximately 25 centers in Mainland China. Approximately 
100 patients with locally advanced unresectable or metastatic ESCC whose disease progressed 
on or after platinum-based chemotherapy doublet and anti-PD-(L)1 antibody therapy will be 
randomized to receive either sitravatinib plus tislelizumab (Arm A), sitravatinib monotherapy 
(Arm B), or ICC (Arm C). Patients must have received ≤ 2 lines of prior systemic therapy for 
locally advanced unresectable or metastatic disease. Other prior immunotherapeutic agents 
specifically targeting T-cell costimulation or checkpoint pathways (eg, anti-TIGIT antibody) are 
allowed if it was administered in combination with an anti-PD-(L)1 antibody. The choice of 
chemotherapy must be determined before randomization at the investigator’s discretion, either 
docetaxel or irinotecan. Randomization will be stratified by PD-L1 expression status (assessed 
by the Ventana PD-L1 [SP263] assay: Tumor Area Positivity [TAP] score ≥ 10% versus TAP 
score < 10%) in a 2:1:2 ratio to receive 1 of treatment regimens: 
• Arm A: Sitravatinib 100 mg orally once daily plus tislelizumab 200 mg intravenously 
once every 3 weeks 
• Arm B: Sitravatinib 100 mg orally once daily 
• Arm C: Docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle OR 
irinotecan 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle 
Switching of chemotherapeutic agent or cross-over between treatment arms will not be allowed 
during the study. 
Efficacy and safety will be assessed between Arm A and Arm C, while efficacy between Arm A 
and Arm B will only be assessed for efficacy contribution analysis of tislelizumab in the 
combination treatment. 
Study treatment will be administered until disease progression as assessed by the investigator per 
RECIST v1.1 (see Section 7.5), unacceptable toxicity, withdrawal of consent, or another 
treatment discontinuation criterion is met, whichever occurs first (see Section 3.4). 
HRQoL will be assessed via 2 validated patient-reported outcome (PRO) instruments: the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Quality of Life 
Questionnaire-Oesophageal Cancer Module (EORTC QLQ-OES18). The study design schematic 
is presented in Figure 1. 
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Figure 1: 
Study Schema 
 
Abbreviations: CBR, clinical benefit rate; D, Day; DCR, disease control rate; DOR, duration of response; ECOG PS, 
Eastern Cooperative Oncology Group Performance Status; ESCC, esophageal squamous cell carcinoma; HRQoL, 
health-related quality of life; INV, investigator; IRC, Independent Review Committee; IV, intravenously; N, number 
of patients; ORR, overall response rate; OS, overall survival; PD-1, programmed cell death protein-1; PD-(L)1, 
programmed cell death protein (ligand)-1; PFS, progression-free survival; PK, pharmacokinetic(s); PO, orally; QD, 
once daily; R, randomization ratio; TAP, Tumor Area Positivity; VEGF(R), vascular endothelial growth factor 
(receptor). 
For all study procedures, see Section 7, Appendix 1, and Appendix 2. 
3.2. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before randomization (see Appendix 1). 
Patients who agree to participate in this study will sign the informed consent form (ICF) before 
undergoing any screening procedure. Patients who are suspected of having concurrent 
obstruction as clinically indicated will take an esophagography/endoscopy test (refer to 
Appendix 1 for details). Screening evaluations may be repeated as needed within the screening 
period; the investigator is to assess preliminary patient eligibility according to the latest 
screening assessment results. For rescreening requirements, see Section 7.1. 
3.3. 
Treatment Period  
After completing all screening activities, eligible patients will be randomized in a 2:1:2 ratio to 
receive either sitravatinib plus tislelizumab (Arm A), sitravatinib monotherapy (Arm B), or ICC 
(Arm C). Randomization will be stratified by PD-L1 expression status (assessed by the Ventana 
PD-L1 [SP263] assay: TAP score ≥ 10% versus TAP score < 10%). 
Patients will receive open-label treatment with one of the following: 
• Arm A: Sitravatinib 100 mg orally once daily plus tislelizumab 200 mg intravenously 
once every 3 weeks 
• Arm B: Sitravatinib 100 mg orally once daily 
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• Arm C: Docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle OR 
irinotecan 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle 
Switching of chemotherapeutic agent or cross-over between treatment arms will not be allowed 
during the study. 
Administration of study treatment will continue until progressive disease as assessed by the 
investigator per RECIST v1.1 (see Section 7.5), unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met (whichever occurs first; see Section 3.4). 
In select cases, patients in Arm A who are in ongoing treatment of sitravatinib plus tislelizumab 
may continue study treatment beyond the initial investigator-assessed RECIST v1.1-defined 
disease progression provided that the patient has investigator-assessed clinical benefit and is 
tolerating study treatment. 
The following criteria must be met to treat patients after initial evidence of radiological disease 
progression: 
• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values) 
• Stable Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 
≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, spinal cord compression) that requires urgent alternative medical 
intervention 
• The investigator must obtain written informed consent for treatment beyond 
radiologic disease progression and inform patients that this practice is not considered 
standard in the treatment of cancer. Patients must be informed that by continuing 
treatment beyond progression they may be forgoing other treatment that has shown 
benefit. 
• The medical monitor must agree, in writing, with the investigator’s decision to 
continue study treatment beyond initial investigator-assessed progression, and the 
decision must be documented in the study records. 
Radiological assessment of tumor-response status will be performed approximately every 
6 weeks (± 7 days) from Cycle 1 Day 1 for the first 55 weeks, then every 9 weeks (± 7 days) 
thereafter based on RECIST v1.1. Tumor response will be assessed by the investigator. See 
Section 7.5 for details. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per National Cancer Institute-Common Terminology Criteria for Adverse Events NCI-CTCAE 
v5.0 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 7.4 and the Schedule of Assessments 
(Appendix 1). 
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3.4. 
Patient Discontinuation From Study Treatment  
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients 
who discontinue study treatment for reasons other than disease progression should be followed 
for assessments of antitumor activity (Section 7.5), safety (Section 7.4) and survival 
(Section 3.7), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons that include but are not limited to the following: 
• Disease progression 
• AE 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she were to continue the study treatment 
• Use of any concurrent systemic 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) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study treatment 
compliance and drug accountability. The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
Patients who discontinue study treatment before disease progression will continue to undergo 
tumor assessments as outlined in Section 7.5. 
3.5. 
End of Treatment  
The End-of-Treatment (EOT) Visit is conducted when the investigator determines that the study 
treatment (ie, sitravatinib and tislelizumab in Arm A, sitravatinib in Arm B, or ICC in Arm C) 
will no longer be used or the patient withdraws from treatment. Patients will be asked to return to 
the clinic for an EOT Visit to occur 30 days (± 7 days) after the last dose of any component of 
the study treatment, or before the initiation of a new anticancer treatment, whichever occurs first. 
See Appendix 1 for assessments to be performed at the EOT Visit. If the decision to end the 
study treatment is made ≥ 23 days after the last dose of any component of the study treatment, 
the EOT Visit may occur later, but no later than 7 days after the decision. 
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3.6. 
Safety Follow-up for Immune-Mediated Adverse Events  
Patients who discontinue tislelizumab in Arm A will be asked to return to the clinic or will be 
contacted by telephone to assess imAEs and relevant concomitant medications (ie, those 
associated with an imAE or any new anticancer therapy). These contacts should be made at 
60 days (± 14 days) and 90 days (± 14 days) after the last dose of tislelizumab, regardless of 
whether the patient starts a new anticancer therapy. If a patient reports a suspected imAE at a 
telephone follow-up contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
3.7. 
Survival Follow-up  
Patients will be followed for survival and for information on subsequent anticancer therapy after 
discontinuation of study treatment. This follow-up will be conducted via telephone calls, patient 
medical records review, and/or clinic visits approximately every 3 months (± 14 days) after the 
EOT Visit or as directed by the sponsor until death, withdrawal of consent, loss to follow-up, or 
the end of the study (see Section 3.9). 
3.8. 
Patient Discontinuation From Study (End of Study for an Individual 
Patient)  
Patients may discontinue study for reasons that include but are not limited to the following: 
• Patient withdrawal of consent 
• Noncompliance 
• AE 
• Start of a new anticancer treatment 
• Disease progression 
• Death 
• Loss to follow-up 
3.9. 
End of Study  
The end of the 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, 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 
• A rollover study becomes available 
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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 the Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs) of the early termination of the study. 
At the end of the study, any patient who, in the opinion of the investigator, continues to benefit 
from tislelizumab and/or sitravatinib will be offered the option to continue treatment in a 
company-sponsored rollover study until the IMP(s) are commercially available in the country of 
the patient’s residence. 
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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.  
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Patient must sign a written ICF and 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 (or the legal age of consent in the 
jurisdiction in which the study is taking place) 
3. Histologically or cytologically confirmed locally advanced unresectable or metastatic 
ESCC, not amenable to treatment with curative intent 
4. Documented radiographic progression per RECIST v1.1 during or after platinum-based 
chemotherapy doublet and anti-PD-(L)1 therapy for locally advanced unresectable or 
metastatic ESCC. The anti-PD-(L)1 therapy could be administered in combination with 
or sequentially following the platinum-based chemotherapy. Patients must have received 
≤ 2 lines of prior systemic therapy for locally advanced unresectable or metastatic 
disease. 
a. Other prior immunotherapeutic agents specifically targeting T-cell costimulation or 
checkpoint pathways (eg, anti-TIGIT antibody) are allowed if it was administered in 
combination with an anti-PD-(L)1 antibody. Patients whose disease progressed on or 
after anti-PD-(L)1 antibody plus anti-CTLA4 antibody as first-line systemic therapy 
followed by a platinum-based chemotherapy doublet are also allowed. 
b. Systemic treatment that had been administered as part of adjuvant/neoadjuvant 
therapy will be considered as a prior line of systemic treatment for the advanced 
disease if it was completed ≤ 6 months (180 days) before the diagnosis of locally 
advanced unresectable or metastatic disease. 
c. For locally advanced unresectable ESCC, systemic treatment that had been 
administered as part of a curatively intended multimodal therapy will be considered 
as a prior line of systemic treatment to the advanced disease if it was completed 
≤ 6 months (180 days) before the disease progression. If chemoradiation is followed 
by planned systemic therapy without documented progression between 
chemoradiation and systemic therapy, the entire treatment course should be counted 
as 1 line of therapy. 
d. The substitution of drug(s) for the drug(s) with the same mechanism of action due to 
any reason other than disease progression is not considered a separate line of therapy. 
When a new component, which is dissimilar to any of the original components, is 
added to the regimen, the new combination is considered a new regimen and is 
considered as a separate line of therapy. 
5. At least 1 measurable lesion as defined per RECIST v1.1 as determined by local site 
investigator/radiology assessment ≤ 28 days before randomization 
Note: Lesions that had been previously irradiated were considered evaluable provided 
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that there was evidence of disease progression following the completion of radiation 
therapy. 
6. ECOG PS score ≤ 1 
7. Adequate organ function as indicated by the following laboratory values as indicated by 
the laboratory tests performed ≤ 7 days before randomization: 
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
ii. 
Platelets ≥ 100 x 109/L 
iii. 
Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 using the Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 9) 
c. Urine protein < 2+ by urine dipstick. If urine protein is ≥ 2+ by dipstick, then total 
protein from a 24-hour urine sample should be < 1 g/24 hours. 
d. Serum total bilirubin ≤ 1 x upper limit of normal (ULN) (total bilirubin must be 
< 2 x ULN for patients with Gilbert syndrome) 
e. International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN 
f. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 
g. AST and ALT ≤ 2.5 x ULN or < 5 x ULN if hepatic metastases are present. If AST 
and/or ALT > 1.5 x ULN, alkaline phosphatase (ALP) should be ≤ 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 and for ≥ 180 days after the last dose of any 
component of study treatment. They must also have a negative urine or serum pregnancy 
test result ≤ 7 days before randomization. See Appendix 10. 
9. Nonsterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 180 days after the last dose of study treatment 
• A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
• Males with known “low sperm counts” (consistent with “subfertility”) are not to be 
considered sterile for purposes of this study. 
• A nonsterile male with a partner of non-childbearing potential may not be required to 
use highly effective method of birth control. 
10. Availability of tumor tissue (archival tumor tissues as formalin-fixed paraffin-embedded 
[FFPE] blocks or approximately 15 freshly cut unstained slides) that is of good quality 
and acceptable sample type for central laboratory assessment of PD-L1 expression status 
during the screening period and for retrospective evaluation of other exploratory 
biomarker analysis. A fresh biopsy is mandatory in the absence of archival tumor tissues. 
See Section 7.7.1 for details. PD-L1 expression status must be available before 
randomization. Patients with PD-L1 expression status of unevaluable is not eligible for 
the study.  
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Note: Patients may be permitted to be enrolled on a case-by-case basis after discussion 
with the sponsor’s medical monitor if < 15 unstained slides are provided. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. Have any contraindication for receiving treatment with both docetaxel and irinotecan 
2. COVID-19 antigen or PCR positive by a certified laboratory during screening period 
3. Patients with tumor located around important vascular structures as shown by imaging or 
the investigator determines that the tumor is likely to invade important blood vessels and 
may cause fatal bleeding (ie, radiologic evidence of tumors invading or abutting major 
blood vessels) 
4. Patients with tumor that invades into organs located adjacent to the esophageal disease 
site (eg, aorta or respiratory tract) or recurrence in a previously irradiated area in the 
esophagus/thorax that has an increased risk of fistula during the study treatment period as 
assessed by the investigator 
5. History of gastrointestinal perforation and/or fistula or aorto-esophageal fistula, and/or 
patients with ≥ CTCAE 5.0 Grade 2 esophageal obstruction/stenosis. 
6. Have received prior anticancer agents that have same mechanism of action as sitravatinib 
(eg, RTK inhibitor with a similar target profile or VEGF- or VEGFR-targeted 
monoclonal antibodies) 
7. Active leptomeningeal disease or uncontrolled, untreated brain metastasis 
Note: Patients with a history of treated and, at the time of screening, stable central 
nervous system (CNS) metastases are eligible, provided they meet all the following 
criteria: 
a. Brain imaging at screening shows no evidence of interim progression, and there is no 
evidence of new brain metastases 
b. Patient clinically stable for ≥ 2 weeks 
c. Have measurable and/or evaluable disease outside the CNS 
d. No ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 
3 days before randomization; anticonvulsants at a stable dose are allowed 
e. No stereotactic radiation or whole-brain radiation ≤ 14 days before randomization 
8. Active autoimmune diseases or history of autoimmune diseases (Appendix 6) that may 
relapse 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type 1 diabetes 
b. Hypothyroidism (provided that it is managed with hormone replacement therapy 
only) 
c. Celiac disease controlled by diet alone 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
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e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
9. Any malignancy ≤ 2 years before randomization except for the specific cancer under 
investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast) 
10. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen 
11. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management, or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before randomization 
12. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence ≤ 14 days after intervention) 
13. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases including pulmonary fibrosis, or acute lung diseases. 
14. Infection (including tuberculosis infection, etc) requiring systemic (oral or intravenous) 
antibacterial, antifungal, or antiviral therapy ≤ 14 days before randomization 
Note: Antiviral therapy is permitted for patients with chronic infection with hepatitis B virus 
(HBV), or infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV). 
Patients receiving prophylactic antibiotics (eg, for prevention of urinary tract infection, 
chronic obstructive pulmonary disease, or for dental extraction) are eligible. 
15. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 2000 IU/mL at 
screening 
Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B 
(HBV DNA < 2000 IU/mL) can be enrolled. Patients with detectable HBsAg or detectable 
HBV DNA should be managed per treatment guidelines (see also Section 6.2.1.2). Patients 
receiving antivirals at screening should have been treated for > 2 weeks before 
randomization. 
16. 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. For treatment guidance, see 
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Section 6.2.1.3. Patients receiving antivirals at screening should have been treated for 
> 2 weeks before randomization. 
17. Untreated HIV infection, if known. Patients with known HIV infection are eligible if the 
following criteria are met: 
a. Stable on antiretroviral therapy for ≥ 4 weeks before randomization 
b. Patient agrees to adhere to antiretroviral therapy per World Health Organization 
(WHO) guidelines 
c. No documented multidrug resistance that would prevent effective antiretroviral 
therapy 
d. Viral load of < 400 copies per mL at screening 
e. CD4+ T-cell count ≥ 350 cells/μL at screening 
f. No history of an AIDS-defining opportunistic infection ≤ 12 months before 
randomization unless eligibility is agreed to by the medical monitor after consultation 
g. If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon 
agreement with the medical monitor 
Note: Patients with unknown HIV status is not required to complete HIV test at screening. 
18. Any major surgical procedure or any esophageal surgery including a dilation procedure 
≤ 28 days before randomization. Patients must have recovered adequately from the 
toxicity and/or complications from the intervention before randomization. 
19. Prior allogeneic stem cell transplantation or organ transplantation 
20. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living (ADL), ≤ 28 days before randomization 
b. Pulmonary embolism ≤ 28 days before randomization 
c. Deep vein thrombosis ≤ 6 months before randomization 
d. Any history of acute myocardial infarction ≤ 6 months before randomization 
e. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV (Appendix 7) ≤ 6 months before randomization 
f. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization 
g. Any history of cerebrovascular accident ≤ 6 months before randomization 
QT interval corrected by Fridericia’s method (QTcF) > 470 msec  
Note: If a patient has QTcF interval > 470 msec on an initial ECG, 3 consecutive 
ECGs will be performed several minutes apart to determine the mean QTcF interval. 
h. Uncontrolled hypertension (defined as systolic blood pressure (BP) > 150 mmHg 
and/or diastolic BP > 100 mmHg) that cannot be managed by standard 
antihypertension medications ≤ 28 days before randomization 
i. Cardiac left ventricular ejection fraction (LVEF) < 50% or lower limit of the 
institution’s normal range as assessed by echocardiography or multigated acquisition 
(MUGA). The method used at screening is required to be used throughout the study. 
j. Any episode of syncope or seizure ≤ 28 days before randomization 
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21. A history of severe hypersensitivity reactions to sitravatinib, tislelizumab, docetaxel, and 
irinotecan, to any ingredient in the formulation, or to any component of the container. 
22. Has received any of the following treatment: 
a. Any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, etc) or any 
investigational therapies ≤ 14 days or ≤ 5 half-lives (whichever is shorter) before the 
first dose of study treatment 
b. Patients with a history of esophagus/thoracic tumor radiotherapy within 6 months 
before randomization and/or with a history of radiotherapy in areas other than 
esophagus/thoracic tumor, any palliative radiation treatment, or other local regional 
therapies ≤ 14 days before the first dose of study treatment 
c. Any Chinese herbal medicine or Chinese patent medicines used to control cancer 
≤ 14 days before randomization 
23. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to 
baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy, and specific laboratory abnormalities) 
24. Was administered a live vaccine ≤ 28 days before randomization. 
Note: Vaccines for COVID-19 are allowed except for any live vaccine that may be 
developed. Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live vaccines and are not allowed. 
25. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study treatment, 
will affect the explanation of drug toxicity or AEs, or will result in insufficient or 
impaired compliance with study conduct 
26. Women who are pregnant or are breastfeeding. 
27. 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. 
28. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, bariatric 
surgery procedures, symptomatic inflammatory bowel disease, or partial or complete 
bowel obstruction. 
29. Patients who use anticoagulants such as warfarin or similar agents requiring therapeutic 
INR monitoring. 
30. Within 3 months before randomization, patients with active bleeding disorder or any 
bleeding events ≥ Grade 3, unhealed wounds, gastrointestinal ulcers, or fractures 
Note: Gastrointestinal ulcers include any esophageal ulcer, gastric ulcer, or intestinal ulcer. 
31. Unacceptable toxicity on prior anti-PD-(L)1 treatment and/or other immune-oncology 
agents, defined as follows: 
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a. ≥ Grade 3 AE related to anti-PD-(L)1 treatment and/or other immune-oncology 
agents that did not respond to standard therapy and warranted treatment 
discontinuation 
b. ≥ Grade 2 imAE associated with anti-PD-(L)1 treatment and/or other 
immune-oncology agents unless the AE resolved or was well controlled by 
withholding the anti-PD-(L)1 treatment and/or treatment with steroids, with the 
exception of prior colitis, encephalitis, myocarditis, hepatitis, pancreatitis, and 
pneumonitis, which are exclusionary 
c. CNS or ocular AE of any grade related to anti-PD-(L)1 treatment and/or other 
immune-oncology agents 
Note: Patients with a prior endocrine AE are permitted to enroll if they are stably maintained 
on appropriate replacement therapy and are asymptomatic. 
32. Patients with spinal cord compression due to metastatic disease not definitively treated 
with surgery and/or radiation or previously diagnosed and treated spinal cord 
compression without evidence that the disease has been clinically stable for > 2 weeks 
before randomization 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Sitravatinib  
Sitravatinib will be provided as 35-mg and 50-mg unit dose strength capsules. Sitravatinib drug 
product is packaged in 30-count, high-density polyethylene, opaque white, round 75-cc bottles. 
A tamper-proof heat-induction seal and a child-resistant closure are used. 
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 light conditions specified on the label and in 
the pharmacy manual. Refer to the pharmacy manual for details regarding administration, 
accountability, and disposal. Refer to the Sitravatinib Investigator’s Brochure for other details 
regarding sitravatinib. 
5.1.2. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20R glass, United States Pharmacopeia [USP] Type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab has been aseptically filled in a single-use glass vial 
with a rubber stopper and capped by an aluminum flip-off seal cap. Each vial is packaged into a 
single-carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and light conditions specified on the label and in 
the pharmacy manual. Refer to the pharmacy manual for details regarding reconstitution, 
intravenous administration, accountability, and disposal. Refer to the Tislelizumab Investigator’s 
Brochure for other details regarding tislelizumab. 
5.1.3. 
Docetaxel and Irinotecan  
Management (eg, handling, storage, administration, and disposal) of docetaxel and irinotecan 
will be in accordance with relevant local guidelines and/or prescribing information. The actual 
appearance and composition of the product may depend on the respective marketed product 
sourced for the participating countries. 
The contents of the labels will be in accordance with all applicable local regulatory requirements. 
All study drugs must be kept at the temperature condition specified on the labels. For further 
details, see the manufacturer’s prescribing information for each chemotherapy agent. 
5.2. 
Dosage, Administration, and Compliance  
Dosing schedules for arms, specified by individual arm, are provided in Table 10. The first dose 
of study treatment is to be administered ≤ 2 business days after randomization. The day of the 
first dose of study treatment will be documented as Day 1 of Cycle 1. All patients will be 
monitored continuously for AEs. Treatment modification (ie, dose delay, reduction, or 
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interruption) or discontinuation will be based on specific laboratory and AE criteria, as described 
in Section 5.5. 
Table 10: 
Selection and Timing of Dose for Each Patient 
Study drug 
Dose 
Frequency of administration 
Route of 
administration 
Duration of 
treatment 
Arm A 
Sitravatinib 
100 mg 
Once a day 
Oral 
See Section 3.3 
AND Tislelizumab a 
200 mg 
Day 1 of a 21-day cycle 
Intravenous 
See Section 3.3 
Arm B 
Sitravatinib 
100 mg 
Once a day 
Oral 
See Section 3.3 
Arm C 
 
 
 
 
Docetaxel 
75 mg/m2 
Day 1 of a 21-day cycle 
Intravenous 
See Section 3.3 
OR Irinotecan 
125 mg/ m2 Days 1 and 8 of a 21-day cycle 
Intravenous 
See Section 3.3 
a On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of sitravatinib should 
precede tislelizumab infusion. 
5.2.1. 
Sitravatinib  
Sitravatinib capsules will be administered orally, once a day continuously for a total daily dose 
of 100 mg. The following guidelines should be followed for sitravatinib administration: 
• Dosing in the morning is preferred. 
• Capsules should be taken with a low-fat meal (Appendix 14) or on an empty stomach 
(defined as ≥ 2-hour fast before each dose and no food for ≥ 1 hour after each dose).  
• Capsules should be taken with ≥ 200 mL (1 cup) of water. 
• Patients should swallow the capsules whole and not chew them. 
• If vomiting occurs after dosing, sitravatinib doses should not be replaced. 
• If a patient forgets to take sitravatinib for more than 12 hours, the patient should skip 
the dose and resume taking the drug the next day. 
On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of 
sitravatinib should precede tislelizumab infusion. 
5.2.2. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks). 
Tislelizumab will be administered by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter. Specific instructions for product preparation, storage, and administration are provided in 
the pharmacy manual. 
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The delivery period of the initial infusion (Day 1 of Cycle 1) will be ≥ 60 minutes; if this is well 
tolerated, then the delivery period of subsequent infusions may be shortened to ≥ 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). 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1, patients must be 
monitored for ≥ 60 minutes afterward in an area with resuscitation equipment and emergency 
agents. From Cycle 2 onward, a monitoring period of ≥ 30 minutes is required. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.5. 
5.2.3. 
Docetaxel  
Docetaxel will be administered on Day 1, given every 21 days after all procedures/assessments 
have been completed as detailed in Appendix 1 and Section 3.2. The initial treatment of 
docetaxel should be administered within 2 business days of randomization. Docetaxel should be 
administered at a dose of 75 mg/m2 by intravenous infusion over 60 minutes according to 
manufacturer standards. Doses lower than 75 mg/m2 are allowed if considered appropriate for 
any given patient. The first dose of docetaxel is dependent upon the patient’s baseline body 
surface area (BSA). Subsequent doses of docetaxel must be recalculated if the change of body 
weight (increase or decrease) is ≥ 10% from baseline. Docetaxel doses do not need to be 
modified for any body weight change of ˂ 10%. Calculating the chemotherapy doses by actual 
body weight is acceptable. 
Before each administration of docetaxel, liver function tests (LFTs) and blood counts should be 
reviewed. Docetaxel should not be given if bilirubin > 1 x ULN or if AST and/or 
ALT > 1.5 x ULN concomitant with ALP > 2.5 x ULN. Docetaxel should not be given if 
neutrophil counts are < 1500 cells/mm3. 
Premedication might be recommended before infusion of docetaxel according to the 
manufacturer’s instructions and local standards. To alleviate the incidence and severity of fluid 
retention as well as the severity of hypersensitivity reactions, premedication of oral 
corticosteroids, such as dexamethasone 16 mg per day (eg, 8 mg twice daily) for 3 days should 
be given starting from the day before infusion of docetaxel. The premedication regimen should 
be determined by the investigator and administered as close to treatment as possible. All 
medications will be documented on the appropriate eCRF. 
For all treatment in subsequent cycles, the treatment interval should be 21 to 24 days (3-day 
window). If dosing is delayed due to administrative or other reasons (holidays, intercurrent 
illnesses, etc), the subsequent dosing visit should be scheduled as clinically appropriate. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
for new AEs, such as worsening of pre-existing conditions, or AEs that cause any change in 
performance status or ADL. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of docetaxel therapy. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.5. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
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5.2.4. 
Irinotecan  
Irinotecan will be administered on Days 1 and 8, given every 21 days after all 
procedures/assessments have been completed as detailed in Appendix 1 and Section 3.2. The 
initial treatment of irinotecan should be administered within 2 business days of randomization. 
Irinotecan should be administered at a dose of 125 mg/m2 by intravenous infusion over 
90 minutes or according to manufacturer standards. The first dose of irinotecan is dependent 
upon the patient’s baseline BSA. Subsequent doses of irinotecan must be recalculated if the 
change of body weight (increase or decrease) is ≥ 10% from baseline. Irinotecan doses do not 
need to be modified for any body weight change of ˂ 10%. Calculating the chemotherapy doses 
by actual body weight is acceptable. Alternate doses/schedules of irinotecan according to local 
standards of care may be used as long as the 21-day cycle length (or multiples of that) are 
maintained. 
Premedication is recommended before infusion of irinotecan according to the manufacturer’s 
instructions and local standards. The premedication regimen should be determined by the 
investigator and administered as close to treatment as possible. To reduce the incidence and 
severity of fluid loss, premedication may include atropine and antiemetic agents, such as 
dexamethasone 10 mg along with another antiemetic agent (eg, ondansetron) on the day of 
irinotecan administered. All medications will be documented on the appropriate eCRF. 
For all treatment in subsequent cycles, the treatment interval should be 21 to 24 days (3-day 
window). If dosing is delayed due to administrative or other reasons (holidays, intercurrent 
illnesses, etc), the subsequent dosing visit should be scheduled as clinically appropriate. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
for new AEs, such as worsening of pre-existing conditions, or AEs that cause any change in 
performance status or ADL. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of irinotecan therapy. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.5. 
Please refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Overdose  
5.3.1. 
Sitravatinib  
Any overdose or incorrect administration of sitravatinib should be noted in the patient’s chart 
and on the appropriate eCRF. AEs associated with an overdose or incorrect administration of 
study drug will be recorded on the AE eCRF. Any SAEs associated with an overdose or incorrect 
administration are required to be reported within 24 hours of awareness via SAE reporting 
process as described in Section 8.6.2. Supportive care measures should be administered as 
appropriate. 
5.3.2. 
Tislelizumab  
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF. 
AEs associated with an overdose or incorrect administration of study drug will be recorded on 
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the AE eCRF. Any SAEs associated with an overdose or incorrect administration must be 
reported ≤ 24 hours after awareness via the SAE reporting process described in Section 8.6.2. 
Supportive care measures should be administered as appropriate. 
5.3.3. 
Docetaxel  
There is no known antidote for docetaxel injection overdosage. In case of overdose, the patient 
should be kept in a specialized unit where vital functions can be closely monitored. Anticipated 
complications of overdose include bone marrow suppression, peripheral neurotoxicity, and 
mucositis. Patients should receive therapeutic granulocyte colony-stimulating factor as soon as 
possible after discovery of overdose. Other appropriate symptomatic measures should be taken 
as clinically indicated. 
5.3.4. 
Irinotecan  
There is no known antidote for irinotecan injection overdosage. In case of overdose, the patient 
should be kept in a specialized unit where vital functions can be closely monitored. Anticipated 
complications of overdose include bone marrow suppression and diarrhoea. Appropriate 
symptomatic measures should be taken as clinically indicated. 
5.4. 
Investigational Medicinal Product Accountability  
The IMP(s) required for completion of this study (sitravatinib, tislelizumab, docetaxel, and 
irinotecan) will be provided by the sponsor, as required by local or country-specific guidance. 
The investigational site will acknowledge receipt of the IMP(s). Any damaged shipments will be 
replaced, as appropriate. 
Accurate records of all IMPs received, dispensed, returned, and disposed of should be recorded 
on the site’s Drug Inventory Log. Refer to the pharmacy manual for details of IMP management. 
5.5. 
Dose Modification  
Dose modification is defined as any of the following: dose reduction, dose delay, missed doses, 
and dose interruption. A dose delay is a deviation from the prescribed dosing schedule (ie, the 
drug is withheld beyond the visit window). A dose interruption is an interruption of an infusion 
or oral administration. 
Every effort should be made to administer the study treatment according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines below. Reasons for dose reductions or delays, the supportive measures taken, and 
the outcome will be documented in the patient's chart and recorded in the eCRF. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay or reduce doses for other reasons (eg, AEs or laboratory 
findings) as appropriate. 
5.5.1. 
Dose Modification for Sitravatinib  
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to study drugs and requires a dose to be withheld. Patients should resume study drugs as 
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soon as possible after the AEs recover to baseline or Grade 1 (whichever is more severe) and 
≤ 28 days for sitravatinib after the last dose of sitravatinib. Sitravatinib should be resumed at a 
reduced dose level (Table 11). In the setting of a Grade 3 or Grade 4 AE,  treatment with study 
drug can be resumed to patients only after investigator consultation with the sponsor. If the 
administration of sitravatinib is interrupted for reasons other than toxicity, then treatment with 
the study drug(s) may be resumed at the same dose.  
Sitravatinib can be interrupted for up to approximately 28 consecutive days. If treatment with 
sitravatinib is delayed for ≥ 14 days, then resumption at a reduced dose should be considered. If 
the drug is planned to be interrupted for > 28 days, the medical monitor should be contacted 
before the patient permanently discontinues from the study drug. 
If the patient is unable to resume sitravatinib within the permitted timeframe after the last dose of 
study drug(s), then the patient should be discontinued from the study drug(s). 
Dose reduction levels for sitravatinib are presented in Table 11. Once the dose has been reduced, 
re-escalation is not recommended. 
Table 11: 
Dose Reductions for Sitravatinib 
Study drug/Dose level 
Starting dose 
Dose level -1 
Dose level -2 
Sitravatinib 
100 mg 
70 mg 
50 mg a 
a Dose reduction below 50 mg once daily may be undertaken after discussion with the sponsor. 
Based on the known toxicity profiles of sitravatinib and tislelizumab, certain AEs are likely to be 
associated with one drug versus the other. For example, treatment-emergent hypertension or 
proteinuria are likely to be associated with sitravatinib rather than tislelizumab; similarly, imAEs 
are likely to be associated with tislelizumab rather than sitravatinib. However, some drug-related 
AEs, such as diarrhoea and elevated LFTs, are overlapping. Therefore, it is crucial to fully 
evaluate each AE to confirm the etiology or exclude other causes in order to determine the 
proper management of the adverse reaction and action regarding study treatment. The 
management guidelines for sitravatinib-specific AEs and tislelizumab-related AEs of special 
interest are provided in detail in Section 8.7 and Section 8.8, respectively. 
For patients in Arm A receiving sitravatinib plus tislelizumab, sitravatinib administration may 
continue if tislelizumab is delayed or discontinued. 
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. 
5.5.2. 
Dose Modification for Tislelizumab  
There will be no dose reduction for tislelizumab in this study. 
Tislelizumab treatment may be temporarily suspended if the patient experiences a toxicity that is 
suspected to be 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) and ≤ 12 weeks after the last dose of tislelizumab. Treatment intervals may be 
increased due to toxicity according to the dose modification guidelines. Cycle numbers will be 
counted based on the dosing of tislelizumab. For example, if the dosing of tislelizumab is 
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delayed for 14 days, the next cycle can resume after an additional 21 days (ie, Day 35). 
Sitravatinib could be given continuously, unless interruption or discontinuation criteria are met. 
If the patient is unable to resume tislelizumab ≤ 12 weeks after the last dose of tislelizumab, then 
the patient should be discontinued from treatment. If the patient is not able to resume 
tislelizumab ≤ 12 weeks after the last dose for unforeseen non-drug-related reasons, continued 
treatment may be allowed if approved by the medical monitor. 
For patients in Arm A receiving sitravatinib plus tislelizumab, sitravatinib can be continued as 
monotherapy at the discretion of the investigator if the unacceptable AE is potentially attributed 
to anti-PD-1 therapy and clearly is not attributed to sitravatinib. Tislelizumab treatment may be 
continued when sitravatinib treatment is interrupted; however, tislelizumab should not be used as 
monotherapy after permanent discontinuation of sitravatinib due to limited anticancer effect of 
rechallenging PD-(L)1 monotherapy after progression on PD-(L)1 inhibitor or 
PD-(L)1-inhibitor-based therapy. 
Specific treatment modifications to manage tislelizumab-related toxicities, such as imAEs and 
infusion-related reactions, are described in Section 8.8 and Appendix 8. 
AEs (both nonserious and serious) associated with tislelizumab exposure may represent an 
immunologic etiology. These AEs may occur shortly after the first dose or several months after 
the last dose of treatment. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Tislelizumab must be withheld for severe or life-threatening AEs. See 
Appendix 8 for supportive care guidelines, including use of corticosteroids. 
5.5.3. 
Dose Modification for Investigator-Chosen Chemotherapy  
Dose modifications for chemotherapy should be performed per applicable local prescribing 
information and per local practice according to the investigator’s clinical judgment. 
Recommended dose modifications for key chemotherapy toxicities are outlined in this section. 
These serve as guidelines and do not replace investigator judgment and applicable local label 
recommendations if more stringent. 
Baseline body weight is used to calculate the required chemotherapy doses. Dose modifications 
are required if the patient’s body weight changes by ≥ 10% from baseline (or the new reference 
body weight). Chemotherapy does not need to be modified for any body weight change of 
˂ 10%. Calculating the chemotherapy doses by actual body weight is acceptable. If reassessment 
of baseline weight is needed, the latest baseline weight is always to be used to calculate percent 
change in weight for all subsequent doses. The Mosteller formula is recommended for BSA 
calculation: 
 
Study treatment-related toxicities must be resolved to baseline level or Grade 1 (whichever is 
more severe) before administering the next dose, except for alopecia, ≤ Grade 2 fatigue, or other 
AEs which, in the opinion of the investigator, would not affect the safety evaluation of the study 
treatment. A maximum of 2 dose reductions for each chemotherapeutic agent are permitted. 
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Dose reduction levels for ICC are presented in Table 12. Guidances for dose reductions of 
docetaxel and irinotecan for specific AEs are provided in Table 13 and Table 14, respectively. 
Once the dose has been decreased, it should remain reduced for all subsequent administrations or 
further reduced if necessary. There will be no dose escalations in this study. If additional 
reductions are required, that chemotherapeutic agent must be discontinued. 
Table 12: 
Dose Reductions for Investigator-Chosen Chemotherapy 
Study drug/Dose level 
Starting dose 
Dose level -1 a 
Dose level -2 b 
Docetaxel 
75 mg/m2 
60 mg/m2 
45 mg/m2 
Irinotecan 
125 mg/m2 
100 mg/m2 
75 mg/m2 
a 20% decrease from the starting dose. 
b 25% decrease from the starting dose. 
Table 13: 
Docetaxel Dose Modifications for Specific Adverse Events 
Docetaxel dose 
Adverse event 
75 mg/m2 
Starting Dose: Administer only if neutrophil count is > 1500 cell/mm3 
60 mg/m2 
• Febrile neutropenia or neutrophils < 500 cells/mm3 for more than 1 week (after 
fully recovering to a neutrophil count ≥ 1500 cells/mm3 
• Platelet count < 100,000 cells/mm3 (after recovering to a platelet count of 
≥ 100,000 cells/mm3) 
• Severe or cumulative cutaneous reactions 
45 mg/m2 
• Second episode febrile neutropenia or neutrophils < 500 cells/mm3 for more 
than 1 week (after fully recovering to a neutrophil count  
≥ 1500 cells/mm3) 
Permanently 
discontinue 
docetaxel 
After any of the following toxicities: 
• Severe hypersensitivity reactions 
• Peripheral neuropathy > Grade 3 
• Severe or cumulative cutaneous reactions that continue at a dose of 45 mg/m2 
without recovery 
• Febrile neutropenia or neutrophils < 500 cells/mm3 without recovery 
• Platelet count < 100,000 cells/mm3 without recovery 
• Total bilirubin > 1 x ULN without recovery 
• Serum transaminase (AST, ALT) levels > 1.5 x ULN concurrent with serum 
ALP levels > 2.5 x ULN without recovery 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, 
upper limit of normal. 
Table 14: 
Irinotecan Dose Modifications for Specific Adverse Events 
Irinotecan dose 
Adverse event 
125 mg/m2 
Starting dose: Administer only if neutrophil count is > 1500 cell/mm3 
100 mg/m2  
Reduction from the starting dose for any of the following toxicities 
• Grade 3 neutropenia (neutrophils 500 cells/mm3 to 999 cells/mm3) 
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Irinotecan dose 
Adverse event 
• Grade 3 diarrhoea (7 to 9 stools/day over pretreatment status)—hold dose until 
resolved to ≤ Grade 2 then restart at 100 mg/m2 
• Other Grade 2 or 3 non-hematologic toxicities except alopecia, anorexia, 
asthenia 
75 mg/m2 
After any of the following toxicities: 
• Neutropenic fever: Omit dose until resolved, restart at 75 mg/m2 
• Grade 4 neutropenia (neutrophils < 500 cells/mm3): Hold dose until neutrophil 
count is ≤ Grade 2 then restart at 75 mg/m2 
• Grade 4 diarrhoea (≥ 10 stools/day over pretreatment status): Hold dose until 
recovery to ≤ Grade 2 then restart at 75 mg/m2 
• Other Grade 4 nonhematologic toxicities except alopecia, anorexia, and 
asthenia: Omit dose until resolved to ≤ Grade 2 then restart at 75 mg/m2  
If ICC-related toxicities warrant a dosing delay, chemotherapy administration may restart as 
soon as is feasible. For example, chemotherapy administration can occur during an unscheduled 
visit. If recovery of ICC-related toxicity is not achieved ≤ 21 days after the scheduled day of the 
course, the patient will discontinue the chemotherapy. All subsequent chemotherapy doses must 
be rescheduled according to the last chemotherapy dose administration date. 
If the patient is unable to resume chemotherapy treatment ≤ 6 weeks after the last dose of 
chemotherapy, then the patient should be discontinued from treatment. If the patient is not able 
to resume chemotherapy ≤ 6 weeks after the last dose because of unforeseen non-drug-related 
reasons, continued treatment may be allowed if approved by the medical monitor. 
Switching of chemotherapeutic agent will not be allowed during the study. 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
All prior systemic anticancer therapy, dates of administration, best response, and date of 
progression for ESCC will be collected at study entry. 
6.2. 
Concomitant Therapy  
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care for supportive care (eg, antiemetics, antidiarrheals) are allowed. 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient ≤ 30 days before 
the first dose of study treatment will be recorded. 
Opiates and other medications required for palliative management of patients are allowed. 
Patients must notify the investigator of all concurrent medications used during the study. 
6.2.1.1. 
Systemic Corticosteroids  
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 8) and be at nonimmunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration. Use of steroids to manage chemotherapy-induced 
nausea and vomiting is permitted. The short-term use of steroids as prophylactic treatment (eg, in 
patients with allergies to diagnostic imaging contrast dyes) is permitted. 
6.2.1.2. 
Hepatitis B Treatment  
Patients with active hepatitis B, defined as HBV DNA ≥ 2000 IU/mL at screening, must initiate 
treatment > 2 weeks before randomization, and continue until 6 months after the last dose of 
study drug(s). The patients would not be eligible unless HBV DNA decreases to < 2000 IU/mL. 
If the patients are treated and eligible, patients should continue effective antiviral treatment 
during the study to decrease potential viral reactivation risk. Tenofovir and entecavir are 
recommended in the American Association for the Study of Liver Disease (AASLD) guideline 
because they lack resistance with long-term use (Terrault et al 2016; AASLD/IDSA HCV 
Guidance Panel 2015). The investigator may use other antiviral agents, if appropriate, following 
local guidelines. However, interferon-based therapy for hepatitis B is not permitted on study. 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 2000 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. Once initiated, antiviral treatment should continue until 6 months after the last dose 
of study treatment or as permitted by local guidance. 
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6.2.1.3. 
Hepatitis C Treatment  
Patients with detectable HCV RNA who are receiving treatment at screening must meet the 
criterion of negative HCV RNA to be eligible. If the patients are treated and eligible, they will 
remain on continuous, effective antiviral therapy during the study. Patients given antiviral 
therapy must not enroll until > 2 weeks after the initiation of such therapy. Investigators can 
consider treatment with sofosbuvir alone or in combination with other antivirals following the 
AASLD guideline or the local guidelines as appropriate. However, interferon-based therapy for 
HCV is not permitted on study. 
6.2.1.4. 
Radiation Therapy  
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline provided that the following criteria 
are met: 
• Repeated imaging demonstrates no new sites of bone metastases 
• The lesion being considered for palliative radiation is not a target lesion for 
RECIST v1.1 
• The case is discussed with the medical monitor, and the medical monitor agrees that 
the conditions required to receive palliative radiation have been met 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if the investigator determines that it is clinically indicated. The medical 
monitor should be informed of the on-study radiotherapy. These patients should have a tumor 
assessment of the lesion(s) before receiving the radiotherapy in order to rule out progression of 
disease. 
6.2.2. 
Prohibited Concomitant Medications/Procedures  
Prohibited concomitant medications/procedures during the study, specified by treatment 
component, are provided in Table 15. Patients must notify the investigator of all herbal remedies 
used during the study. 
Table 15: 
Prohibited Concomitant Medications/Procedures by Treatment Component 
Component of 
study treatment 
Prohibited concomitant medications/procedures 
Any component of 
study treatment 
• Less than 28 days before randomization: Live vaccines 
• During screening and through the EOT Visit: Any concurrent systemic 
anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard anticancer agents, or investigational anticancer 
agents 
• During screening and through the EOT Visit: Herbal remedies for the 
treatment of cancer or Chinese patent medicines with approval from the 
China NMPA for use as anticancer treatment (regardless of cancer type) 
Sitravatinib 
• During sitravatinib treatment: Anticoagulants, such as warfarin or similar 
agents, requiring therapeutic INR monitoring 
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Tislelizumab 
• During tislelizumab treatment and ≤ 60 days after the last dose of 
tislelizumab: Live vaccines 
• During tislelizumab treatment: Herbal remedies with immune-stimulating 
properties (eg, mistletoe extract) or that are known to potentially interfere 
with liver or other major organ functions (eg, hypericin) 
Abbreviations: EOT, end of treatment; INR, international normalized ratio; NMPA, National Medical Products 
Administration 
6.2.3. 
Restricted Concomitant Medications/Procedures  
Restricted concomitant medications/procedures during the study, specified by treatment 
component, are provided in Table 16. 
Table 16: 
Restricted Concomitant Medications/Procedures by Treatment Component 
Component of 
study treatment 
Restricted concomitant medications/procedures 
Any component of 
study 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 
• Radiation therapy is not allowed, except for palliative radiation therapy 
described in Section 6.2.1.4 
Sitravatinib 
• During sitravatinib treatment: Medications have potential interactions with 
sitravatinib (See Section 6.3 and Appendix 11) 
Tislelizumab 
• During tislelizumab treatment: Immunosuppressive agents (except to treat a 
drug-related AE) 
• During tislelizumab treatment: 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 
Docetaxel/irinotecan 
• During chemotherapy: Medications have potential interactions with 
docetaxel or irinotecan (See Section 6.3 and Appendix 11) 
Abbreviation: AE, adverse event. 
6.3. 
Potential Interactions Between the Study Treatment and 
Concomitant Medications  
Potential Interaction of Sitravatinib With Cytochrome P450 Enzyme Inhibitors/Substrates 
Sitravatinib is not considered a high-risk compound as a victim of drug-drug interaction because 
multiple enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, 
CYP2E1, and CYP3A4, are involved in its metabolism. 
In vitro, sitravatinib showed direct inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4/5 (Section 1.3.1). Concomitant medications that are sensitive substrates or substrates 
with a narrow therapeutic index for these CYP enzymes (examples listed in Appendix 11) should 
be used with caution during sitravatinib treatment. 
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Sitravatinib With Medications That Prolong QT/QTc 
Per the International Council for Harmonisation (ICH) E14 guidance, it is recommended to use 
with caution for medications with a potential to prolong QT/QTc or cause torsades de pointes 
(examples listed in Appendix 11). 
Potential Interaction of Sitravatinib With Transporter Modulators/Substrates 
Sitravatinib was identified to be a substrate of P-gp and an inhibitor of both P-gp and BCRP 
(Section 1.3.1). Inhibitors of P-gp (eg, clarithromycin, itraconazole, propafenone, quinidine, 
ranolazine, ritonavir, and verapamil) may increase sitravatinib exposure while inducers of P-gp 
(eg, rifampin) may decrease sitravatinib exposure. Caution should therefore be taken when 
administering sitravatinib to patients taking medications that inhibit or induce P-gp. Concomitant 
medications that are sensitive substrates or substrates with narrow therapeutic indices for P-gp 
and/or BCRP transporters (examples listed in Appendix 11) should be used with caution during 
sitravatinib treatment. 
Potential Interaction of Sitravatinib With Tislelizumab 
Sitravatinib administered in combination with tislelizumab is unlikely to result in clinically 
relevant drug-drug interactions based on absorption, metabolism, elimination, or protein binding. 
Tislelizumab is a monoclonal antibody and is administered intravenously, whereas sitravatinib is 
a small-molecule therapy administered orally. Like most therapeutic proteins, tislelizumab is not 
expected to be metabolized by CYP or other drug-metabolizing enzymes and is unlikely to affect 
CYPs or other metabolizing enzymes in terms of inhibition or induction. 
Potential Interaction of Docetaxel With Cytochrome P450 3A4 Inhibitors/Inducers/ 
Substrates 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel 
may be modified by the concomitant administration of compounds that induce, inhibit, or are 
metabolized by CYP3A4. 
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was 
coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, 
particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel and 
drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided unless 
there are no therapeutic alternatives. Do not administer strong CYP3A4 inducers (phenytoin, 
phenobarbital, carbamazepine, or St. John’s wort) in patients treated by docetaxel unless there 
are no therapeutic alternatives. In patients receiving treatment with docetaxel, close monitoring 
for toxicity and a docetaxel dose reduction could be considered if systemic administration of a 
potent CYP3A4 inhibitor cannot be avoided (examples listed in Appendix 11). 
Potential Interaction of Irinotecan With Cytochrome P450 3A4 Inhibitors/Inducers/ 
Substrates 
Irinotecan and its bioactive metabolite SN-38 are metabolized by CYP3A4 and UGT1A1. The 
metabolism of irinotecan could be modified by the concomitant administration of compounds 
that induce, inhibit, or are metabolized by CYP3A4 and/or UGT1A1. 
Do not administer strong CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine, or St. 
John’s wort) with irinotecan unless there are no therapeutic alternatives. Do not administer 
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strong CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telaprevir, or voriconazole) and UGT1A1 inhibitors (eg, 
atazanavir, gemfibrozil, or indinavir) or both CYP3A4 and UGT1A1 inhibitors (such as 
ketoconazole) in patients treated by irinotecan unless there are no therapeutic alternatives. 
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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. 
Screening  
Screening evaluations will be performed ≤ 28 days before randomization. Patients who agree to 
participate will sign the ICF before undergoing any screening procedure. The screening period 
begins on the date the ICF is signed. Screening evaluations may be repeated as needed within the 
screening period; the investigator will assess patient eligibility according to the latest screening 
assessment results. 
Results of standard-of-care tests or examinations performed before obtaining informed consent 
and ≤ 28 days before randomization may be used for the purposes of screening rather than 
repeating the standard-of-care tests unless otherwise indicated. 
For descriptions of other assessments conducted during screening, see Section 7.4 for safety 
assessments, Section 7.5 for tumor and response evaluations, and Section 7.7 for biomarker 
evaluations. The PK sampling schedule is shown in Appendix 2. 
Rescreening under limited conditions may be allowed after consultation with the sponsor. For 
example, rescreening may be considered when a patient narrowly misses a laboratory criterion 
that is correctable and not due to rapidly deteriorating condition or disease progression. 
Rescreening is allowed only once. Rescreened patients must provide new informed consent, as 
described in Section 7.1.1; a new patient number will be assigned as described in Section 7.1.2. 
Any new result will override the previous one (ie, the most recent result before randomization) 
and is the value by which study inclusion will be assessed, as it represents the patient’s most 
current clinical state. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before any 
study-specific procedures are performed. ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization or first dose of study treatment. The investigator will 
maintain a screening log to record details of all patients screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
7.1.2. 
Patient Numbering  
After obtaining informed consent, study site personnel will access the interactive response 
technology (IRT) system to assign a unique patient number to a potential study participant. 
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Patients who are rescreened (see Section 7.1) will be assigned a new patient number. Screening 
numbers that are assigned to the same patient within the IRT system will be linked. 
7.1.3. 
Demographic Data and Medical History  
Demographic data will include the age or year of birth, sex, self-reported race/ethnicity, etc. 
Medical history includes any history of clinically significant disease, surgery, or cancer-related 
symptoms or signs; reproductive status (ie, of childbearing potential or no childbearing 
potential); history of alcohol consumption and tobacco (ie, former, current, or never); and all 
medications (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient ≤ 30 days before the first dose of study treatment. 
If appropriate, clinically significant disease should be graded according to NCI-CTCAE v5.0 and 
recorded in the medical history page of eCRF. 
Cancer history will include pathologic diagnosis, stage at screening, tumor location, location of 
metastatic disease at study baseline, an assessment of prior surgery, prior radiotherapy, prior 
drug therapy, including start and stop dates, best response, and reason for discontinuation. 
Radiographic studies performed before study entry may be collected for review by the 
investigator. 
7.1.4. 
Women of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 10 for contraception guidelines and definitions of “women of childbearing 
potential” and “no childbearing potential”. 
7.2. 
Enrollment  
7.2.1. 
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 ICH Good Clinical Practice (GCP) Guidelines (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. 
7.2.2. 
Enrollment/Randomization  
Site personnel will access the IRT system to randomly assign the patient to a treatment arm and 
to assign study treatment. Study treatment must commence ≤ 2 business days after 
randomization/treatment assignment. 
Patient randomization will be stratified by PD-L1 expression status (assessed by the Ventana 
PD-L1 [SP263] assay: TAP score ≥ 10% versus TAP score < 10%). The choice of chemotherapy 
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regimen must be decided before randomization, and interchanging chemotherapy regimen is not 
permitted during the study period. 
Once enrolled in the IRT, patients that have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for patient randomization: 
• Patient number 
• Year of birth 
• PD-L1 expression status (assessed by the Ventana PD-L1 [SP263] assay: TAP score 
≥ 10% versus TAP score < 10%) 
7.3. 
Dispensation of Study Treatment  
Sitravatinib, tislelizumab, and chemotherapy agents will be dispensed and administered as 
described in Section 5.2. 
7.4. 
Safety Assessments  
7.4.1. 
Vital Signs  
See Appendix 1 for vital signs collected and the timing of their collection. 
7.4.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of 1) head, eyes, ears, nose, and throat, 2) cardiovascular, 3) dermatological, 
4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs on the eCRF. Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements (Appendix 1). 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS (Appendix 4) will be assessed during the study. 
7.4.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of serum chemistry, hematology, coagulation, 
urinalysis, and thyroid function will be conducted as described in Appendix 1. Specific 
assessments to be performed are listed in Appendix 3. 
If laboratory tests at screening are not performed ≤ 7 days before the first dose of study 
treatment, these tests should be repeated and reviewed before administration of study treatment. 
After Cycle 1, results are to be reviewed within 48 hours before study treatment administration. 
Laboratory tests of hematology and serum chemistry as specified in Appendix 3 should be 
performed weekly for the first 3 cycles, at the beginning of each subsequent cycle, and at the 
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EOT Visit. Laboratory tests of coagulation parameters and urinalysis as specified in Appendix 3 
should be performed at the beginning of each cycle and at the EOT Visit. Laboratory tests of 
thyroid function will be performed every 3 cycles and at the EOT Visit. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring, 
and dosing decision. 
7.4.4.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune CPIs, serum creatine 
kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all tislelizumab studies to 
protect study participants and to quantify the risk of muscle inflammation (see Appendix 1 for 
the blood collection schedule and Appendix 8 for guidelines for management of suspected 
immune-mediated myocarditis). Serum troponins may be substituted per local guidelines if used 
consistently throughout the study. 
7.4.5. 
Electrocardiograms  
A 12-lead/15-lead/18-lead ECG is required during screening, at the beginning of each cycle, at 
the EOT Visit, and as clinically indicated at other time points (Appendix 1). 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. 
When coinciding with blood sample collection at the same timepoint, ECG assessment should be 
performed either before blood sample collection or ≥ 30 minutes after the blood sample 
collection. Patients should rest for ≥ 10 minutes before ECG collection. If a patient has QTcF 
interval > 450 msec for males or > 470 msec for females on an initial ECG, 3 consecutive ECGs 
will be performed several minutes apart to determine the mean QTcF interval. 
7.4.6. 
Echocardiogram  
Cardiac function will be evaluated at screening and every 12 weeks thereafter (Appendix 1). 
Evaluations by echocardiogram is preferred but evaluations by MUGA scan are acceptable, if 
necessary. The method used to assess cardiac function at screening is required to be used 
throughout the study. 
7.4.7. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.8. 
Hepatitis B and C Testing  
Viral hepatitis B and C serologic markers and viral load (if applicable) will be tested by a central 
laboratory and/or the local laboratory. HBV testing will include hepatitis B surface antibody 
(HBsAb), HBsAg, and hepatitis B core antibody (HBcAb). In addition, HBV DNA will be 
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quantified in patients positive for HBsAg. For patients who have positive test results of HCV 
antibody, a test to quantify HCV RNA will be required. 
Additional viral load assessment after screening is described in Appendix 1. 
7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed ≤ 28 days before randomization. Results of standard-of-care 
tests or examinations performed before obtaining informed consent and ≤ 28 days before 
randomization may be used for the purposes of screening rather than repeating the 
standard-of-care tests (only applicable if the same radiographic procedure will be used 
throughout the study). During the study treatment period, evaluation of tumor response by the 
investigator per RECIST v1.1 will be performed every 6 weeks (± 7 days) from Day 1 of Cycle 1 
for the first 55 weeks and then every 9 weeks (± 7 days) thereafter (Appendix 1). If a tumor 
assessment is missed or conducted outside of the specified assessment window, all subsequent 
scans should be conducted on the planned schedule. 
Screening assessments and each subsequent assessment of the tumor must include computed 
tomography (CT) scans (with oral and/or intravenous contrast, unless contraindicated) or 
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. Other known or suspected 
sites of disease must be included in the imaging assessments. 
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). 
• MRI scan of brain at baseline is required for patients who are suspected to have CNS 
metastases. Screening evaluations will be performed ≤ 28 days before randomization. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards of a 
diagnostic CT scan. 
• Bone scans (technetium-99m) or PET should be performed at screening if clinically 
indicated. If bone metastases are present at screening and cannot be seen on CT or 
MRI scans, technetium-99m or PET bone scans should be repeated when a CR is 
suspected in the target lesion or when progression in bone is suspected. 
− If bone metastases are visualized on the bone scan or PET scan at screening, a 
confirmatory CT/MRI scan should be performed. If the metastases are confirmed 
by CT/MRI, then evaluation by CT/MRI should be given preference for 
subsequent assessments. If the metastases are not confirmed by CT/MRI, then the 
use of bone scan or CT/MRI for subsequent assessments is at the investigator’s 
discretion. 
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− If an increase in the uptake of existing lesions is seen on a bone scan, or the 
appearance of new osteoblastic bone lesions is seen on an x-ray, CT, or MRI, this 
should not automatically be considered evidence of progression in an otherwise 
stable or responding subject. It may in fact be indicative of response to therapy. 
− New areas of uptake seen on a bone scan should not automatically result in 
diagnosis of progressive disease but should be correlated with other available 
imaging (eg, CT, MRI, or x-ray). 
• CT scans of the neck or extremities should be performed at screening only if 
clinically indicated and should be repeated throughout the study if there is evidence 
of metastatic disease in these regions at screening. 
• At the investigator’s discretion, other methods of assessing target lesions and 
nontarget lesions per RECIST v1.1 may be used. However, CT or MRI should be 
given preference for assessment of target lesions. 
Tumor response will be assessed by the investigator using RECIST v1.1 (see Appendix 5). The 
same evaluator should perform assessments, if possible, to ensure internal consistency across 
visits. At the sponsor’s discretion, response assessment imaging may be collected during the 
study for the purpose of independent central review. 
After initial documentation of response (CR or PR), confirmation of tumor response should 
occur ≥ 4 weeks after the first response or at the next scheduled assessment timepoint. 
Once progressive disease has been assessed by the investigator, an additional confirmatory 
assessment is recommended if there is any reason to doubt the first assessment (eg, scan quality, 
suspected pseudoprogression). This confirmatory assessment should occur approximately 4 to 
8 weeks after the first investigator assessment of progressive disease. Study treatment of 
sitravatinib plus tislelizumab is permitted to continue after the initial investigator assessment of 
progressive disease, provided that the criteria for treatment beyond disease progression in 
Section 3.3 are met. 
At the investigator’s discretion, patients may continue their assigned treatment in Arm A after 
progressive disease has been confirmed by the investigator per RECIST v1.1. To continue 
treatment, the criteria for treatment beyond disease progression in Section 3.3 must be met. 
Tumor assessment should continue as planned in patients receiving study treatment beyond 
initial investigator-assessed progression. Tumor assessment in such patients should continue 
until study treatment discontinuation. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original plan until the patient 
begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is 
lost to follow-up, dies, or until the study terminates, whichever occurs first. 
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. That is, assessments should not be adjusted for delays 
in cycles. 
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7.6. 
Pharmacokinetic and Antidrug Antibody Testing  
The PK concentrations will be determined using plasma (sitravatinib and its metabolite M10) or 
serum (tislelizumab) samples collected at specified time points within a reasonable variation 
window (see Appendix 1 and Appendix 2). Sitravatinib PK samples will be sparsely collected 
from patients who receive sitravatinib (Arms A and B) and used for determining the 
concentrations of both sitravatinib and M10. PK and ADA samples for tislelizumab will be 
sparsely collected from patients who receive tislelizumab (Arm A). An additional sitravatinib PK 
blood sample may be drawn before a daily sitravatinib dose at a clinic visit ≥ 1 week after a dose 
modification of sitravatinib, or as soon as possible after a SAE. If deemed necessary, samples 
may be used for characterization of other sitravatinib metabolites. The actual time of each 
sample collection will be recorded on the source document and eCRF. 
Tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response to tislelizumab will be closely monitored. Validated screening and confirmatory assays 
will be employed to detect ADAs at multiple timepoints throughout the study (see Appendix 1 
and Appendix 2). The immunogenicity evaluation will utilize a risk-based immunogenicity 
strategy (Koren et al 2008; Rosenberg and Worobec 2004a; Rosenberg and Worobec 2004b) to 
characterize ADA responses to tislelizumab in support of the clinical development program. 
The following assessments will be performed at a bioanalysis laboratory: 
• ADA assay: ADA serum samples will be tested for the presence of ADAs to 
tislelizumab using a validated immunoassay 
• Tislelizumab PK assay: serum samples for tislelizumab will be assayed for 
concentrations with use of a validated immunoassay 
• Sitravatinib PK assay: plasma samples for sitravatinib will be assayed for 
concentrations of sitravatinib with use of a validated LC-MS/MS method 
• M10 PK assay: plasma samples for sitravatinib will be assayed for M10 
concentrations using a validated method 
Shipping, storage, and handling of samples for the assessment of sitravatinib PK, M10 PK, 
tislelizumab PK, and tislelizumab ADA assays will be managed through a central laboratory. 
Refer to the laboratory manual for instructions. 
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. 
7.7.1. 
Tissue Biomarkers  
See Appendix 1 for the tissue biomarker sample collection schedule. 
Separate written patient consent is required for optional tumor tissue collection. 
Archival tumor tissues (FFPE blocks or approximately 15 freshly cut unstained slides) need to be 
sent for central laboratory assessment of PD-L1 expression status during the screening period 
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and for retrospective analysis of other exploratory biomarkers related to response and resistance 
for all patients in a sponsor-designated central/test laboratory. Patients may be permitted to be 
enrolled on a case-by-case basis after discussion with the sponsor’s medical monitor if 
< 15 unstained slides are provided. These exploratory biomarkers also include, but not be limited 
to, TMB/DNA mutation/MSI, GEP, and tumor-infiltrated immune cells. 
A fresh biopsy is mandatory in the absence of archival tumor tissues. Acceptable fresh biopsy 
samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Tumor tissue should be of 
good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell 
pellets from pleural effusion, lavage samples, and bone/bone marrow aspirates are not 
acceptable. 
In addition to baseline tumor tissues, fresh biopsies from an accessible tumor site(s) at the time 
of confirmed progressive disease are recommended to explore response or resistance 
mechanisms. If feasible, any follow-up biopsy should ideally be taken from the same tumor 
lesion as the baseline biopsy. 
7.7.2. 
Blood Biomarkers  
See Appendix 1 for the blood biomarker sample collection schedule. 
Separate written patient consent is required for optional blood sample collections. 
Approximately 10 ml of peripheral blood samples will be collected at baseline (pre-dose, on 
Day 1 of Cycle 1, required). For patients who have confirmed CR/PR and progressive disease as 
assessed by the investigator, additional blood samples (approximately 10 ml, optional) will be 
collected at each timepoint. 
Blood-based biomarkers will consist of bTMB/ctDNA monitoring/MSI/DNA mutation profile. 
Analyses may examine the association between these biomarkers and clinically relevant 
outcomes including response, resistance, and prognosis. 
7.8. 
Patient-Reported Outcomes  
HRQoL measured via PRO endpoints of global health status (GHS), physical function, and 
fatigue; and dysphagia, reflux, eating, and pain measured via PRO instruments of the 
EORTC-QLQ-C30 (Appendix 12) and EORTC-QLQ-OES18 (Appendix 13), respectively. 
Patients will be asked to complete the questionnaires during on-study clinic visits according to 
the schedule before any clinical activities (including blood draws or imaging scans) are 
performed or any health-related discussion. The study clinic visit schedules are in Appendix 1. 
The questionnaires will be provided in the patient’s preferred language. 
7.9. 
Visit Windows  
All visits must occur within ± 3 days of the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1 of each cycle) should be performed before study treatment administration 
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unless otherwise noted. Laboratory results should also be reviewed before study treatment 
administration. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
event, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1). 
A cycle is defined as every 21 days. For patients in Arms A and C, subsequent visits should be 
conducted according to a new 21-day schedule based on the date of the patient’s last infusion of 
tislelizumab or ICC, respectively. For patients in Arm B and patients in Arm A who continue 
sitravatinib monotherapy, subsequent visits should be conducted according to the fixed 21-day 
schedule from Day 1 of Cycle 1 (Arm B) or the start of sitravatinib monotherapy (Arm A), no 
matter if sitravatinib is interrupted or not. 
7.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; ECOG PS; AE review; review of 
concomitant medications and procedures; radiographic assessments; physical examination of 
liver, spleen, and lymph nodes; review 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 suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment, and the results of 
diagnostic tests and images 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 Treatment  
8.1.1. 
Risks Associated With Sitravatinib  
The most notable AEs for sitravatinib included diarrhoea, fatigue, palmar-plantar 
erythrodysesthesia syndrome, and hypertension. The majority of AEs were mild to moderate in 
severity and manageable. The guidelines for management of potential AEs specific to treatment 
with sitravatinib or agents in the same class of cancer treatment are presented in Section 8.7. 
8.1.2. 
Risks Associated With Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.8.2. 
An imAE may occur at any time during or after treatment. Often, the etiology of imAEs is not 
clear, and other causes should be ruled out. This may require diagnostic testing and consultation 
with a specialist. Suggested evaluation and management guidelines for suspected imAEs are 
provided in Appendix 8. 
 
8.1.3. 
Risks Associated With Investigator-Chosen Chemotherapy  
Most common adverse reactions across all docetaxel indications are infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhoea, 
vomiting, mucositis, alopecia, skin reactions, and myalgia. Most frequent Grade 3 or 4 AEs are 
neutropenia, anemia, leukopenia, infection, and thrombocytopenia. Treatment-related mortality 
will increase if patients have abnormal liver function. Severe hypersensitivity, including very 
rare fatal anaphylaxis, has also been reported in patients despite receiving dexamethasone 
premedication. 
Common adverse reactions of irinotecan observed in single-agent therapy clinical studies are 
nausea, vomiting, abdominal pain, diarrhoea, constipation, anorexia, neutropenia, leukopenia 
(including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. 
Most frequent Grade 3 or 4 AEs are diarrhoea, nausea, vomiting, leukopenia, neutropenia, 
abdominal pain, and asthenia. Early and late forms of diarrhoea can occur. Early diarrhoea may 
be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. 
Late diarrhoea can be life-threatening and should be treated promptly with loperamide. Monitor 
patients with diarrhoea and give fluid and electrolytes as needed. If patients develop ileus, fever, 
or severe neutropenia, they should receive antibiotic therapy, per institution-specific guidelines. 
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If severe diarrhoea and myelosuppression occur, irinotecan should be interrupted and either 
discontinued or dose reduced for subsequent cycles to subsequent doses. 
Patients should be tested locally for the UGT1A1*28 allele as outlined in the prescribing 
information or according to local guidelines to determine if modifications to the starting dose are 
needed. 
Refer to the most recent, locally approved prescribing information for information on the risks 
associated with docetaxel and irinotecan. 
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-(L)1 inhibitors, were considered. Specifically, patients at 
risk for developing study-emergent active autoimmune diseases or who have a history of 
autoimmune diseases that may relapse, patients who have undergone allogeneic stem cell or 
organ transplantation, and patients who have received a live vaccine ≤ 28 days before 
randomization are excluded from the study. Patients with contraindications for sitravatinib, 
tislelizumab, or ICC are also excluded from the study (see Section 4.2 for the full list of 
exclusion criteria). Patients must be eligible for ≥ 1 of the 2 chosen chemotherapy agents in the 
study. 
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 (except as noted in Section 8.6.4). All enrolled patients will be 
evaluated clinically and with standard laboratory tests at intervals described in Appendix 1. 
Safety evaluations will consist of medical interviews, physical examinations, laboratory 
measurements (hematology, chemistry, etc), imaging, consultations (as needed), and other 
assessments including those listed in Appendix 1. In addition, patients will be closely monitored 
for the development of any signs or symptoms of infections or autoimmune conditions. 
At the start of each cycle, study treatment will only be administered after clinical laboratory 
results have been reviewed. Administration of study treatment at study sites will be performed in 
a setting where emergency medical equipment and staff who are trained to respond to medical 
emergencies are available (see Section 5.2). 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomly 
assigned to Arm A. 
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 for sitravatinib-specific AEs and Section 8.8 
for tislelizumab-related AEs of special interest. 
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8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study treatment or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, or duration, and/or an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study treatment administration, even 
though the condition may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concurrent medication (overdose per se should not be reported as an 
AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers must be blinded or 
redacted 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 v5.0 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 ADL 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
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regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study treatment and the 
occurrence of each AE or SAE, using best clinical judgment. Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the AE or SAE to the administration of study treatment should be considered and 
investigated. The investigator should consult the Tislelizumab Investigator’s Brochure, 
Sitravatinib Investigator’s Brochure, and prescribing information for individual chemotherapy 
drugs in making his/her assessment. 
There may be situations when an SAE has occurred and the investigator has only limited 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before transmitting the SAE report to the 
sponsor, because the causality assessment is one of the criteria used in determining regulatory 
reporting requirements. After considering follow-up information, the investigator may 
subsequently change his/her opinion of causality and may amend the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on all information available at the time of reporting. An AE is considered 
related if there is “a reasonable possibility” that the AE may have been caused by the study 
treatment (ie, there are facts, evidence, or arguments to suggest possible causation). A number of 
factors should be considered in making this assessment, including the following: 
• Temporal relationship of the AE to the administration of study treatment or study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study treatment 
• Biological plausibility 
• An AE should be considered “related” to study treatment if any of the following 
criteria are met. Otherwise, the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study treatment). However, 
the influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
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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 the sponsor with further information 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 consultations with other health care professionals. 
The sponsor may request that the investigator performs or arranges 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 timeframes outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that 
• are associated with clinical signs or symptoms, or 
• 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, ALP and 
bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, cholestasis) should be 
recorded on the AE page of eCRF. Clinically associated events can be reported as a single event 
(eg, simultaneous occurrence of anemia, thrombocytopenia, and leukopenia may be reported as 
myelosuppression). 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 (or mmol/L) should be recorded as “hyperkalemia.” 
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Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the AE eCRF unless the etiology or grade changes. The initial 
grade of the event should be recorded, and the grade and seriousness should be updated any time 
the event changes. 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose, meet any of the following criteria: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency department 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, diarrhoea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator or by the sponsor based on 
medical judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are not considered to be SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
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8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Recording Period  
After informed consent has been signed but before the administration of the study treatment, 
only SAEs should be reported. 
After initiation of study treatment, all AEs and SAEs, regardless of relationship to study 
treatment, will be reported until either 30 days after the last dose of study treatment or initiation 
of new anticancer therapy, whichever occurs first. Immune-mediated AEs (serious or nonserious) 
should be recorded until 90 days after the last dose of tislelizumab, regardless of initiation of 
new anticancer therapy. SAEs considered related to the study treatment 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 17. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2. 
Table 17: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms 
Event type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEs (not treatment related) 
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 
Treatment-related SAEs 
Signing of informed 
consent 
Patient death, withdrawal of consent, or 
loss to follow-up, whichever occurs first 
Nonserious AEs due to PD 
Do not record (see Section 8.6.4) 
Nonserious AEs other than 
those due to PD 
First dose of study 
treatment 
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 
treatment 
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; PD, progressive disease; SAE, serious adverse event. 
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 (≤ 24 hours after determination) to the sponsor or designee as 
described in Table 18. 
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Table 18: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for sending 
initial/follow-up report a    
Documentation method 
Reporting method 
All SAEs 
≤ 24 hours after first 
knowledge of the SAE 
SAE report 
Electronic submission of 
SAE form to portal b            
Abbreviation: SAE, serious adverse event. 
a Report follow-up information that is clinically relevant and pertains to the SAE, which includes but is not limited 
to the following: Update to the SAE, new additional SAE, outcome, seriousness criteria, investigator causality, 
event start date/date of onset, date of death, relationship to each study drug. Follow-up information will also be 
reported as per the discretion of the investigator if the new or updated information changes the medical 
assessment of the case. 
b SAE reports should be submitted to the sponsor safety database electronically from within the electronic data 
capture system. If the electronic submission is not available for any reason, a paper SAE form should be 
submitted by email or fax. 
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 or 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 or she must not wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5) will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
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8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask 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 is 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. When a patient dies, if the only 
information available is death and the cause of death is unknown, then the death is reported as an 
AE, eg, “death NOS.” In all other cases, death is captured as an outcome. 
8.6.6. 
Pregnancies  
If a female patient or the female partner of a male patient becomes pregnant while the patient is 
receiving investigational therapy or ≤ 180 days after the last dose of study treatment, a pregnancy 
report form must be submitted to the sponsor. The pregnancy report must follow the same 
prompt reporting guidelines described in Section 8.6.2.1. The outcome of the pregnancy, 
including any premature termination of the pregnancy must also be reported to the sponsor. 
While pregnancy itself is not considered 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 always be reported as an SAE. Similarly, 
any congenital anomaly or birth defect in a child born to a patient exposed to the study treatment 
should be recorded and reported as an SAE. 
Patients who become pregnant must immediately discontinue treatment (see Section 3.4). For 
patients who are no longer pregnant, resumption of treatment may be discussed with the medical 
monitor. 
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 treatment 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 RSI documents: 
• Sitravatinib Investigator’s Brochure 
• Tislelizumab Investigator’s Brochure 
• Local prescribing information for docetaxel 
• Local prescribing information for irinotecan 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Treatment with anti-PD-1 therapy can cause autoimmune disorders. All AEs considered by the 
investigator to be immune mediated (see Section 8.8.2) should be classified as imAEs and 
identified as such on the AE page of eCRF. 
8.6.9. 
Recording Infusion-Related Reactions  
The signs and symptoms of an infusion-related reaction should be recorded as the adverse terms 
for those individual signs and symptoms. Each individual sign and symptom of an infusion 
reaction should be recorded as a separate AE in the eCRF and identified as an infusion-related 
reaction as the event term, and graded as such with the respective sign or symptom. In assessing 
whether an AE is infusion related, note that 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. 
8.7. 
Sitravatinib-Specific Adverse Events  
8.7.1. 
Non-Hematological Toxicities of Sitravatinib  
Patients experiencing symptomatic Grade 2 non-hematological sitravatinib-related AEs are 
recommended to have a dose reduction to the next lower dose level at the discretion of the 
investigator and patient, per the reduction schedule (Table 19). Dose reductions are expected to 
improve treatment tolerability. 
Non-hematological toxicities ≥ Grade 3 and considered to be related to sitravatinib treatment 
should be managed with sitravatinib interruption, until resolution of toxicity to ≤ Grade 1 or to 
baseline value. In the case of Grade 3 or 4 electrolyte abnormalities that are not clinically 
complicated and resolve spontaneously or with conventional medical treatment within 72 hours, 
or Grade 3 asymptomatic amylase or lipase elevations in the absence of other clinical evidence of 
pancreatitis, treatment may be resumed at the same dose at the investigator’s discretion; if not, 
treatment may be resumed at a reduced dose as outlined in Table 19. Sitravatinib should be 
interrupted for any grade pancreatitis, and the patient should be managed according to the 
standard of care. After resolution of pancreatitis, sitravatinib resumption is at the discretion of the 
investigator; if pancreatitis is assessed as related to sitravatinib treatment and treatment is 
resumed, a dose reduction is recommended. Recurrence of the toxicity may be managed 
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similarly. If treatment is interrupted for ≥ 28 days, permanent discontinuation from study 
treatment should be considered. 
Table 19: 
Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities 
Toxicity a 
Treatment delay 
Dose modification 
Grade 1 
May be implemented based on investigator’s and patient’s discretion 
Grade 2 - Asymptomatic 
May be implemented based on investigator’s and patient’s discretion 
Grade 2 - Symptomatic 
May be implemented based on 
investigator’s and patient’s 
discretion 
Recommend dose reduction to 
next lower dose level 
Grade 3 or 4 b 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at ≥ 1 dose levels below 
that inducing the toxicity. 
Exceptions presented in 
footnote b. 
a Management of specific adverse events (eg, hypertension) for sitravatinib are presented in sections below. 
b Patients may resume at the same dose in the following cases: 
• Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with 
conventional medical treatment within 72 hours. 
• Grade 3 amylase or lipase elevation that is not associated with the symptoms or the clinical manifestations of 
pancreatitis. 
8.7.2. 
Hematological Toxicities of Sitravatinib  
Hematological toxicities are not a frequent cause of treatment interruption or discontinuation of 
sitravatinib treatment. Observed ≥ Grade 3 hematological events that are considered to be 
causally related to sitravatinib should initially be managed using treatment interruption. In 
addition, dose reduction of sitravatinib at the discretion of the investigator should be 
implemented in the following cases: 
• Grade 3 or 4 febrile neutropenia 
• Grade 4 neutropenia persisting for ≥ 8 days 
• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding 
8.7.3. 
Dose Modification Guidelines for Sitravatinib-Specific Adverse Events  
Dose modification guidelines for increased BP are presented in Table 20. 
For cases where transaminase increases are not likely to be immune-mediated, treatment 
management decisions should be made per the investigator discretion in consideration of clinical 
factors. Recommended treatment modifications for sitravatinib are provided in Table 21. 
Guidance for the management of Hy’s Law cases is presented in Section 8.7.3.1. 
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Table 20: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity 
Drug interruption 
Dose modification 
Grade 1 or 2 hypertension  
May be implemented based on investigator and patient 
discretion 
Grade 3 hypertension without clinically 
significant increases in BP as defined below  
Investigator discretion 
Consider antihypertensives per Section 8.7.4 
Grade 3 hypertension with clinically 
significant increases in BP defined as either 
an increase of ≥ 30 mmHg in systolic BP to 
≥ 180 mmHg or increase of ≥ 20 mmHg in 
diastolic BP to ≥ 110 mmHg, confirmed 
with repeated testing after at least 5 minutes  
Hold until ≤ Grade 2 or 
return to baseline  
Investigator discretion  
Grade 4 hypertension  
Discontinue sitravatinib  
Discontinue sitravatinib  
Abbreviations: BP, blood pressure; Hg, mercury. 
Table 21: 
Sitravatinib Dose Modification for Increased Hepatic Transaminases 
Toxicity  
Drug interruption 
Dose modification  
Grade 1  
May be implemented based on investigator and patient discretion  
Grade 2  
May be implemented based 
on investigator and patient 
discretion 
Decrease by 1 dose level 
Grade 3 or 4  
Hold until ≤ Grade 1 or return 
to baseline 
If resolution occurs within 
22 days, decrease by 1 dose 
level. 
If no resolution within 22 days, 
discontinue sitravatinib. 
Table 22: 
Sitravatinib Dose Modification for Palmar-Plantar Erythrodysesthesia 
Syndrome  
Toxicitya           
Treatment Delay 
Dose Modification 
Grade 1 
Not required 
Not required 
Grade 2 
Based on investigator discretion 
Dose reduction to the next lower level 
Grade 3 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at dose one or more levels 
below that inducing the toxicity 
a For any event of Palmar-Plantar Erythrodysesthesia syndrome, regardless of severity, patients are to be counseled 
on measures to mitigate the effects of PPE, including avoidance of exposure of hands and feet to hot water, other 
sources of heat, activities that cause unnecessary force or friction (rubbing), chemicals (eg, cleaning products) and 
wearing well-ventilated shoes or clothing. Treatment may include topical moisturizing agents, topical anesthetics, 
or topical anti-inflammatory medications such as corticosteroid creams. 
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8.7.3.1. 
Management of Hy’s Law Cases  
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 x ULN, and  
bilirubin ≥ 2 x ULN but without concurrent increases in ALP (ie, ALP < 2 x ULN), that is not 
attributable to liver metastases or biliary obstruction, sitravatinib and tislelizumab should be 
permanently discontinued and steroids should be administered. 
8.7.4. 
Hypertension  
Hypertension, including Grade 4 events, has been reported with sitravatinib. Dihydropyridine 
calcium channel blockers such as nifedipine, amlodipine, and nicardipine may be considered if 
antihypertensive therapy is required and should be considered for patients with Grade 3 
hypertension without clinically significant increases in BP (see Table 20). In cases of Grade 3 
hypertension with clinically significant increases in BP, temporary suspension of sitravatinib 
dosing is recommended until BP is controlled. Treatment with sitravatinib may resume at the 
same or a lower dose at the discretion of the investigator. If significant hypertension recurs, 
options include change in medical management of the patient, reduction of sitravatinib dose, or 
discontinuation of study treatment, at the discretion of the investigator. In the event of Grade 4 
hypertension, sitravatinib should be permanently discontinued (see Table 20). 
8.7.5. 
Palmar-Plantar Erythrodysesthesia Syndrome  
Palmar-plantar erythrodysesthesia syndrome has been reported as a DLT in the Phase 1 study of 
sitravatinib. Measures that can be taken to manage include avoidance of exposure of hands and 
feet to hot water when washing dishes or bathing or to other sources of heat; avoidance of 
activities that cause unnecessary force or friction (rubbing) on the hands or feet; avoiding contact 
with harsh chemicals such as cleaning products; avoiding use of tools or household items that 
result in pressure on the hands, such as garden tools, knives, and screwdrivers, and wearing of 
loose fitting, well-ventilated shoes and clothes. Treatment may include use of topical 
moisturizing agents, topical anesthetics, or topical anti-inflammatory medications such as 
corticosteroid creams. In more severe cases, dose interruption and reduction may be warranted 
(see Table 22). 
8.7.6. 
Diarrhoea  
Diarrhoea has been reported with sitravatinib treatment, though the mechanism remains unclear, 
as with other small-molecule RTK inhibitors. Patients should be counseled that diarrhoea is a 
possible side effect and advised to take loperamide or a similar medication as needed if diarrhoea 
develops. Any patients developing dehydration or clinically significant electrolyte abnormalities 
should interrupt treatment, but treatment may be restarted once diarrhoea is controlled. 
Investigators should also evaluate whether diarrhoea may be attributable to the imAE of colitis. 
The presence of abdominal pain, mucus or blood in the stool, or peritoneal signs should raise the 
index of suspicion for immune-mediated colitis, as these features are generally not observed with 
sitravatinib-associated diarrhoea. The diarrhoea observed with sitravatinib generally improves 
within several days of interrupting study medication, and close observation may help establish 
the most likely causality. 
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8.7.7. 
Hemorrhagic Events  
The risk of hemorrhagic events with sitravatinib is unknown; however, such events have been 
reported with inhibitors of VEGFR. Patients with active hemoptysis or gastrointestinal bleeding 
should not take sitravatinib, and interruption of treatment is recommended for patients 
developing clinically significant bleeding. 
8.7.8. 
Thrombotic Events  
Arterial and venous thrombotic events have been observed with sitravatinib and other inhibitors 
of the VEGFR pathway. The majority of thrombotic events observed with sitravatinib have been 
venous thrombotic events. The occurrence of thrombotic events with sitravatinib is being 
monitored for further characterization. Precautions should be taken in patients with recent, 
clinically significant thrombotic events, and treatment should be permanently discontinued in 
patients who develop clinically significant thromboembolic complications such as acute 
myocardial infarction or severe pulmonary embolism. 
8.7.9. 
Thyroid Dysfunction Other Than Immune-Mediated  
Hypothyroidism and increases in thyroid-stimulating hormones have been reported in patients 
taking sitravatinib. Thyroid stimulating hormone level should be monitored during treatment 
with sitravatinib. Patients diagnosed with hypothyroidism should be treated with thyroid 
replacement therapy and may continue treatment with sitravatinib at the investigator’s discretion. 
8.7.10. 
Decreased Left Ventricular Ejection Fraction  
Decreased LVEF has been reported with sitravatinib. In addition, decreases of LVEF to < 50% 
on-study were observed in patients undergoing scheduled MUGA scans or echocardiograms. The 
dose of sitravatinib should be interrupted and/or reduced in patients with an ejection fraction 
< 50% and > 20% below baseline. Discontinuation should be considered for patients requiring 
acute hospitalization for treatment of congestive heart failure. 
8.7.11. 
Proteinuria  
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
inhibitors of the VEGFR pathway. Patients who develop ≥ 2+ proteinuria should undergo 
24-hour urine collection for assessment of urine protein; treatment with sitravatinib should be 
discontinued in the presence of ≥ 2 grams of proteinuria/24 hours and may restart when protein 
levels decrease to less than 2 grams/24 hours. Patients who develop nephrotic syndrome should 
be withdrawn from treatment with sitravatinib. 
8.7.12. 
Gastrointestinal Perforation/Fistula  
Gastrointestinal perforation has been reported with inhibitors of VEGFR as an infrequent event 
(Kim et al 2020). The risk of gastrointestinal perforation with sitravatinib has not been fully 
characterized. However, such events have been reported with sitravatinib, and a potential exists 
for such events to be observed with increased frequency in patients with ESCC. 
Sitravatinib and tislelizumab should be interrupted if gastrointestinal perforation is suspected and 
discontinued when it is confirmed. 
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For more details on the detection and management of gastrointestinal perforation/fistula, please 
refer to Appendix 15. 
8.8. 
Tislelizumab-Related Adverse Events of Special Interest  
Infusion-related reactions, severe hypersensitivity reactions, and imAEs according to the 
NCI-CTCAE v5.0 criteria are outlined below. 
8.8.1. 
Infusion-Related Reactions and Hypersensitivity Reactions  
Patients should be closely monitored during and after study treatment administration for 
infusion-related reactions and hypersensitivity reactions. See Section 5.2.2 for the monitoring 
periods required. Immediate access to an Intensive Care Unit (ICU) or equivalent environment 
and appropriate medical therapy (including epinephrine, corticosteroids, antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 
See Appendix 8 for management of infusion-related reactions and hypersensitivity reactions as 
well as treatment modifications. 
8.8.2. 
Immune-Mediated Adverse Events  
In this study, imAEs are of special interest. Potential imAEs are listed in Table 23 below. All 
AEs similar to those listed in the table should be evaluated in patients receiving tislelizumab to 
determine whether the AE is immune mediated. The investigator should exclude alternative 
explanations (eg, combination drugs, infectious disease, metabolic causes, toxins, disease 
progression, or other neoplastic causes) with appropriate diagnostic tests that may include but are 
not limited to serologic, immunologic, and histologic (biopsy) data (see Appendix 8). If 
alternative causes have been ruled out and the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy, and it is consistent with an immune-mediated 
mechanism of action, the imAE indicator in the eCRF AE page should be checked. 
Recommendations for managing imAEs are detailed in Appendix 8. 
Table 23: 
Examples of Immune-Mediated Adverse Events 
Body system affected 
Events 
Skin (mild) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; sweet 
syndrome 
Skin (severe) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhoea with abdominal pain or 
endoscopic/radiographic evidence of inflammation); pancreatitis; 
hepatitis; 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 
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Body system affected 
Events 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Musculoskeletal 
arthritis; arthralgia; myalgia; myasthenic syndrome/myasthenia 
gravis; myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Neurologic 
encephalitis; Guillain-Barre syndrome; meningitis; 
meningoradiculitis; meningoencephalitis; neuropathy 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released. Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan (SAP). 
9.1. 
Statistical Analysis  
9.1.1. 
Randomization Methods  
As discussed in Section 7.2.2, patients will be randomly assigned to treatment arms using the 
IRT system for this study by permuted block stratified randomization. 
9.1.2. 
Analysis Sets  
The ITT Analysis Set includes all patients randomly assigned to a treatment arm. Patients’ data 
will be analyzed according to their randomized treatment arm. This will be the primary analysis 
population for all efficacy analysis. 
The Safety Analysis Set includes all patients who receive at least 1 dose of any component of 
study treatment; it will be the population for the safety analyses. 
The Sitravatinib PK Analysis Set includes all patients who receive ≥ 1 dose of sitravatinib per 
the protocol and for whom any quantifiable postbaseline PK data for sitravatinib are available. 
The M10 PK Analysis Set includes all patients who receive ≥ 1 dose of sitravatinib per the 
protocol and for whom any quantifiable postbaseline PK data for M10 are available. 
The Tislelizumab PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab per 
the protocol and for whom any quantifiable postbaseline PK data for tislelizumab are available. 
The ADA Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab and for whom 
both baseline and ≥ 1 postbaseline ADA result are available. 
9.1.3. 
Patient Disposition  
The number of patients randomized, treated, discontinued from study treatment and/or study, and 
those with important protocol deviations will be counted. The primary reason for study treatment 
and/or study discontinuation will be summarized according to the categories in the eCRF. The 
end-of-study status (alive, dead, withdrew consent, or lost to follow-up) at the clinical cutoff date 
will be summarized using the data from the eCRF. 
Important protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics of the ITT Analysis Set will be summarized 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis, and time since locally advanced unresectable or metastatic disease 
diagnosis, etc. Categorical variables include sex, ECOG PS, race, TNM Classification of 
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Malignant Tumor staging, alcohol consumption, tobacco use, primary tumor location (ie, 
cervical, upper, middle, and lower), previous treatment, and metastatic site, etc. 
9.1.5. 
Prior and Concomitant Medications  
Concomitant medications will be coded using the WHO Drug Dictionary drug codes. 
Concomitant medications will be further coded to the appropriate Anatomical Therapeutic 
Chemical (ATC) code indicating therapeutic classification. Prior and concomitant medications 
will be summarized and listed by drug and drug class in the clinical study report for this protocol. 
Prior medications will be defined as medications that stopped before the day of first dose of 
study treatment. Concomitant medications will be defined as medications that 1) started before 
the first dose of study treatment and were continuing at the time of the first dose of study 
treatment, or 2) started on or after the date of the first dose of study treatment up to 30 days after 
the patient’s last dose (as of the EOT Visit). In addition, telephone contact with patients in 
Arm A should be conducted to assess imAEs and concomitant medications (ie, those associated 
with an imAE or any new anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of 
tislelizumab regardless of whether the patient starts a new anticancer therapy. 
9.2. 
Efficacy Analyses  
9.2.1. 
Primary Efficacy Analysis  
9.2.1.1. 
Primary Estimand  
The primary estimand is defined in Section 2.2. 
9.2.1.2. 
Primary Analysis for Primary Estimand  
The primary analysis of ORR as assessed by the investigator is descriptive and exploratory; no 
formal testing is designed. 
The crude odds ratio and risk difference of ORR, along with their exact 95% CIs (Thomas 1971; 
Chan and Zhang 1999) will be calculated between Arms A and C. The ORR rate and its 
Clopper-Pearson 95% CI will be calculated for each arm. 
The primary analysis for ORR as assessed by the investigator will be conducted ≥ 4 months 
(approximately 3 tumor assessments) after the enrollment of the last patient. 
9.2.1.3. 
Handling of Missing Values Not Related to Intercurrent Event  
Patients without any postbaseline response assessment (for any reason) will be considered 
nonresponders. 
9.2.1.4. 
Sensitivity and Supplementary Analyses for Primary Endpoint/Estimand  
Sensitivity analyses and supplementary analyses may be considered and will be detailed in the 
SAP. 
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9.2.2. 
Secondary Efficacy Analysis  
DOR as assessed by the investigator is defined as the time from the first confirmed objective 
response until the first documented disease progression or death date, whichever occurred first. 
Only patients who have achieved objective responses will be included in the analysis of DOR. 
Kaplan-Meier methodology will be used to estimate median or other quartiles of DOR along 
with its 95% CI by using Brookmeyer and Crowley method for Arms A and C. Event-free rate at 
selected timepoints will be estimated with 95% CI estimated using Greenwood formula. No 
assessment of DOR between Arm A and C will be performed as it would be based on 
non-randomized subgroups. 
OS is defined as the time from randomization date to death from any cause. For patients who are 
not reported as having died at the time of analysis, OS will be censored at the date the patients 
were last known to be alive. Kaplan-Meier methodology will be used to estimate median or other 
quartiles of OS along with its 95% CI by using Brookmeyer and Crowley method for Arms A 
and C. Kaplan-Meier curves will be constructed to provide a visual description of the OS 
distribution. Event-free rate at selected timepoints (eg, 6 months and 12 months) will be 
estimated with 95% CI estimated using Greenwood formula. The HR of OS between Arms A 
and C will be estimated using a stratified Cox regression model with PD-L1 expression status 
(assessed by the Ventana PD-L1 [SP263] assay: TAP score ≥ 10% versus TAP score < 10%) as 
strata. The 95% CI for the HR will be provided. Unstratified analysis will also be presented. 
PFS assessed by the investigator is defined as the time from the randomization date to disease 
progression or death, whichever occurs first. The PFS censoring rule will follow US FDA 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(US FDA 2018). Similar methodology used to evaluate OS between Arms A and C will be 
applied to the analysis of PFS for the assessment between Arms A and C. 
DCR as assessed by the investigator is defined as proportion of patients with PR or CR or a 
stable disease per RECIST v1.1. Similar methodology used to evaluate ORR between Arms A 
and C in the primary analysis will be applied to the analysis of DCR for the assessment between 
Arms A and C. 
CBR as assessed by the investigator is defined as proportion of number of patients with PR or 
CR or a durable stable disease per RECIST v1.1. Similar methodology used to evaluate ORR 
between Arms A and C in the primary analysis will be applied to the analysis of CBR for the 
assessment between Arms A and C. 
ORR, DCR, and CBR as assessed by the investigator with its Clopper-Pearson 95% CI will be 
calculated for Arms A and B. Kaplan-Meier methodology will be used to estimate median or 
other quartiles of DOR and PFS along with its 95% CI by using Brookmeyer and Crowley 
method for Arms A and B. Event-free rate at selected timepoints will be estimated with 95% CI 
estimated using Greenwood formula.  
9.2.3. 
Exploratory Efficacy Analysis  
OS between Arms A and B will be analyzed using the same methodology as OS between 
Arms A and C in the secondary efficacy analysis. 
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ORR assessed by the Independent Review Committee (IRC) and its Clopper Pearson 95% CI 
will be calculated for each arm.  
9.3. 
Safety Analyses  
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (milligrams), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events  
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study treatment and up to 30 days after study treatment 
discontinuation or initiation of new anticancer therapy, whichever occurs first. Only those AEs 
that were treatment-emergent will be included in the 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 
after the last dose of tislelizumab, regardless of whether the patient starts a new anticancer 
therapy. If an imAE occurs outside of the above mentioned 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 
System Organ Class (SOC) and Preferred Term. A patient will be counted only once by the 
highest severity grade per NCI-CTCAE v5.0 within an SOC and Preferred Term, even if the 
patient experienced more than 1 TEAE within a specific SOC and Preferred Term. The number 
(percentage) of patients with TEAEs will also be summarized by relationship to the study 
treatment. Treatment-related TEAEs include those events considered by the investigator to be 
related to a study drug or with missing assessment of the causal relationship. SAEs, deaths, 
TEAEs ≥ Grade 3, infusion-related reactions, imAEs, treatment-related TEAEs, and TEAEs that 
led to treatment discontinuation, dose interruption, dose reduction, or dose delay will be 
summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated for 
each laboratory parameter as appropriate. Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be provided. Descriptive summary statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
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variables) for laboratory parameters and their changes from baseline will be calculated. 
Laboratory values will be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, sodium) will 
be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (body temperature, pulse rate, systolic and 
diastolic BP) and changes from baseline will be presented by visit for all visits. Vital signs will 
be listed by patient and visit. 
9.3.5. 
Pulmonary Function Test  
Pulmonary function test results will be listed by patient if available. 
9.4. 
Pharmacokinetic Analysis  
The sitravatinib, M10, and tislelizumab concentration data will be tabulated and summarized by 
visit/cycle at which these concentrations are collected. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate. 
Additional PK assessments, including population PK analyses, may be conducted as appropriate, 
and the results of such analyses may be reported separately from the clinical study report. 
9.5. 
Immunogenicity Analyses  
The anti-tislelizumab antibody results will be summarized using descriptive statistics by the 
number and percentage of patients who develop detectable ADAs. The incidence of positive 
ADAs and neutralizing ADAs will be reported for evaluable patients. The effect of 
immunogenicity on PK, efficacy, and safety may be evaluated if data allow and reported 
separately from the clinical study report. 
9.6. 
Other Exploratory Analyses  
Exploratory biomarkers may also be assessed. Analyses may examine the association between 
relevant biomarkers and clinically relevant outcomes including patient prognosis, response, and 
resistance. 
HRQoL will be assessed via changes in PRO key endpoints’ scores from baseline. 
9.7. 
Sample Size Consideration  
This exploratory study is not powered for the hypothesis testing between treatment arms but 
rather to obtain preliminary efficacy and safety data for sitravatinib in combination with 
tislelizumab and sitravatinib monotherapy for patients with locally advanced unresectable or 
metastatic ESCC that progressed on or after anti-PD-(L)1 antibody therapy. This study will 
enroll approximately 100 patients into 3 arms, with approximately 40, 20, and 40 patients in 
Arms A, B, and C, respectively. The efficacy of tislelizumab in combination with sitravatinib 
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versus chemotherapy will be demonstrated by descriptive analysis of ORR, PFS, OS, DCR, 
CBR, and DOR as assessed by the investigator in the assessment between Arms A and C. The 
contribution of adding tislelizumab to sitravatinib monotherapy will be demonstrated by 
similarly descriptive analysis in the assessment of Arms A and B. With a sample size of 
40 patients in Arm A (sitravatinib plus tislelizumab), the binomial probabilities of detecting 
≥ 1 TEAE with a frequency of 5% and 1% are approximately 0.87 and 0.33, respectively. 
9.8. 
Interim Analyses  
No formal interim analyses will be conducted; administrative interim analysis is allowed. 
Summaries of efficacy and safety data may be generated to inform subsequent clinical 
development planning or to address emergent safety concerns.  
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Independent Review Committee  
An IRC will be established to perform an independent review of all scheduled radiological 
images and relevant unscheduled images to determine response and disease progression based on 
RECIST v1.1. During the study, sites will submit specific radiographic image files to the 
centralized data review facility on an ongoing basis or at the sponsor’s request. A sample-based 
tumor assessment by the IRC will be used for exploratory analyses in this study.  
All decisions made during the performance of the study will be based on the local investigator’s 
assessment of radiographic images, clinical status, and relevant examination of the patients. 
Detailed rules and guidelines for radiographic imaging and tumor assessments by the IRC are 
outlined separately in the Imaging Manual and IRC Charter. 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study can be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with ICH GCP Guidelines (ICH E6), the study monitor must have direct access to 
the investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of 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 the representatives of a regulatory agency or 
representatives of the sponsor with access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements. Alternatively, the 
sponsor will file the protocol to the appropriate regulatory agency before the study is initiated at 
a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledging receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product. Dispensation records will document quantities received from 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 sponsor’s requirements specified in 
the pharmacy manual. At appropriate times during the conduct of the study or at the end of the 
study after final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet 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 reviewed periodically and verified by the 
study monitor over the course of the study. A patient diary will be provided to each patient in 
Arms A and B to record the sitravatinib dose taken each day. Any missed doses with 
explanations should be recorded in the diary. The diary should be returned to the site personnel 
for review and will be reviewed by the investigator or study personnel on a regular basis. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the guidelines for GCP (ICH E6) and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the patient. The study will also comply with the Definitions and 
Standards for Expedited Reporting (ICH E2A). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, 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 or other information and the 
approved amended ICF or 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 the IRB/IEC. Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements. 
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The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must reconsent to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality  
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 GCP Guideline (ICH E6), 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 principal investigator and site must ensure that any personal and medical 
information transmitted to the sponsor or its service providers is: 1) required by the protocol, and 
2) appropriately de-identified (eg, 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 or medical information to the sponsor or its 
representatives. Such personal or medical information may not be provided as part of the 
protocol (eg, as part of the eCRF, on samples or reports submitted to the central laboratory, 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 the sponsor for sharing and transfers of personal and medical information. 
In the event of a breach of the confidentiality of a patient’s personal or medical information, the 
investigator, site personnel, 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 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.  
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
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ethnicity data are collected in accordance with ICH guidance (ICH E5 1998, ICH E17 2017) 
adopted by the EMA and FDA, to understand whether race/ethnicity could influence the PK, 
safety, and/or efficacy of the study drug. For example, population PK analysis is a well-
established, quantitative method that can quantify and explain the variability in drug 
concentrations among patients. Such variability can be attributed to intrinsic factors (eg, body 
weight, age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant medications), and 
can lead to clinically relevant changes in drug concentrations that require a change in the dose or 
dosing regimen. Results from race/ethnicity and other demographic analyses will be incorporated 
into drug product labeling to provide guidance on safety and efficacy variations (if any) linked to 
certain populations (eg, race or ethnic group) as well any potential dose adjustment needed for 
those populations. Therefore, collecting race/ethnicity data in the study is essential to understand 
whether race/ethnicity could influence the PK, safety, and/or efficacy.  
13.5. 
Financial Disclosure  
Investigators (including any subinvestigators and coinvestigators) are required to provide the 
sponsor with sufficient accurate financial information in accordance with regulations to allow the 
sponsor to submit complete disclosure or certification to the absence of certain financial interest 
of the clinical investigators, and/or disclose those financial interests, as required, to the 
appropriate health authorities. This is intended to ensure financial interests and arrangements of 
the clinical investigators with 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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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
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. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an EDC system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of 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. 
14.1.3. 
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 that includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA by the lowest-level term, Preferred Term, and primary SOC. Concomitant medications 
will be coded using the WHO Drug Dictionary. Concomitant diseases/medical history will be 
coded using MedDRA. 
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14.2. 
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 
system. Although the study is open-label, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into ≥ 1 of the following categories: 1) investigator’s study file, and/or 2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, 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 documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, etc. 
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, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to ≥ 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers away from the site so that they can be returned sealed to the 
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investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage away from the site. 
Subject to patient consent, or as otherwise allowed under applicable law, biological samples at 
the conclusion of this study may be retained for ≤ 10 years or as allowed by your IRB/IEC, 
whichever is shorter. 
14.4. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert 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. Any 
major deviations that might impact patient safety and/or data integrity must be promptly reported 
by the investigator to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
14.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies). The sponsor 
will ensure that the report meets the standards set out in the Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including but not limited to those for PK, ADA, and 
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 reason. 
Potential reasons for suspension or discontinuation include, but are not limited to, safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations. If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IRB/IEC promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study. 
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to the following: 
• 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 IRB/IEC 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 14.5 
If a written contract for the conduct of the study is executed and it includes provisions 
inconsistent with this statement, that contract’s provisions shall apply rather than this statement. 
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15. 
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subsequent anticancer therapy. If patients report a suspected imAE at a follow-up visit or a telephone contact, the investigator should arrange an unscheduled 
visit if further assessment is indicated. 
d Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (± 14 days) 
after the EOT Visit or as directed by the sponsor until death, loss to follow-up, withdrawal of consent, or study termination by the sponsor. All patients will be 
followed up for survival and subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
e Patients will be randomized into either the sitravatinib plus tislelizumab (Arm A), or sitravatinib monotherapy (Arm B), or ICC (docetaxel or irinotecan, 
Arm C) via IRT. All patients are required to receive the study treatment ≤ 2 business days after randomization. 
f 
Includes age or year of birth, sex, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior medication, loco-regional 
treatment(s), and surgical treatment(s). Information on radiographic studies performed before study entry may be collected for review by the investigator. 
Pre-existing AEs at baseline should be recorded as medical history. 
g Vital signs include temperature, pulse rate, respiratory 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. For tislelizumab treatment, the patient’s vital signs must be recorded ≤ 60 minutes before, 
during, and ≤ 30 minutes after the first infusion of tislelizumab. For subsequent infusions of tislelizumab, vital signs will be collected ≤ 60 minutes before 
infusion and, if clinically indicated, during and/or ≤ 30 minutes after the infusion. Vital signs should also be recorded before the administration of sitravatinib; 
recorded values may be used for pre-tislelizumab assessment if vital signs are collected ≤ 60 minutes before tislelizumab infusion. Patients randomized to 
receive ICC (Arm C) will follow the same procedure as receiving tislelizumab infusion. Patients who receive ICC will also be monitored for anaphylaxis and 
severe hypersensitivity reactions characterized by dyspnea and hypotension. Patients who receive irinotecan will be monitor for diarrhoea and provided fluid 
and electrolytes supplementation as clinically indicated. 
Height should only be measured and recorded during screening. Weight will be measured before study treatment administration in every cycle. 
h A complete physical examination is required at Screening Visit while subsequent visits entail limited, symptom-directed physical examinations (as detailed in 
Section 7.4.2). For patients who receive tislelizumab, investigators should solicit patients regarding changes in vision, visual disturbance, or ocular 
inflammation at each scheduled study visit during tislelizumab treatment. For any change in vision, an appropriate specialist will be consulted for further 
management guidance. 
i 
The ECG recordings will be obtained during screening, at the beginning of each cycle, the EOT Visit, and as clinically indicated at other time points. Patients 
should be resting for ≥ 10 minutes before each ECG collection. When coinciding with blood sample collection at the same timepoint, ECG assessment should 
be performed either before blood sample collection or ≥ 30 minutes after the blood sample collection. If a patient has QTcF interval > 450 msec for males or 
> 470 msec for females on an initial ECG, 3 consecutive ECGs will be performed several minutes apart to determine the mean QTcF interval. If an ECG has 
been performed ≤ 3 days before the first study treatment or before the EOT Visit, the test does not need to be repeated on Cycle 1 Day 1 or the EOT Visit, 
respectively. 
j 
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 before the first administration of study treatment, only SAEs should be recorded. After initiation of study treatment, all AEs and SAEs, 
regardless of relationship to study treatment, except AEs clearly due to disease progression (see Section 8.6.4), will be reported until either 30 days after last 
dose of study treatment or initiation of new anticancer therapy, whichever occurs first (see Section 8.6.1). The imAEs (serious or nonserious) should be 
reported until 90 days after the last dose of tislelizumab, regardless of whether the patient starts a new anticancer therapy. SAEs considered related to the 
study treatment that are brought to the attention of the investigator should be reported regardless of time since the last dose of treatment. 
k Review of AEs and concomitant medications may be conducted by telephone on Days 8 and 15. 
l 
All medications used by the patient ≤ 30 days before the first dose of study treatment (Section 7.1.3) and ≤ 30 days after the last dose of study treatment 
(Section 9.1.5) should be recorded. 
m Local laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will be collected as 
specified in Appendix 3. If the laboratory tests at screening are not performed ≤ 7 days before the first dose of study treatment, these tests should be repeated 
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and reviewed before administration of study treatment. Hematology and serum chemistry (including liver function tests, data collected as specified in 
Appendix 3) will be performed weekly for the first 3 cycles, then at the beginning of each subsequent cycle and the EOT Visit. If CK-MB fractionation is not 
available, assess troponin I and/or troponin T instead. Coagulation test and urinalysis will be performed at screening, then at the beginning of each treatment 
cycle, at the EOT Visit, and as clinically indicated. Urine protein by dipstick must be < 2+ within 7 days before the first study treatment. Patients that have 
≥ 2+ proteinuria on urine dipstick at baseline should undergo a 24-hour urine collection and must demonstrate < 1g of protein in 24 hours. After Cycle 1, the 
above-mentioned tests are to be performed and the results are to be reviewed ≤ 48 hours before study treatment administration. For patients in Arm C (treated 
with irinotecan), these tests should be performed every CXD8 from C4D8 as clinically indicated according to investigator decision. 
n Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented 
with a negative result ≤ 7 days before randomization. Urine pregnancy tests will be performed at each visit before dosing, and at the EOT Visit. A serum 
pregnancy test must be performed if the urine pregnancy test is positive or equivocal. Refer to Section 8.3.5 for additional information regarding clinical 
assessment and management of clinical laboratory abnormalities. 
o Analysis of FT3, FT4, and TSH will be performed by a central laboratory or the local study site laboratory. Thyroid function tests will be performed at 
screening, every 3 cycles from Cycle 1 Day 1 (ie, Day 1 of Cycles 4, 7, 10, etc), and at the EOT Visit. 
p Testing will be performed by a central laboratory or the local laboratory at screening and will consist of HBV/HCV serology (HBsAg, HBsAb, HBcAb, and 
HCV antibody). HBV DNA or HCV RNA will be assessed in patients who test positive for HBsAg or HCV antibody, respectively. Patients who have 
detectable HBV DNA or HCV RNA at screening will undergo the respective viral load test every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc).  
q COVID-19 testing should be performed by a certified local laboratory, which may be located at the study site. Testing may alternatively be performed at a 
certified offsite laboratory, clinic, or hospital, with the agreement of the investigator. 
r 
Evaluations of cardiac function will be performed at screening and every 12 weeks (± 7 days) thereafter. Evaluations by echocardiogram is preferred but 
evaluations by MUGA scan are acceptable, if necessary. The method used to assess cardiac function at screening is required to be used throughout the study. 
s 
PK samples for sitravatinib and M10 will be collected from patients in Arms A and B. PK samples for tislelizumab will be collected from patients in Arm A. 
Procedures for collection of PK samples are described in the laboratory manual. See Appendix 2 for schedule of PK sampling for sitravatinib, M10, and 
tislelizumab. 
t 
Blood samples for PK and ADA sampling of tislelizumab should be obtained 30 ± 7 days after the last dose of tislelizumab. 
u All blood samples used to test for anti-tislelizumab antibodies should be drawn from patients in Arm A at the same time as blood collection for predose PK 
samples. See Appendix 2 for schedule of ADA sampling. These tests are required when allowed by local regulations/IRBs/IECs. 
v Blood samples for biomarker analysis (approximately 10 mL for each timepoint) will be collected for all patients at baseline (predose on Cycle 1 Day 1, 
required), at the time of first tumor response (predose on Day 1 of the following cycle, optional), and at the time of progressive disease (optional). Collection 
at all 3 timepoints is preferred. Separate written patient consent is required for optional blood sample collections. Instructions for the processing, storage, and 
shipping of samples will be provided in the laboratory manual. See Section 7.7 for additional details. 
w Radiological images captured as standard of care before obtaining written informed consent and ≤ 28 days before randomization may be used rather than 
repeating tests. MRI scan of brain at baseline is required for patients who are suspected to have CNS metastases. All measurable and evaluable lesions are 
required to be assessed and documented at the Screening Visit 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 imaging protocol for CT or MRI). Bone scan or PET is required if 
clinically indicated. During the study treatment period, evaluations of tumor response by the investigator per RECIST v1.1 will be performed every 6 weeks 
(± 7 days) from Day 1 of Cycle 1 for the first 55 weeks and then every 9 weeks (± 7 days) thereafter. After the first documentation of response (CR or PR), 
confirmation of tumor response should occur ≥ 4 weeks after the first response or at the next scheduled assessment timepoint. 
Tumor assessments are required to be performed on schedule regardless of whether study treatment has been administered or held. That is, assessments 
should not be adjusted for possible delays in cycles. Tumor assessment should continue until study treatment discontinuation. Patients who discontinue study 
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treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments following the original plan until the 
patient begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to follow-up, or dies, or until the study 
terminates, whichever occurs first. See also Section 7.5. 
x EORTC-QLQ-C30 and EORTC QLQ-OES18 are to be completed at baseline (Cycle 1 Day 1), every 6 weeks (± 7 days) from Cycle 1 Day 1 for the first 
55 weeks (at Weeks 7, 13, 19, 25, 31, 37, 43, 49, and 55), and then at 9-week intervals (± 7 days) thereafter until EOT. If the disease evaluation does not 
coincide with a clinic visit for a patient, the assessment of PRO should be completed at the clinic visit closest to the disease evaluation for that patient. 
Questionnaires will be completed before any clinical activities or health-related discussions during on-study site visits. 
y Archival tumor tissues (FFPE blocks or approximately 15 freshly cut unstained slides) must be sent to the central laboratory for PD-L1 expression status 
detection during the screening period and to a sponsor designated central/test laboratory for retrospective analysis of exploratory biomarkers. If archival 
tumor tissues are not available during the screening period, a fresh tumor biopsy is mandatory. Optional fresh biopsies in patients who have confirmed 
progressive disease will be collected from accessible tumor sites. Separate written patient consent is required for optional tumor tissue collection. See 
Section 7.7 for additional details. 
z For patients randomized to Arm A, tislelizumab will be administered by intravenous infusion once every 3 weeks beginning with the first dose on Day 1 of 
Cycle 1. The delivery period of the initial infusion (Day 1 of Cycle 1) will be ≥ 60 minutes. If this is well tolerated, the delivery period of subsequent 
infusions can be shortened to ≥ 30 minutes. Patients must be monitored for ≥ 60 minutes after the infusion is complete on Day 1 of Cycle 1. For Cycle 2 
onward, patients must be monitored for ≥ 30 minutes after the infusion. 
Note: Tislelizumab must not be concurrently infused with any other drug. 
aa For patients randomized to Arms A and B, sitravatinib capsules should be taken with a low-fat meal (Appendix 14) or on empty stomach (defined as 
≥ 2-hours fast before each dose and no food for ≥ 1 hour after each dose). Taking the sitravatinib capsules in the morning is preferred. 
bb Patients may receive premedications before the initiation of chemotherapy according to the routine standard of care. Docetaxel should be administered at a 
dose of 75 mg/m2 intravenously over 60 minutes on Day 1 of each 21-day cycle (once every 3 weeks). Doses lower than 75 mg/m2 are allowed if considered 
appropriate for any given patient. If irinotecan is chosen, it should be administered at a dose of 125 mg/m2 intravenously over 90 minutes on Days 1 and 8 of 
each 21-day cycle (once every 3 weeks). For all treatment in subsequent cycles, the treatment interval should be 21 to 24 days (3-day window). If dosing is 
delayed due to administrative or other reasons (holidays, intercurrent illnesses, etc.), the subsequent dosing visit should be scheduled as clinically appropriate. 
cc A patient diary will be provided to each patient in the Arms A and B to record the sitravatinib dose taken each day. Any missed doses with explanations 
should be recorded in the diary. The diary should be returned to the site personnel for review and will be reviewed by the investigator or/study personnel on a 
regular basis. 
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APPENDIX 2. SCHEDULE OF ASSESSMENT OF PHARMACOKINETIC 
AND ANTIDRUG ANTIBODY  
Sitravatinib and M10 PK (For Patients in Arms A and B): 
 
Day 1 of Cycles 1, 2, and 5 
Collection time and 
allowable window a, b 
Predose of sitravatinib 
(≤ 60 minutes before administration) 
Postdose of sitravatinib 
(6 hours [± 20 minutes] after 
administration) 
Sparse PK sampling 
X 
X 
Abbreviations: IEC, Independent Ethics Committee; IRB, Institutional Review Board; PK, pharmacokinetic(s). 
a The PK samples for sitravatinib and M10 will only be collected from the patients who received sitravatinib 
treatment (Arms A and B). 
b An additional PK blood sample may be drawn before a daily sitravatinib dose (trough sample) at any of the 
following events: 1) as soon as an occurrence of a serious adverse event, 2) at a clinic visit that is conducted 
≥ 1 week following after a dose modification of sitravatinib. These tests are required when it is allowed by local 
regulations/IRBs/IECs. 
 
Tislelizumab PK and ADA (Only for Patients in Arm A) 
 
Day 1 of Cycles 1, 2, 5, 9, and 17 (if achieved)  
EOT Visit  
Collection time and 
allowable window a 
Predose of tislelizumab 
(≤ 60 minutes  
before the start of 
infusion)  
Postdose of tislelizumab 
(≤ 30 minutes after the 
end of infusion) 
30 ± 7 days after last 
dose of tislelizumab 
Sparse PK sampling b 
X 
X 
(Day 1 of Cycles 1 and 5 
only) 
X 
ADA sampling c 
X 
 
X 
Abbreviations: ADA, antidrug antibodies; EOT, End-of-Treatment; imAE, immune-mediated adverse event; PK, 
pharmacokinetic(s). 
a The PK and ADA samples for tislelizumab will only be collected from the patients who received tislelizumab 
treatment (Arm A). 
b Should a patient present with any ≥ Grade 3 imAE, an additional blood sample for PK may be taken to determine 
the serum concentration of tislelizumab. These tests are required when it is allowed by local 
regulations/IRBs/IECs. 
c All blood samples used to test for anti-tislelizumab antibodies should be drawn at the same time as blood 
collection for predose PK samples.
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS  
Serum chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
function 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Potassium 
Sodium 
Total calcium a  
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
Creatine kinase b 
CK-MB b 
Hematocrit 
Hemoglobin 
Platelet counts 
WBC count 
Lymphocyte 
count 
Neutrophil count 
Prothrombin time 
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
International 
normalized ratio 
Glucose 
Protein 
Blood 
24-hour protein c 
Free 
triiodothyronine 
Free thyroxine 
Thyroid 
stimulating 
hormone 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme; WBC, white blood cell. 
a Total calcium values will be corrected for patients with hypoalbuminemia. 
b All patients will have creatine kinase and CK-MB testing at screening, and to be repeated at all scheduled visits 
during the first 3 treatment cycles, all predose assessments from Cycle 4 onwards, and at the 
End-of-Treatment Visit. If CK-MB fractionation is not available, assess troponin I and/or troponin T instead. 
Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical 
laboratory abnormalities. 
c On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein. 
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APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: Oken et al 1982. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 
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APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS GUIDELINES VERSION 1.1  
Source: Eisenhauer et al 2009. 
Definitions 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no 
less than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered 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 malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered 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. 
• The concept of cystic metastases also applies to metastatic lesions with a necrotic 
component. Hence, measurable lesions with a necrotic component may be selected as 
target lesions. However, if non-necrotic lesions are present, these are preferred for 
selection as target lesions. 
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. A maximum of 2 measurable 
lymph nodes, inclusive of all lymphatic chains involved, may be chosen as target lesions (ie, the 
lymphatic system is considered one organ). Target lesions should be selected based on size 
(lesions with the longest diameter), how representative they are of all involved organs, and 
whether they 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 perpendicular 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, but the axial plane is recommended for 
measurements). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm by 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should 
be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required, and 
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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 nodes” or “multiple liver metastases”). If a nontarget lymph node normalizes 
(< 10 mm in short axis) after baseline, the respective evaluation should be “absent.” 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than x-ray, particularly in 
identifying new lesions. However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: Target lesion measurements should be performed in the axial plane. 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). If there is a change from CT to MRI or the reverse, target lesions should 
continue to be measured provided the imaging parameters do not render 
measurements incomparable. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
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pathological response when biopsies are obtained or to determine relapse in studies 
where recurrence after 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 studies in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and 
progressive disease (PD). 
Response Criteria 
Evaluation of Target Lesions 
• CR: Disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to < 10 mm. 
• PR: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters 
• 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 1 or 
more new lesions is also considered progression). 
• Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
• Both PR and PD: If the change in sum of diameters is consistent with both PR and PD 
at a tumor assessment visit, PD should take precedence. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm. Case report form may be designed to have target 
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nodal lesions recorded in a separate section where, to qualify for CR, each node must 
achieve a short axis <10 mm. For PR, stable disease, 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 electronic case report form 
(eCRF). If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat, such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially nonreproducible; therefore, providing this default value 
will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that 
measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions. All lymph nodes must be nonpathological 
in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of 1 or more nontarget lesion(s). 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions. (Note: 
The appearance of 1 or more new lesions is also considered progression.) 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of stable 
disease or PR in target disease, the overall tumor burden has increased sufficiently to 
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merit discontinuation of therapy. A modest “increase” in the size of 1 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 stable disease or PR of target disease will therefore be 
extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
phase 3 studies when it is not a criterion of study entry to have measurable disease. 
The same general concept applies here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden. Because worsening in nontarget disease cannot be 
easily quantified (by definition: if all lesions are truly nonmeasurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in nonmeasurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: 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 it may be described 
in protocols as “sufficient to require a change in therapy.” If “unequivocal 
progression” is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to nonmeasurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered that reveals metastases. The patient’s brain metastases are considered evidence of PD 
even if he or she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
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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. 
• Timepoint Response 
• It is assumed that at each protocol specified timepoint, a response assessment occurs. 
The following table provides a summary of the overall response status calculation at 
each timepoint for patients who have measurable disease at baseline: 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
Stable disease 
Non-PD or not all evaluated 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial 
response. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Stable disease (Non-CR/non-PD) 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
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Nontarget Lesions 
New Lesions 
Overall Response 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease. 
Evaluation of Best Overall Response 
The best overall response (BOR) is the best response recorded from the start of the study 
treatment until the end of treatment considering 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 study and the protocol requirements, it may also require confirmatory measurement. 
Specifically, in nonrandomized studies where response is the primary endpoint, confirmation of 
PR or CR is needed to deem either one the “BOR.” 
The BOR is determined once all the data for the patient is known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these studies is defined as the best response across all timepoints 
(for example, a patient who has stable disease at first assessment, PR at second assessment, and 
PD on last assessment has a BOR of PR). When stable disease 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 stable disease is otherwise the best timepoint response, the patient’s best response 
depends on the subsequent assessments. For example, a patient who has stable disease at first 
assessment, PD at second and does not meet minimum duration for stable disease, will have a 
best response of PD. The same patient lost to follow-up after the first stable disease assessment 
would be considered inevaluable. 
Best response determination in studies where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero.” 
In studies where confirmation of response is required, repeated “not evaluable (NE)” timepoint 
assessments may complicate best response determination. The analysis plan for the study must 
address how missing data/assessments will be addressed in determination of response and 
progression. For example, in most studies it is reasonable to consider a patient with timepoint 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective progression 
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even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and inevaluability” are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response 
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies. However, in all other circumstances, ie, in 
randomized studies (Phase 2 or 3) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies which are not blinded. 
In the case of stable disease, measurements must have met the stable disease criteria at least once 
after study entry at a minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD 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. 
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Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular study, the protocol should specify the minimal time interval 
required between 2 measurements for determination of stable disease. 
Note: The DOR and stable disease as well as the progression free survival (PFS) are influenced 
by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to 
define a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between studies are to be made. 
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APPENDIX 6. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Churg Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves disease 
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) nephropathy  
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome 
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Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Koyangai-Harada disease 
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APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin 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 8. INFUSION-RELATED REACTIONS, 
HYPERSENSITIVITY REACTIONS AND 
IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT  
Management of Infusion-Related Reactions and Hypersensitivity Reactions 
Management and treatment modifications for symptoms of infusion-related reactions associated 
with study treatment administration are provided in the table below. 
If a hypersensitivity reaction occurs, the patient must be managed according to the best available 
medical practice, as described in the guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). Patients 
should be instructed to report any delayed reactions to the investigator immediately. 
Treatment Modifications for Symptoms of Infusion-Related or Hypersensitivity Reactions 
Associated with Study Treatment Administration 
NCI-CTCAE grade 
Treatment modification for study treatment 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Closely monitor 
for worsening signs or symptoms. Medical 
management as needed. 
Subsequent infusions should be given after 
appropriate premedication and at the reduced 
infusion rate. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, corticosteroids, and/or intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity. 
Closely monitor for worsening signs or 
symptoms. Appropriate medical management 
should be instituted, as described below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
observation or clinical management. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
treatment. 
Grade 4 – life-threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
treatment. 
Hospitalization is recommended. 
Abbreviation: NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Event. 
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If the infusion rate of study treatment has been decreased by 50% or suspended due to an 
infusion-related reaction, this decreased rate must be maintained for all subsequent infusions and 
be administered with premedication. If the patient has a second infusion-related reaction 
(≥ Grade 2) on the slower infusion rate, infusion should be discontinued, and the patient should 
be withdrawn from tislelizumab treatment. 
For the prophylaxis of mild events (eg, nasal congestion or flu-like symptoms), a dose of 25 mg 
indomethacin or a comparable dose of nonsteroidal anti-inflammatory drugs (eg, 600 mg 
ibuprofen or 500 mg naproxen sodium) may be administered 2 hours before and 8 hours after the 
start of each dose of study treatment infusion. Alternative treatments for fever (eg, paracetamol) 
may be given to patients at the discretion of the investigator. 
National Cancer Institute-Common Terminology Criteria for Adverse Event 
(NCI-CTCAE) Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted as indicated per the type of reaction. This includes, but is not limited to, an 
antihistamine (eg, diphenhydramine), an antipyretic (eg, paracetamol), and if considered 
indicated, oral or intravenous glucocorticoids, epinephrine, bronchodilators, and oxygen. In 
subsequent cycles, the patient should receive oral premedication with an antihistamine (eg, 
diphenhydramine) and an antipyretic (eg, paracetamol), and 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 antihistamines, antipyretics, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
In the event of a systemic anaphylactic/anaphylactoid reaction the infusion must be stopped 
immediately, and the patient discontinued from study treatment. Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes following administration 
of the drug/antigen and are characterized by respiratory distress; laryngeal edema; and/or intense 
bronchospasm; and often followed by vascular collapse or shock without antecedent respiratory 
difficulty; cutaneous manifestations such as pruritus and urticaria (with or without edema); and 
gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhoea. 
The patient will be administered epinephrine injection and dexamethasone infusion if severe 
hypersensitivity reaction is observed. The patient should be closely monitored, and ICU should 
be alerted for possible transfer as indicated. 
Evaluation of Immune-Mediated Adverse Events 
The recommendations below for the diagnosis and management of any immune-mediated 
adverse event (imAE) are intended as 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 recommendations for diagnostic evaluation and management of imAEs are based on 
European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology 
(ASCO) guidelines (Haanen et al 2017; Brahmer et al 2018). For any adverse events (AEs) not 
included in the tables below, 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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Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs. In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of tislelizumab and the AE? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the electronic case report form (eCRF) should be checked. If further 
diagnostic evaluations change the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse 
Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeated thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. 
Perform pituitary and whole brain MRI in patients with headache, visual 
disturbance, unexplained fatigue, asthenia, weight loss, and unexplained 
constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is 
detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or 
signs, such as an upper respiratory infection, new cough, shortness of 
breath, or hypoxia should be assessed by high-resolution CT. Consider 
pulmonary function test including DLCO. 
Radiographic appearance is often nonspecific. Depending on the location 
of the abnormality, bronchoscopy and bronchoalveolar lavage or lung 
biopsy may be considered. Consult with a respiratory medicine physician 
for cases of uncertain cause.  
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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Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive 
testing, including the following: FBC, UEC, LFTs, CRP, TFTs, stool 
microscopy and culture, viral PCR, Clostridium difficile toxin, and 
cryptosporidia (drug-resistant organism). 
In case of abdominal discomfort, consider imaging, eg, x-ray, CT scan. If a 
patient experiences bleeding, pain, or distension, consider colonoscopy 
with biopsy and surgical intervention as appropriate. 
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye 
inflammation; blurred vision; or other visual disturbances, refer the patient 
urgently to an ophthalmologist for evaluation and management. 
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend 
on severity of the AE (eg, daily if Grade 3 to 4; every 2 to 3 days if 
Grade 2, until recovering). Review medications (eg, statins, antibiotics) 
and alcohol history. Perform liver screen including Hepatitis A/B/C 
serology, Hepatitis E PCR and assess anti-ANA/SMA/LKM/SLA/LP/LCI, 
iron studies. Consider imaging (eg, ultrasound scan for metastases or 
thromboembolism). Consult with a hepatologist and consider liver biopsy. 
Renal toxicity 
Review hydration status and medication history. Test and culture urine. 
Consider renal ultrasound scan, protein assessment (dipstick/24-hour urine 
collection), or phase-contrast microscopy. Refer to a nephrologist for 
further management assistance. 
Dermatology 
Consider other causes by conducting a physical examination. Consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint x-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to 
rheumatology for further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, 
CRP, troponin, and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
Management of Immune-Mediated Adverse Events 
Immune-mediated AEs can escalate quickly. Study treatment interruption, close monitoring, 
timely diagnostic work-up, and treatment intervention as appropriate is required. 
Immune-mediated AEs should improve promptly after introduction of immunosuppressive 
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therapy. If this does not occur, review the diagnosis, seek further specialist advice, and contact 
the study medical monitor. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study treatment should be 
discontinued after consultation with the sponsor. Patients who experience a recurrence of any 
event at the same or higher severity grade after restart of study treatment should permanently 
discontinue treatment. 
For some Grade 3 toxicities that resolve quickly, rechallenge with study treatment 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. 
Management of Immune-Mediated Adverse Events 
Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
Thyroid 
disorders 
1-2 
Asymptomatic TFT abnormality or 
mild symptoms 
Replace thyroxine if 
hypothyroid, until 
TSH/T4 levels return to 
normal range. 
Thyrotoxic patients 
should be referred to an 
endocrinologist. In 
cases with systemic 
symptoms: withhold 
study treatment, treat 
with a beta blocker, 
and consider oral 
prednisolone 
0.5 mg/kg/day for 
thyroid pain. 
Taper corticosteroids 
over 2-4 weeks. 
Monitor thyroid 
function regarding the 
need for hormone 
replacement. 
Continue study 
treatment or 
withhold treatment 
in cases with 
systemic 
symptoms. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
3-4 
Severe symptoms, hospitalization 
required 
Refer patient to an 
endocrinologist. 
If hypothyroid, replace 
with thyroxine 
0.5-1.6 µg/kg/day (for 
the elderly or those 
with comorbidities, the 
suggested starting dose 
is 0.5 µg/kg/day). Add 
oral prednisolone 
0.5 mg/kg/day for 
thyroid pain. 
Thyrotoxic patients 
require treatment with 
a beta blocker and may 
require carbimazole 
until thyroiditis 
resolves. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1. 
 
Hypophysitis 
1-2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for 
hormone replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for 
patients with pituitary 
inflammation. Taper 
corticosteroids over at 
least 1 month. 
If there is no 
improvement in 
48 hours, treat as 
Grade 3-4. 
Continue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
3-4 
Severe or life-threatening 
symptoms 
Refer patient to an 
endocrinologist for 
assessment and 
treatment. 
Initiate pulse 
intravenous 
methylprednisolone 
1 mg/kg for patients 
with headache/visual 
disturbance due to 
pituitary inflammation. 
Convert to oral 
prednisolone and taper 
over at least 1 month. 
Maintain hormone 
replacement according 
to endocrinologist’s 
advice. 
Hold study 
treatment for 
patients with 
headache/visual 
disturbance due to 
pituitary 
inflammation until 
resolved/improved 
to ≤ Grade 2. 
Discontinuation is 
usually not 
necessary. 
 
Pneumonitis 
1 
Radiographic changes only 
Monitor symptoms 
every 2-3 days. 
If appearance worsens, 
treat as Grade 2. 
Consider holding 
study treatment 
until appearance 
improves and 
cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics 
if infection suspected. 
Add oral prednisolone 
1 mg/kg/day if 
symptoms/appearance 
persist for 48 hours or 
worsen. 
Consider Pneumocystis 
infection prophylaxis. 
Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis 
for adverse steroid 
effects: eg, blood 
glucose monitoring, 
vitamin D/calcium 
supplement. 
Hold study 
treatment. 
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
3-4 
Severe or life-threatening 
symptoms: breathless at rest 
Admit to a hospital and 
initiate treatment with 
intravenous 
methylprednisolone 
2-4 mg/kg/day. If there 
is no improvement, or 
worsening after 
48 hours, add 
infliximab 5 mg/kg (if 
no hepatic 
involvement). 
Convert to oral 
prednisolone and taper 
over at least 2 months. 
Cover with empiric 
antibiotics and consider 
prophylaxis for 
Pneumocystis infection 
and other adverse 
steroid effects, eg, 
blood glucose 
monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral 
prednisolone 
0.5-1 mg/kg/day. Taper 
over at least 4 weeks. 
Obtain neurology 
consultation. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1. 
3-4 
Severe/life-threatening symptoms 
Initiate treatment with 
oral prednisolone or 
intravenous 
methylprednisolone 
1-2 mg/kg/day, 
depending on 
symptoms. Taper 
corticosteroids over at 
least 4 weeks. 
Consider azathioprine, 
MMF, cyclosporine if 
no response within 
72-96 hours. 
Discontinue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
Colitis/ 
diarrhoea 
1 
Mild symptoms: ≤ 4 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: ≥ 7 liquid stools 
per day over baseline, or if 
episodic within 1 hour of eating 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone and taper 
over at least 4 weeks. 
Consider prophylaxis 
for adverse steroid 
effects, eg, blood 
glucose monitoring, 
Hold study 
treatment; 
retreatment may be 
considered when 
resolved/improved 
to baseline grade 
and after 
discussion with the 
study medical 
monitor. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
4 
Life-threatening symptoms 
vitamin D/calcium 
supplement. 
If no improvement in 
72 hours or symptoms 
worsen, consider 
infliximab 5 mg/kg if 
no perforation, sepsis, 
TB, hepatitis, NYHA 
Class III/IV CHF or 
other 
immunosuppressive 
treatment: MMF or 
tacrolimus. 
Consult 
gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
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 treatment 
management 
3 
Rash covers > 30% BSA or Grade 
2 with substantial symptoms 
Avoid skin irritants and 
sun exposure; topical 
emollients 
recommended. 
Initiate steroids as 
follows based on 
clinical judgement: 
For moderate 
symptoms: oral 
prednisolone 
0.5-1 mg/kg/day for 
3 days then taper over 
2-4 weeks. 
For severe symptoms: 
intravenous 
methylprednisolone 
0.5-1 mg/kg/day; 
convert to oral 
prednisolone and taper 
over at least 4 weeks. 
Hold study 
treatment. 
Re-treat when AE 
is resolved or 
improved to mild 
rash (Grade 1-2) 
after discussion 
with the study 
medical monitor. 
 
4 
Skin sloughing > 30% BSA with 
associated symptoms (eg, 
erythema, purpura, epidermal 
detachment) 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone and taper 
over at least 4 weeks. 
Admit to a hospital and 
seek urgent 
dermatology 
consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3 x ULN 
Check LFTs within 
1 week and before the 
next dose; check LFTs 
to verify that there has 
been no worsening. 
If LFTs are worsening, 
recheck every 
48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs 
are unchanged or 
improving. 
Hold study 
treatment if LFTs 
are worsening until 
improvement is 
seen. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
2 
ALT or AST >3 x to 5 x ULN 
Recheck LFTs every 
48-72 hours. 
For persistent 
ALT/AST elevation: 
consider oral 
prednisolone 
0.5-1 mg/kg/day for 
3 days, then taper over 
2-4 weeks. 
For rising ALT/AST: 
start oral prednisolone 
1 mg/kg/day and taper 
over 2-4 weeks; 
re-escalate dose if 
LFTs worsen, 
depending on clinical 
judgement.  
Hold study 
treatment; 
treatment may be 
resumed when 
resolved/improved 
to baseline Grade 
and prednisolone 
tapered to 
≤ 10 mg. 
3 
ALT or AST > 5 x to 20 x ULN 
ALT/AST < 400 IU/L 
and normal 
bilirubin/INR/albumin: 
Initiate oral 
prednisolone 1 mg/kg 
and taper over at least 
4 weeks. 
ALT/AST > 400 IU/L 
or raised 
bilirubin/INR/low 
albumin: Initiate 
intravenous 
(methyl)prednisolone 
2 mg/kg/day. 
When LFTs improve to 
Grade 2 or lower, 
convert to oral 
prednisolone and taper 
over at least 4 weeks. 
If ALT and AST 
≤ 10 x ULN: Hold 
study treatment 
until improved to 
baseline grade; 
reintroduce only 
after discussion 
with the medical 
monitor. 
If ALT or 
AST > 10 x ULN: 
Discontinue study 
treatment. 
4 
ALT or AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 
2 mg/kg/day. Convert 
to oral prednisolone 
and taper over at least 
6 weeks. 
Discontinue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed intravenous methylprednisolone. 
• 
If on intravenous methylprednisolone, add mycophenolate mofetil (MMF) 
500 to 1000 mg twice a day. 
• 
If worsens on MMF, consider addition of tacrolimus. 
Duration and dose of steroid required will depend on severity of event. 
Nephritis 
1 
Creatinine 1.5 x baseline 
or > ULN to 1.5 x ULN 
Repeat creatinine 
weekly. 
If symptoms worsen, 
manage as per criteria 
below. 
Continue study 
treatment. 
2 
Creatinine > 1.5-3 x baseline 
or > 1.5-3 x ULN 
Ensure hydration and 
review creatinine in 
48-72 hours; if not 
improving, consider 
creatinine clearance 
measurement by 
24-hour urine 
collection. 
Discuss with 
nephrologist the need 
for kidney biopsy. 
If attributed to study 
treatment, 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 treatment 
and 
resolved/improved 
to baseline grade: 
Restart study 
treatment if 
tapered to < 10 mg 
prednisolone. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
3 
Creatinine > 3 x baseline 
or > 3-6 x ULN 
Hospitalize patient for 
monitoring and fluid 
balance; repeat 
creatinine every 
24 hours; refer to a 
nephrologist and 
discuss need for 
biopsy. 
If worsening, initiate 
intravenous 
(methyl)prednisolone 
1-2 mg/kg. Taper 
corticosteroids over at 
least 4 weeks. 
Hold study 
treatment until the 
cause is 
investigated. 
If study treatment 
suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6 x ULN 
As per Grade 3, patient 
should be managed in a 
hospital where renal 
replacement therapy is 
available. 
Discontinue study 
treatment. 
Diabetes/ 
hyperglycemia 
1 
Fasting glucose value ULN to 
160 mg/dL; ULN to 8.9 mmol/L 
Monitor closely and 
treat according to local 
guideline. Check for 
C-peptide and 
antibodies against 
glutamic acid 
decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-13.9 mmol/L 
Obtain a repeat blood 
glucose level at least 
every week. Manage 
according to local 
guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. 
Resume treatment 
when blood 
glucose is 
stabilized at 
baseline or 
Grade 0-1. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
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. 
Hold study 
treatment until 
patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or 
Grade 0-1. 
Ocular toxicity 
1 
Asymptomatic eye 
examination/test abnormality 
Consider alternative 
causes and prescribe 
topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild symptoms 
Refer patient to an 
ophthalmologist for 
assessment and topical 
corticosteroid 
treatment. 
Consider a course of 
oral steroids. 
Continue study 
treatment or hold 
treatment if 
symptoms worsen 
or if there are 
symptoms of 
visual disturbance. 
3 
Posterior uveitis/panuveitis or 
significant symptoms 
Refer patient urgently 
to an ophthalmologist. 
Initiate oral 
prednisolone 
1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study 
treatment until 
improved to 
Grade 0-1; 
reintroduce only 
after discussion 
with the study 
medical monitor. 
4 
Blindness (at least 20/200) in the 
affected eyes 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day. Convert 
to oral prednisolone 
and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic 
enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea and 
vomiting 
Admit to hospital for 
urgent management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone when 
amylase/lipase 
improved to Grade 2 
and taper over at least 
4 weeks. 
Hold study 
treatment; 
reintroduce only 
after discussion 
with the study 
medical monitor. 
4 
Acute abdominal pain, surgical 
emergency 
Admit to hospital for 
emergency 
management and 
appropriate referral. 
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with inflammation, 
swelling 
Management per local 
guideline. 
Continue study 
treatment. 
2 
Moderate pain with inflammation, 
swelling, limited instrumental (fine 
motor) activities 
Management as per 
local guideline. 
Consider referring 
patient to a 
rheumatologist. 
If symptoms worsen on 
treatment, manage as a 
Grade 3 event. 
Continue treatment 
or, if symptoms 
continue to 
worsen, hold study 
treatment until 
symptoms improve 
to baseline or 
Grade 0-1. 
3 
Severe pain with inflammation or 
permanent joint damage, daily 
living activity limited 
Refer patient urgently 
to a rheumatologist for 
assessment and 
management. 
Initiate oral 
prednisolone 
0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study 
treatment unless 
improved to 
Grade 0-1; 
reintroduce only 
after discussion 
with the study 
medical monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or minimal 
symptoms 
Consider topical 
treatment or analgesia 
as per local guideline. 
Continue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
2 
Moderate pain, reduced oral 
intake, limited instrumental 
activities 
As per local guidelines, 
treat with analgesics, 
topical treatments, and 
oral hygiene care. 
Ensure adequate 
hydration. 
If symptoms worsen or 
there is sepsis or 
bleeding, manage as a 
Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food and fluid 
intake, daily living activity limited 
Admit to hospital for 
appropriate 
management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone when 
symptoms improve to 
Grade 2 and taper over 
at least 4 weeks. 
Hold study 
treatment until 
improved to 
Grade 0-1. 
4 
Life-threatening complications or 
dehydration 
Admit to hospital for 
emergency care. 
Consider intravenous 
corticosteroids if not 
contraindicated by 
infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness with/without pain 
Prescribe analgesics. 
If CK is significantly 
elevated and patient 
has symptoms, 
consider oral steroids 
and treat as Grade 2. 
Continue study 
treatment. 
2 
Moderate weakness with/without 
pain 
If CK is 3 x ULN or 
worse, initiate oral 
prednisolone 
0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study 
treatment until 
improved to 
Grade 0-1. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
3-4 
Severe weakness, limiting self-care 
Admit to hospital and 
initiate oral 
prednisolone 1 mg/kg. 
Consider bolus 
intravenous 
(methyl)prednisolone 
and 1-2 mg/kg/day 
maintenance for severe 
activity restriction or 
dysphagia. 
If symptoms do not 
improve, add 
immunosuppressant 
therapy. 
Taper oral steroids over 
at least 4 weeks. 
For Grade 3: Hold 
study treatment 
until improved to 
Grade 0-1. 
Discontinue upon 
any evidence of 
myocardial 
involvement. 
Myocarditis a 
< 2 
Asymptomatic but significantly 
increased CK-MB or increased 
troponin OR clinically significant 
intraventricular conduction delay 
Initiate cardiac 
evaluation under close 
monitoring with repeat 
serum testing and 
including ECG, cardiac 
echo/MUGA, and/or 
other interventions per 
institutional guidelines; 
consider referral to a 
cardiologist. 
If diagnosis of 
myocarditis is 
confirmed, treat as 
Grade 2. 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered 
immune mediated, 
permanently 
discontinue study 
treatment in 
patients with 
moderate or severe 
symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to 
baseline and after 
discussion with the 
study medical 
monitor. 
2 
Symptoms on mild-moderate 
exertion 
Admit to hospital and 
initiate oral 
prednisolone or 
intravenous 
(methyl)prednisolone 
at 1-2 mg/kg/day. 
Consult with a 
cardiologist and 
manage symptoms of 
3 
Severe symptoms with mild 
exertion 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study treatment 
management 
4 
Life-threatening 
cardiac failure 
according to local 
guidelines. 
If no immediate 
response, change to 
pulsed doses of 
(methyl)prednisolone 
1 g/day and add MMF, 
infliximab, or 
anti-thymocyte 
globulin. 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered 
immune related, 
permanently 
discontinue study 
treatment in 
patients with 
moderate or severe 
symptoms. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial 
cardiac enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly 
be considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION EQUATION  
In adults, the most widely used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (Levey et al 2009) and the Modification of Diet in Renal Disease (MDRD) Study 
equation. The National Kidney Disease Education Program (NKDEP) calculators rely on 
creatinine determinations which are isotope dilution mass spectrometry (IDMS) traceable. All 
laboratories should be using creatinine methods calibrated to be IDMS traceable. 
This CKD-EPI equation calculator should be used when serum creatinine (Scr) is reported in 
mg/dL. This equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1)α x max(Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
BSA, 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 
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APPENDIX 10. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group (CTFG) recommendations related to contraception and 
pregnancy testing in clinical studies include the use of highly effective forms of birth control 
(Clinical Trials Facilitation and Coordination Group [CTFG] 2020). These methods include the 
following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth control, and 
if they are selected, they must be used with a second, barrier method of contraception such as 
condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the vasectomized 
partner is the sole partner of the study participant and there has been a medical assessment 
confirming surgical success. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in line 
with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), declaration of abstinence for the duration of 
exposure to study treatment, and withdrawal are not acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
 
 
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Definitions of “Women of Childbearing Potential” AND “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 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 mIU/mL 
and all alternative medical causes for the lack of spontaneous menses for 
≥ 12 months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation and Coordination Group [CTFG] 2020. 
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APPENDIX 11. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
STUDY DRUGS  
Examples of Drugs With a Known Risk of Torsades de Pointes 
Aclarubicin (only on 
non-US market) 
Disopyramide 
lbutilide 
Procainamide 
Amiodarone 
Dofetilide 
Levofloxacin 
Propofol 
Anagrelide 
Domperidone (Only on 
Non US Market) 
Levomepromazine 
(methotrimeprazine) 
(only on non-US 
market) 
Quinidine 
Arsenic trioxide 
Donepezil 
Levomethadyl acetate 
(removed from US 
market) 
Roxithromycin (only 
on non-US market) 
Astemizole (removed 
from US market) 
Dronedarone 
Levosulpiride (only on 
non-US market) 
Sertindole (only on 
non-US market) 
Azithromycin 
Droperidol 
Meglumine antimoniate 
(only on non-US 
market) 
Sevoflurane 
Bepridil 
Erythromycin 
Mesoridazine (removed 
from US market) 
Sotalol 
Cesium Chloride 
Escitalopram 
Methadone 
Sparfloxacin (removed 
from US market) 
Chloroquine 
Flecainide 
Mobocertinib 
Sulpiride (only on 
non-US market) 
Chlorpromazine 
Fluconazole 
Moxifloxacin 
Sultopride (only on 
non-US market) 
Chlorprothixene (only 
on non-US market) 
Gatifloxacin (removed 
from US market) 
Nifekalant (only on 
non-US market) 
Terfenadine (removed 
from US market) 
Cilostazol 
Grepafloxacin 
(removed from US 
market) 
Ondansetron 
Terlipressin (only on 
non-US market) 
Ciprofloxacin 
Halofantrine (only on 
non-US market) 
Oxaliplatin 
Terodiline (only on 
non-US market) 
Cisapride (removed 
from US market) 
Haloperidol 
Papaverine HCI 
(intra coronary) 
Thioridazine 
Citalopram 
Hydroquinidine 
(dihydroquinidine) 
(only on non-US 
market) 
Pentamidine 
Vandetanib 
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Clarithromycin 
Hydroxychloroquine 
Pimozide 
Cocaine 
lbogaine (only on 
non-US market) 
Probucol (removed 
from US market) 
 
Adapted from CredibleMeds 2022; for the most current information, access the website: www.CredibleMeds.org. 
Examples of Sensitive Substrates and Substrates With Narrow Therapeutic Index for P-gp 
and BCRP Transporters 
Transporter 
Substrates 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, 
fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, 
saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, and topotecan 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, and topotecan 
Abbreviations: BCRP, breast cancer resistance protein; P-gp, P-glycoprotein. 
Examples of Sensitive Substrates and Substrates With Narrow Therapeutic Index for the 
Indicated Cytochrome P450 Enzymes 
Enzyme 
Substrates 
CYP2C8 
Repaglinide 
CYP2C9 
Celecoxib 
CYP2C19 
S-mephenytoin and omeprazole 
CYP2D6 
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, 
perphenazine, tolterodine, and venlafaxine 
CYP3A 
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, 
ibrutinib, indinavir, lomitapide, lovastatin, lurasidone, maraviroc, midazolam, 
naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, 
tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam, and vardenafil 
Abbreviation: CYP, cytochrome P450. 
Examples of Inhibitors of Cytochrome P450 3A4 or P-gp 
Strong 
CYP3A4 
inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, 
paritaprevir/ritonavir/ombitasvir plus dasabuvir, posaconazole, ritonavir, 
saquinavir/ritonavir, telaprevir, tipranavir/ritonavir, troleandomycin, and voriconazole 
Moderate 
CYP3A4 
inhibitors 
Aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, 
dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and 
verapamil 
P-gp 
inhibitors 
Amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir 
and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, and verapamil 
Abbreviations: CYP, cytochrome P450; P-gp, P-glycoprotein. 
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APPENDIX 12. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
QUESTIONNAIRE CORE CANCER (EORTC QLQ-C30)  
 
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APPENDIX 13. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
QUESTIONNAIRE-OESOPHAGUS CANCER MODULE 
(EORTC QLQ-OES18)  
 
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APPENDIX 14. DEFINITION OF HIGH-FAT AND LOW-FAT MEALS  
The definitions of high-fat and low-fat meals: 
Meal Type 
Total kcal 
Fat 
kcal 
Grams 
Percent 
High-fat 
800~1000 
500~600 
55~65 
≥ 50% 
Low-fat 
400~500 
100~125 
11~14 
25% 
 
Composition of a high-fat meal: 
Total Calories (kcal) 
800~1000  
Calories from Protein (kcal) 
150  
Calories from Carbohydrates (kcal) 
250 
Calories from Fat (kcal) 
500~600 
Percent Calories from Fat (%) 
≥ 50% 
An example of a High-Fat Breakfast 1* 
• Two fried eggs (approximately 100 g) 
• 100 g of deep-fried dough stick 
• 100 g of ham sausage 
• 240 mL of whole milk 
An example of a High-Fat Breakfast 2* 
• Two eggs fried in butter (eggs 100 g, butter 
15 g) 
• Two strips of bacon (50 g) 
• Two slices of toast with butter (butter 20 g, 
toast 30 g × 2) 
• 113 g of hash brown potatoes 
• 240 mL of whole milk 
*50% of calories are derived from fat. Substitutions can be made to this meal if the content, 
volume, and viscosity are maintained. 
 
Composition of a low-fat meal: 
Total Calories (kcal) 
400~500 
Calories from Fat (kcal) 
100~125 
Fat (g) 
11~14  
Percent Calories from Fat (%) 
25%  
An example of a Low-Fat Breakfast 1* 
• One boiled egg (approximately 50 g) 
• 100 g of steamed buns 
• 30 g of oatmeal or cornflakes 
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• 240 mL of skim milk  
An example of a Low-Fat Breakfast 2* 
• 240 mL of milk (1% fat) 
• One boiled egg (approximately 50 g) 
• 30 g of oatmeal or cornflakes (can be made with 
240 mL of 1% fat milk)  
*25% of calories are derived from fat. Substitutions can be made to this meal if the content, 
volume, and viscosity are maintained. 
 
Sources:  
a. 
US FDA. Guidance for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs-Clinical 
Pharmacology Considerations, 2022. 
b. CDE. Technical Guidelines for Food Impact Research in the Process of New Drug Development, 2021. 
 
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APPENDIX 15. THE DETECTION AND MANAGEMENT OF 
GASTROINTESTINAL PERFORATION/FISTULA  
It is preferred to use a combination of thoracic imaging studies and endoscopy (both flexible 
bronchoscopy and upper endoscopy, if possible) for diagnosis (Kim et al 2020). Esophagography 
is performed preferentially with barium, given its favorable physiological profile compared to 
gastrograffin. The contrast-enhanced esophagogram demonstrates the defect in approximately 
70% of patients with trachea-esophageal fistula (TOF).  
The management of TOF requires a prompt multidisciplinary approach, including interventional 
pulmonology, gastroenterology, and thoracic surgery (Kim et al 2020).The general principle of 
preoperative management is to treat complications arising from the anatomic deformity, while 
addressing modifiable risk factors of fistula formation. Acid-suppressive therapy with H2-
receptor antagonists or proton-pump inhibitors should be used to decrease the acidity and the 
volume of gastric acid. Patient positioning with head of bed elevated to ≥ 45°, strict limitation of 
oral intake, and frequent oral suctioning are used in conjunction with pharmacological therapy. 
Operative management could be considered if possible. Minimally invasive endoscopic 
procedures including stenting are typically preferred in patients with malignant TOF to improve 
nutritional status while preventing further complications. The main endoscopic technique to 
manage TOF is esophageal and/or airway stenting with the goal to seal the fistula and prevent the 
spillover to the respiratory tract. 
 
Version
.0
VV-CLIN-086353
3


Version
.0
VV-CLIN-086353
3

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
 
Study Protocol Number: 
BGB-A317-Sitravatinib-203 
Study Protocol Title: 
A Phase 2, Randomized, Open-Label Study to Investigate the 
Efficacy and Safety of Sitravatinib in Combination With 
Tislelizumab in Patients With Locally Advanced Unresectable or 
Metastatic Esophageal Squamous Cell Carcinoma That Progressed 
on or After Anti-PD-(L)1 Antibody Therapy 
Date: 
28 February 2024 
Version: 
1.0 


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SIGNATURE PAGE 
 
 
 
 
 
 
 


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TABLE OF CONTENT 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................5 
1................. INTRODUCTION ........................................................................................................7 
2................. STUDY OVERVIEW ...................................................................................................7 
3................. STUDY OBJECTIVES.................................................................................................8 
3.1.............. Primary Objective .........................................................................................................8 
3.2.............. Secondary Objective .....................................................................................................8 
4................. STUDY ENDPOINTS ..................................................................................................9 
4.1.............. Primary Endpoints ........................................................................................................9 
4.2.............. Secondary Endpoints ....................................................................................................9 
5................. SAMPLE SIZE CONSIDERATIONS..........................................................................9 
6................. STATISTICAL METHODS .......................................................................................10 
6.1.............. Analysis Sets ...............................................................................................................10 
6.2.............. Data Analysis General Considerations .......................................................................10 
6.2.1........... Definitions and Computations ....................................................................................10 
6.2.2........... Conventions ................................................................................................................11 
6.2.3........... Handling of Missing Data ...........................................................................................11 
6.3.............. Patient Characteristics.................................................................................................11 
6.3.1........... Patient Disposition ......................................................................................................11 
6.3.2........... Protocol Deviations.....................................................................................................11 
6.3.3........... Demographic and Other Baseline Characteristics ......................................................12 
6.3.4........... Disease History ...........................................................................................................12 
6.3.5........... Prior Anticancer Drug Therapies ................................................................................12 
6.3.6........... Medical History ..........................................................................................................12 
6.4.............. Efficacy Analysis ........................................................................................................13 
6.4.1........... Primary Efficacy Endpoints ........................................................................................13 
6.4.2........... Secondary Efficacy Endpoints ....................................................................................13 
6.4.3........... Subgroup Analyses .....................................................................................................15 
6.4.4........... Post and during-treatment Anti-Cancer Therapy ........................................................15 
6.5.............. Safety Analyses...........................................................................................................15 
6.5.1........... Extent of Exposure......................................................................................................15 
6.5.2........... Adverse Events ...........................................................................................................16 


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7................. INTERIM ANALYSES ..............................................................................................17 
8................. CHANGES IN THE PLANNED ANALYSIS ...........................................................17 
9................. REFERENCES ...........................................................................................................18 
APPENDIX 1 IMPUTATION OF MISSING OR PARTIALLY MISSING DATES ..................19 
 
 
 
LIST OF TABLES 
Table 1: Censoring Rules for Progression-Free Survival per RECIST Version 1.1 ......................14 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
ADI 
Actual dose intensity 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
BLQ 
Below the assay quantification limit 
BOR 
Best overall response 
BSA 
Body surface area 
CI 
Confidence interval 
CR 
Complete response 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DCR 
Disease Control Rate 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
HRQoL 
Health Related Quality of Life 
imAE 
Immune-mediated adverse event 
IRC 
Independent Review Committee 
IRR 
Infusion-Related Reactions 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
LS-SCLC 
Limited-Stage Small Cell Lung Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-L1 
Programmed cell death protein-ligand 1 
PK 
Pharmacokinetic  
PFS 
Progression-free survival 


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PR 
Partial response 
PT 
Preferred term 
RDI  
Relative dose intensity  
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TCM 
Traditional Chinese Medication 
TEAE 
Treatment-emergent adverse event 
TTD 
Time to Deterioration 
TTR 
Time to Response 
VAS 
Visual Analog Scale 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


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1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for BGB-A317-Sitravatinib-203: a Phase 
2, randomized, open-label study to investigate the efficacy and safety of Sitravatinib in 
combination with tislelizumab in patients with locally advanced unresectable or metastatic 
esophageal squamous cell carcinoma that progressed on or after anti-PD-(L)1 antibody therapy. 
This SAP is developed based on BGB-A317-Sitravatinib-203 protocol amendment 2.0, dated on 
Jul 10, 2023. BeiGene decided to terminate the study on Oct 9, 2023 based on the modifications 
of company development strategy. Due to the early termination of the study, the enrollment is 
not completed and efficacy data is not matured. The focus of this SAP is to briefly analyze the 
primary and secondary efficacy endpoints and treatment emergent adverse events (TEAE) in the 
study protocol. 
2 STUDY OVERVIEW 
This is an open-label, randomized, multicenter, Phase 2 study to investigate the efficacy and 
safety of sitravatinib in combination with tislelizumab given as a second or third line treatment in 
patients with locally advanced unresectable or metastatic ESCC whose disease progressed after 
prior systemic chemotherapy, which is platinum-based chemotherapy doublet and anti-PD-(L)1 
antibody therapy, with the anti-PD-(L)1 antibody administered in combination with or 
sequentially following the platinum-based chemotherapy. 
The study will be conducted at approximately 25 centers in Mainland China. Approximately 
100 patients with locally advanced unresectable or metastatic ESCC whose disease progressed 
on or after platinum-based chemotherapy doublet and anti-PD-(L)1 antibody therapy will be 
randomized to receive either sitravatinib plus tislelizumab (Arm A), sitravatinib monotherapy 
(Arm B), or ICC (Arm C). Patients must have received ≤ 2 lines of prior systemic therapy for 
locally advanced unresectable or metastatic disease. Other prior immunotherapeutic agents 
specifically targeting T-cell costimulation or checkpoint pathways (eg, anti-TIGIT antibody) are 
allowed if it was administered in combination with an anti-PD-(L)1 antibody. The choice of 
chemotherapy must be determined before randomization at the investigator’s discretion, either 
docetaxel or irinotecan. Randomization will be stratified by PD-L1 expression status (assessed 
by the Ventana PD-L1 [SP263] assay: Tumor Area Positivity [TAP] score ≥ 10% versus TAP 
score < 10%) in a 2:1:2 ratio to receive 1 of treatment regimens: 
x Arm A: Sitravatinib 100 mg orally once daily plus tislelizumab 200 mg intravenously 
once every 3 weeks 
x Arm B: Sitravatinib 100 mg orally once daily 
x Arm C: Docetaxel 75 mg/m2 intravenously on Day 1 of every 21-day cycle OR 
irinotecan 125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle 
Switching of chemotherapeutic agent or cross-over between treatment arms will not be allowed 
during the study. 


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Efficacy and safety will be assessed between Arm A and Arm C, while efficacy between Arm A 
and Arm B will only be assessed for efficacy contribution analysis of tislelizumab in the 
combination treatment. 
Study treatment will be administered until disease progression as assessed by the investigator per 
RECIST v1.1, unacceptable toxicity, withdrawal of consent, or another treatment discontinuation 
criterion is met, whichever occurs first. 
The study design schema is presented in Figure 1. 
Figure 1: Study Schema 
 
Abbreviations: CBR, clinical benefit rate; D, Day; DCR, disease control rate; DOR, duration of response; ECOG PS, 
Eastern Cooperative Oncology Group Performance Status; ESCC, esophageal squamous cell carcinoma; HRQoL, 
health-related quality of life; INV, investigator; IRC, Independent Review Committee; IV, intravenously; N, number 
of patients; ORR, overall response rate; OS, overall survival; PD-1, programmed cell death protein-1; PD-(L)1, 
programmed cell death protein (ligand)-1; PFS, progression-free survival; PK, pharmacokinetic(s); PO, orally; QD, 
once daily; R, randomization ratio; TAP, Tumor Area Positivity; VEGF(R), vascular endothelial growth factor 
(receptor). 
3 STUDY OBJECTIVES 
3.1  Primary Objective 
x To assess the overall response rate (ORR) by the investigator per Response Evaluation 
Criteria in Solid Tumors (RECIST) Version (v) 1.1 in the Intention-to-Treat (ITT) 
Population between Arm A (sitravatinib plus tislelizumab) and Arm C 
(investigator-chosen chemotherapy) 
3.2 Secondary Objective 
x To evaluate the duration of response (DOR) as assessed by the investigator per 
RECIST v1.1 in Arm A and Arm C  
x To assess the efficacy between Arm A and Arm C through overall survival (OS) 


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x To assess the efficacy between Arm A and Arm C through disease control rate (DCR), 
clinical benefit rate (CBR), and progression-free survival (PFS) as assessed by the 
investigator per RECIST v1.1 
x To assess the efficacy of Arm A and Arm B (sitravatinib monotherapy) through ORR, 
DOR, DCR, CBR, and PFS as assessed by the investigator per RECIST v1.1 
x To assess the safety and tolerability of sitravatinib as monotherapy and in combination 
with tislelizumab 
4 STUDY ENDPOINTS 
4.1  Primary Endpoints 
x ORR as assessed by the investigator, defined as the proportion of patients with a 
confirmed complete response (CR) or partial response (PR) per RECIST v1.1, in Arms A 
and C in the ITT Analysis Set  
4.2 Secondary Endpoints 
x DOR as assessed by the investigator, defined as the time from the first confirmed 
objective response until the first documentation of disease progression or death, 
whichever comes first, in Arms A and C in the ITT Analysis Set 
x OS, defined as the time from the date of randomization until the date of death from any 
cause, in Arms A and C in the ITT Analysis Set 
x DCR as assessed by the investigator, defined as the proportion of patients who achieve 
CR, PR, or stable disease, in Arms A and C in the ITT Analysis Set 
x CBR as assessed by the investigator, defined as the proportion of patients who achieve 
CR, PR, or durable stable disease (stable disease ≥ 24 weeks), in Arms A and C in the 
ITT Analysis Set 
x PFS as assessed by the investigator, defined as the time from the date of randomization to 
the date of first documentation of disease progression or death, whichever occurs first, in 
Arms A and C in the ITT Analysis Set 
x ORR, DOR, DCR, CBR, PFS as assessed by the investigator, in Arms A and B in the ITT 
Analysis Set 
5 SAMPLE SIZE CONSIDERATIONS 
This exploratory study is not powered for the hypothesis testing between treatment arms but 
rather to obtain preliminary efficacy and safety data for sitravatinib in combination with 
tislelizumab and sitravatinib monotherapy for patients with locally advanced unresectable or 
metastatic ESCC that progressed on or after anti-PD-(L)1 antibody therapy. This study will 
enroll approximately 100 patients into 3 arms, with approximately 40, 20, and 40 patients in 
Arms A, B, and C, respectively. The efficacy of tislelizumab in combination with sitravatinib 


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versus chemotherapy will be demonstrated by descriptive analysis of ORR, PFS, OS, DCR, 
CBR, and DOR as assessed by the investigator in the assessment between Arms A and C. The 
contribution of adding tislelizumab to sitravatinib monotherapy will be demonstrated by 
similarly descriptive analysis in the assessment of Arms A and B. With a sample size of 
40 patients in Arm A (sitravatinib plus tislelizumab), the binomial probabilities of detecting 
≥ 1 TEAE with a frequency of 5% and 1% are approximately 0.87 and 0.33, respectively. 
6 STATISTICAL METHODS 
6.1  Analysis Sets 
The ITT Analysis Set includes all patients randomly assigned to a treatment arm. Patients’ data 
will be analyzed according to their randomized treatment arm. This will be the primary analysis 
population for all efficacy analyses. 
The Safety Analysis Set includes all patients who receive at least 1 dose of any component of 
study treatment, and patients will be grouped by actual treatment received, where actual 
treatment received is defined as (i) the intended treatment if it was received at least once, or (ii) 
the first treatment received when starting therapy with study medication if intended treatment is 
never received. Each patient will be classified into and analyzed consistently within one (and 
only one) treatment arm. The safety analysis set will be the population for all the safety 
analyses.. 
6.2  Data Analysis General Considerations 
6.2.1 Definitions and Computations 
Study drugs include sitravatinib, tislelizumab, docetaxel and Irinotecan. 
Study day will be calculated in reference to the first dose date for safety analysis. For 
assessments conducted on or after the first dose date, the study day will be calculated as the 
assessment date – first dose date + 1. For assessments conducted before the first dose date, study 
day is calculated as the assessment date – first dose date. There is no study day 0. In the situation 
where the event date is partial or missing, the date will appear partial or missing in the listings. 
Study day and any corresponding durations will be presented based on the imputations specified 
in Appendix 1. 
To derive the duration of any efficacy endpoint, the reference date will be the date of 
randomization. 
Baseline Measurements: 
x 
For efficacy evaluation: a baseline value is defined as the last non-missing value collected 
prior to the randomization. 
x 
For safety: a baseline value is defined as the last non-missing value prior to the first study 
drug administration. 
Study Follow-up Duration (SFD): Study follow-up duration is defined as the duration from the 
randomization date to the study discontinuation date (e.g. death, consent withdrawal, lost to 
follow-up) or to the cutoff date if a patient is still ongoing. 


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All calculations and analyses will be conducted using SAS® Version 9.4 or higher. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
x 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
x 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 significant digit. 
x BMI (݇݃/݉ଶ) will be calculated as Weight(kg)/(Height(cm)/100)2. 
x Duration of image-based event endpoints (such as PFS) will be based on the actual date 
the radiograph was obtained rather than the associated visit date. 
x For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
x For discrete endpoints, summary statistics will include frequencies and percentages. 
6.2.3 Handling of Missing Data 
Handling of missing data related to primary endpoints will be further elaborated in Section 6.4.1. 
Missing dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures. Specific rules for the handling of missing or partially 
missing dates for adverse events prior/concomitant medications/procedures, and subsequent anti-
cancer therapies, etc. are provided in Appendix 1. Other missing data will not be imputed unless 
otherwise specified elsewhere in this SAP. 
By-visit endpoints will be analyzed using observed data unless otherwise specified. For observed 
data analyses, missing data will not be imputed, and only the observed records will be included. 
6.3 Patient Characteristics 
6.3.1 Patient Disposition 
The number (percentage) of patients who signed informed consent, enrolled in the study, and 
screened failure including re-screened will be summarized. The screen failure reasons will also 
be summarized. 
The number (percentage) of patients randomized, treated, discontinued from the study, reasons 
for discontinued from the study, and the duration of study follow-up will be summarized in the 
ITT analysis set. The patients who discontinued treatment and the primary reason for the end of 
treatment will be summarized among patients who were treated.  
6.3.2 Protocol Deviations 
Important protocol deviation criteria will be established, and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be summarized 
for all patients in the ITT analysis set. Deviation categories are not mutually exclusive. Multiple 
deviations within the same category are counted once per patient. 


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6.3.3 Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using descriptive statistics 
in the ITT analysis set, including the following variables: 
x Age (continuously and by categories [≤65 or >65 years]) 
x Sex 
x Race 
x Weight (kg) 
x BMI (kg/m2) 
x ECOG performance score  
x Ethnicity 
x Geographic Region 
In addition, the stratification factors per Interactive Response Technology (IRT) and per eCRF 
will be summarized based on the ITT population: 
x PD-L1 TAP score (< 10% versus ≥ 10%) 
6.3.4 Disease History 
The number (percentage) of patients reporting a history of disease and characteristics, as 
recorded on the eCRF, will be summarized in the ITT analysis set. Disease characteristics 
include clinical stage at initial diagnosis, time from diagnosis of metastatic/locally advanced 
disease to randomization date, primary site of esophageal cancer, metastasis status and site, etc. 
6.3.5 Prior Anticancer Drug Therapies 
Prior anti-cancer drug therapies, prior anti-cancer local therapy (including surgery and 
radiotherapy) will be summarized in the ITT analysis set. 
The variables include the number of patients with any prior anticancer drug therapies, number of 
prior lines, type of prior anticancer drug therapies, best response to last anticancer drug therapy, 
treatment setting of last line, time from end of last anticancer drug therapy to randomization date, 
time from last disease progression to randomization date for prior anti-cancer drug therapies, and 
number of patients with any prior radiotherapy, treatment intent, treatment setting of last regimen 
and time from end of last prior radiotherapy to randomization date for prior anti-cancer 
radiotherapy, number of patients with any prior curative anticancer surgery. The therapies with 
the same sequence/regimen number are counted as one prior therapy. 
6.3.6 Medical History 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(Version 25.0 or higher). The number (percentage) of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by system organ class and preferred term 
in the ITT Analysis Set.  


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6.4  Efficacy Analysis 
Due to the exploratory purpose of this study, all the below efficacy analyses are descriptive and 
exploratory; no formal testing is designed. 
 
6.4.1 Primary Efficacy Endpoints 
ORR as assessed by the investigator is defined as the proportion of patients with a confirmed CR 
or PR assessed by investigator per RECIST v1.1. Patients without any postbaseline response 
assessment (for any reason) will be considered nonresponders.  
The crude odds ratio and risk difference of ORR, along with their exact 95% CIs (Thomas 1971; 
Chan and Zhang 1999) will be calculated between Arms A and C. The ORR rate and its 
Clopper-Pearson 95% CI will be calculated for each arm. 
ORR based on unconfirmed PR or CR will also be summarized.  
6.4.2 Secondary Efficacy Endpoints 
DOR as assessed by investigator  
DOR as assessed by the investigator is defined as the time from the first confirmed objective 
response until the first documented disease progression or death date, whichever occurred first. 
All the censoring rules for PFS will be applied to DOR. Only patients who have achieved 
objective responses will be included in the analysis of DOR. Kaplan-Meier methodology will be 
used to estimate median or other quartiles of DOR along with its 95% CI by using Brookmeyer 
and Crowley method (Brookmeyer & Crowley, 1982) for Arms A and C. Event-free rate at 
selected timepoints will be estimated with 95% CI estimated using Greenwood formula 
(Greenwood, 1926). No assessment of DOR between Arm A and C will be performed as it would 
be based on non-randomized subgroups. 
OS  
OS is defined as the time from randomization date until the date of death from any cause. For 
patients who are alive by the clinical cutoff date, OS will be censored at the last known alive date 
(LKADT). The last known alive date will be defined as either the clinical data cutoff date for 
patients who are still on treatment, or last available date showing patients alive or cut-off date 
whichever comes first for other alive patients.  
Every effort should be made to ensure complete death dates. In the rare case, if day of death date 
is missing, death date is imputed as the max (last available date showing patients alive + 1, first 
day of year/month of death date). The patient with imputed death date will be considered as an 
event for OS analysis. 
Kaplan-Meier methodology will be used to estimate median or other quartiles of OS along with 
its 95% CI by using Brookmeyer and Crowley method (Brookmeyer & Crowley, 1982) for 
Arms A and C. Kaplan-Meier curves will be constructed to provide a visual description of the 
OS distribution. Event-free rate at selected timepoints (eg, 6 months and 12 months) will be 
estimated with 95% CI estimated using Greenwood formula (Greenwood, 1926). The HR of OS 
between Arms A and C will be estimated using a stratified Cox regression model with PD-L1 
TAP score (≥ 10% versus < 10%) collected from IRT system as strata. The 95% CI for the HR 
will be provided. Unstratified analysis will also be presented. 


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PFS as assessed by investigator 
PFS assessed by the investigator is defined as the time from the randomization date to the first 
documented disease progression, as assessed by the investigators based on RECIST v1.1 or 
death, whichever occurs first.  
The censoring rules for the analysis of PFS are presented in Table 1.   
Table 1: Censoring Rules for Progression-Free Survival per RECIST Version 1.1 
 
Derivation rules 
Outcome  
No progression at the time of 
data cut-off or withdrawal from 
study or lost to follow up 
Date of last adequate radiologic assessment 
prior to or on date of data cut-off or withdrawal 
from study or lost to follow up 
Censored  
New anticancer therapy started  
Last adequate radiological assessment before 
the new anticancer therapy 
Censored 
No baseline or post-baseline 
tumor assessments without 
death within 13 weeks after 
randomization  
Date of randomization 
Censored 
No baseline or post-baseline 
tumor assessments with death 
within 13 weeks after 
randomization 
Date of death 
Event 
Death or progression after more 
than one missed visit 
Date of last adequate radiologic assessment 
before missed tumor assessments 
Censored 
Death prior to progression 
Date of death 
Event 
Similar methodology used to evaluate OS between Arms A and C will be applied to the analysis 
of PFS for the assessment between Arms A and C. 
DCR and CBR as assessed by investigator 
DCR as assessed by the investigator is defined as proportion of patients with PR or CR or a 
stable disease per RECIST v1.1. 
CBR as assessed by the investigator is defined as proportion of number of patients with PR or 
CR or a durable stable disease per RECIST v1.1.  
Similar methodology used to evaluate ORR between Arms A and C in the primary analysis will 
be applied to the analysis of DCR and CBR for the assessment between Arms A and C. 
Besides, ORR, DOR, DCR, CBR, PFS as assessed by the investigator will also be analyzed in 
Arms A and B in the ITT Analysis Set using similar methodology as the above analyses of ORR, 
DOR, DCR, CBR and PFS in Arms A and C.  


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6.4.3 Subgroup Analyses 
Subgroup analysis on ORR by investigator will be conducted in ITT analysis set, to evaluate the 
uniformity of treatment effect across variety of subgroups. Subgroup variables may include, but 
not limited to:  
x Age group (< 65 years, >= 65 years)  
x Sex (Male, Female)  
x ECOG performance status (0, 1)  
x PD-L1 expression (>=10% TAP, <10% TAP) 
x Disease status at study entry (metastatic, locally advanced) 
x Number of lines of prior systemic therapy (1, 2) 
 
6.4.4 Post and during-treatment Anti-Cancer Therapy 
Post treatment anti-cancer therapy is defined as the anti-cancer therapy started after the last dose 
of study drug(s). During-treatment anti-cancer therapy is defined as the anti-cancer therapy 
started after randomization and before the last dose of study drug(s). Subsequent anti-cancer 
therapy contains post and during-treatment anti-cancer therapy.  
Separate flags of start date of new anti-cancer therapy for efficacy and safety analyses are 
derived individually. 
- As for efficacy analysis, start date of new anti-cancer therapy will be the earliest date of 
prohibited anti-cancer therapy taken during treatment, date of the post-treatment systemic 
anti-cancer therapy and date of other anti-cancer therapy such as post-treatment surgery and 
radiotherapy as deemed appropriate. 
- The start date of new anti-cancer therapy in defining TEAE for safety is always the first 
date of new systemic anti-cancer therapy taken after the last study treatment. 
Tumor response per RECIST or event driven endpoints have not been commonly used for the 
efficacy evaluation of the traditional Chinese medicine (TCM). ORR, PFS or OS benefit of 
Chinese herbal medicines or Chinese patent medicines has not yet been established. Therefore, 
they will not be taken into account as the new anti-cancer therapy in the efficacy and safety 
analyses. 
6.5 Safety Analyses 
All safety analyses will be performed by treatment arms based on the safety analysis set. Safety 
and tolerability will be assessed, where applicable, by incidence and severity for AEs.  
6.5.1 Extent of Exposure 
The following measures of the extent of exposure will be summarized with descriptive statistics 
for each study drug in the safety analysis set. One cycle is defined as 21 days of treatment. 
x Duration of exposure (months) for tislelizumab or docetaxel or irinotecan: defined as (last 
date of exposure - first dose date + 1) / 30.4375. For treatment ongoing patients, use 
cutoff date as the 'last date of exposure'; for patients discontinued from treatment, 'last 
date of exposure' is defined as the earliest date of cutoff date, death date and last dose 
date + 20 (tislelizumab or docetaxel) or 13 (irinotecan).  


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x Duration of exposure (months) for sitravatinib: defined as (last date of exposure - first 
dose date + 1) / 30.4375. For treatment ongoing patients, use cutoff date as the 'last date 
of exposure'; for patients treated with sitravatinib and discontinued from treatment, use 
last dose date as 'last date of exposure'. 
x Number of treatment cycles received: defined as the total number of treatment cycles in 
which at least one dose of the study drug is administered. 
x Total dose received per patient: For tislelizumab or sitravatinib (mg), it is defined as the 
cumulative dose of the study drug during the treatment period of the study up to clinical 
cutoff date. For the docetaxel or irinotecan, the total dose received per patient (mg/m2) is 
defined as the cumulative dose of the docetaxel or irinotecan during the treatment period 
of the study divided by body surface area (BSA), where the BSA is defined as the square 
root of weight * height /3600. The BSA is derived using baseline weight at each visit 
unless weight change for one visit is at least 10% greater compared to baseline weight. 
x Actual dose intensity for tislelizumab (mg/cycle) or docetaxel (mg/m2/cycle) is defined as 
the cumulative dose received by a patient / (last dose date prior to cut off date – first dose 
date + 21)/21). Actual dose intensity for irinotecan (mg/m2/cycle) is defined as the 
cumulative dose received by a patient / (last dose date prior to cut off date – first dose 
date + 14)/21). Actual dose intensity for sitravatinib (mg/day) is defined as the total 
cumulative dose (mg) / (last dose date prior to or on cutoff date – first dose date +1 
(days)).  
x Relative dose intensity (%): defined as the ratio of the actual dose intensity and the 
planned dose intensity. The planned dose intensity is 200 mg/cycle for tislelizumab, 75 
mg/m2/cycle for docetaxel, 125×2 mg//m2/cycle for irinotecan and 100 mg/day for 
sitravatinib. 
x Number (%) of patients with dose reductions and number of dose reductions per patient 
x Number (%) of patients with dose interruptions 
x Number (%) of patients with dose delay 
x Number (%) of patients with dose modifications, including dose reductions, dose delays 
and dose interruptions. 
6.5.2 Adverse Events  
AEs will be graded by the investigators using NCI-CTCAE version 5.0. The AE verbatim 
descriptions (investigator terms from the eCRF) will be classified into standardized medical 
terminology using MedDRA. Adverse events will be coded to the MedDRA (Version 25.0 or 
higher) lowest level term closest to the verbatim term, along with the linked MedDRA preferred 
term (PT) and primary system organ class (SOC). 
6.5.2.1 Treatment Emergent Adverse Event 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever occurs first. Only those AEs 


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that were treatment emergent will be included in summary tables. All AEs, treatment emergent 
or otherwise, will be presented in patient data listings.  
An AE overview table, including the number and percentage of patients with TEAEs, treatment-
emergent serious adverse events (SAEs), TEAEs with Grade 3 or above, TEAEs that led to 
death, TEAEs that led to treatment discontinuation, TEAEs that led to dose modification, 
treatment-related TEAEs, and treatment-related version of any of the above categories will be 
provided in the safety analysis set. Treatment-related AEs include those events considered by the 
investigator to be related to any of the study drugs or with a missing assessment of the causal 
relationship. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
PT. A patient will be counted only once by the highest severity grade within a PT, even if the 
patient experienced more than 1 TEAE within a specific PT. The number (percentage) of patients 
with TEAEs, treatment-emergent SAEs, TEAEs with grade 3 or above, treatment-related 
TEAEs, treatment-related SAEs, treatment-related TEAEs with grade 3 or above, TEAEs that led 
to death, treatment-related TEAEs that led to death, TEAEs that led to treatment discontinuation, 
and TEAEs that led to dose modification, will be summarized by PT.  
6.5.2.2 Immune-Mediated Adverse Event 
Immune-mediated adverse events (imAEs) are of special interest and summarized by category 
within a pre-defined list. The identification of immune-mediated adverse events is described in 
immune-mediated adverse event charter version 1.2. 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 study drug and up to 90 days after the last dose of study drug, 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.  
The number (percentage) of patients with imAEs will be summarized by category and PT. 
6.5.2.3 Death 
All deaths and causes of death will be summarized by treatment arms, including those occurred 
within 30 days after the last dose and those reported after 30 days after the last dose. 
7 INTERIM ANALYSES 
No formal interim analyses will be conducted; administrative interim analysis is allowed. 
Summaries of efficacy and safety data may be generated to inform subsequent clinical 
development planning or to address emergent safety concerns. 
8 CHANGES IN THE PLANNED ANALYSIS 
Because of the early termination of the study, the planned statistical analysis in PA2.0 is 
condensed. No supplementary or sensitivity analysis is planned for the primary analysis. All the 
exploratory analyses, laboratory analyses, vital signs, pharmacokinetic and immunogenicity 
analyses are removed.  
 


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9 REFERENCES 
Brookmeyer, R., & Crowley, J. (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38(1), 29. https://doi.org/10.2307/2530286 
Greenwood, M. (1926). A Report on the Natural Duration of Cancer. A Report on the Natural 
Duration of Cancer., 33. 
Thomas DG. Exact confidence limits for the odds ratio in a 2 x 2 table. Journal of the Royal 
Statistical Society: Series C (Applied Statistics). 1971;20(1):105-10.  
Chan IS, Zhang Z. Test‐based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999;55(4):1202 9. 
 
 


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APPENDIX 1 IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES 
In general, missing or partial dates will not be imputed at the data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only. The last known 
alive date only is based on complete dates without imputation. 
1. 
Prior/Concomitant Medications/Procedures 
When the start date or end date of medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rules will be applied to 
impute partial dates for medications: 
If the start date of medication is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01. 
x If only day is missing, then set to the first of the month. 
x If the imputed start date > min(death date, end of study date) then set to min(death 
date, end of study date). 
If the end date of medication is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If the imputed end date > min(death date, end of study date), then set to min(death 
date, end of study date). 
If start date or end date of medication is completely missing, do not impute. 
2. 
Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment-emergent by default. If year of the start date is missing or start date 
is completely missing, do not impute. Impute AE end date first if both AE start date and end date 
are partially missing. The following rules will be applied to impute partial dates for adverse 
events: 
If the end date of an AE is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31. 
x If only day is missing, then set to last day of the month. 
x If the imputed end date > min(death date, end of study date), then set to min(death date, 
end of study date). 
If the year of the end date or end date is completely missing, do not impute. 
If start date of an adverse event is partially missing, impute as follows: 


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x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
x If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date 
x If day is missing and month and year ≠ month and year of treatment start date, the set to 
first of the month 
x If the imputed AE start date is after AE end date (maybe imputed), then update AE start 
date with AE end date as final imputed AE start date 
x If the imputed start date > min(death date, end of study date), then set to min(death date, 
end of study date) 
3. 
Subsequent Anti-cancer Therapies 
If the start date of subsequent anti-cancer therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed start date > min (death date, data cutoff date, study discontinuation date, 
start date of the next subsequent therapy), then set it as min (death date, data cutoff date, 
study discontinuation date, start date of the next subsequent therapy) 
If stop date of is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed stop date > min (death date, study discontinuation date, start date of the 
next subsequent therapy), then set it as min (death date, study discontinuation date, start 
date of the next subsequent therapy) 
The (imputed) stop date must be after or equal to the (imputed) start date. If year of the start 
date/stop date is missing, do not impute.  
4. 
Diagnosis 
If date of initial diagnosis is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed date > randomization date, then set to randomization date – 1 
If diagnosis date of metastatic disease/locally advanced is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed date > randomization date, then set to randomization date – 1 


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x If the imputed date < (imputed) date of initial diagnosis date, then set to initial diagnosis 
date. 
If a diagnosis date is completely missing, do not impute. 
5. 
Prior Therapy/Response to Prior Therapy 
The following rules will be applied to impute partial dates for prior therapy and response to prior 
therapy. Impute end date of prior therapy first if both start date and end date of prior therapy are 
partially missing. 
If end date of a disease history or prior therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > randomization date, then set to randomization date -1 
If start date of a disease history or prior therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > end date, then set to end date  
If the date of disease progression to prior therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed date > randomization date, then set to randomization date – 1 
x If the imputed date < the start date of prior therapy, then set to the start date of prior therapy 
+1.