Clinical trial NCT03941873
Conditions: Carcinoma, Hepatocellular Gastric/Gastroesophageal Junction Cancer
Keywords: Carcinoma HCC G/GEJ Cancer
Sponsor: BeiGene
Start date: 2019-02-28; Completion date: 2023-03-31
Enrollment: 111 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of sitravatinib as monotherapy and in combination with tislelizumab in participants with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) or gastric/gastroesophageal junction (G/GEJ) cancer.

Detailed description:
This was an open-label, multicenter Phase 1/2 clinical study for participants with histologically or cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer. All participants received study treatment (s) until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor.

Arms: arm 1: Sitravatinib 80 mg orally once daily in 21-day cycles in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer arm 2: Sitravatinib 120 mg orally once daily in 21-day cycles in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer arm 3: Sitravatinib 80 mg orally once daily in 21-day cycles with tislelizumab 200 mg intravenously (IV) once every 3 weeks in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer arm 4: Sitravatinib 120 mg orally once daily in 21-day cycles with tislelizumab 200 mg IV once every 3 weeks in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer
Interventions: intervention 1: Sitravatinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: Administered orally as a capsule intervention 2: Administered intravenously

Protocol documents:
Prot_000.pdf: 
BGB-900-104 
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Protocol Amendment 4.0 
28 April 2020 
CONFIDENTIAL 
Page 1 
Title Page 
CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Phase 1/2 Study to Investigate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Antitumor Activity of Sitravatinib 
as Monotherapy and in Combination With Tislelizumab in Patients 
With Unresectable Locally Advanced or Metastatic Hepatocellular 
Carcinoma or Gastric/Gastroesophageal Junction Cancer 
Protocol Identifier: BGB-900-104 
Phase: 
1/2 
Investigational 
Products: 
Sitravatinib (MGCD516) and Tislelizumab (BGB-A317) 
Indication: 
Advanced Solid Tumors 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, California 94403 
USA 
BeiGene, Ltd. 
c/o BeiGene AUS Pty Ltd 
1C/528 Compton Road Stretton 
Queensland 4116, Australia 
BeiGene (Beijing) Co., Ltd. 
No. 30 Science Park Road 
Zhong-Guan-Cun Life Science 
Park 
Changping District 
Beijing, China 102206 
P.R. China 
Sponsor Medical 
Monitor: 
 
Telephone: 
 
Email: 
 
Original Protocol: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 3.0: 
Amendment 4.0: 
05 July 2018 
23 August 2018 
08 January 2019 
30 April 2019 
28 April 2020 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries. This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries. Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries. 
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FINAL PROTOCOL APPROVAL SHEET 
BGB-900-104: A Phase 1/2 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and 
Preliminary Antitumor Activity of Sitravatinib as Monotherapy and in Combination With 
Tislelizumab in Patients With Unresectable Locally Advanced or Metastatic Hepatocellular 
Carcinoma or Gastric/Gastroesophageal Junction Cancer 
BeiGene, Ltd., Approval: 
 
___
________________ 
Yu 
Spo
tor 
 
___________________________________ 
Date 
 
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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A Phase 1/2 Study to Investigate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Antitumor Activity of Sitravatinib 
as Monotherapy and in Combination With Tislelizumab in Patients 
With Unresectable Locally Advanced or Metastatic Hepatocellular 
Carcinoma or Gastric/Gastroesophageal Junction Cancer 
Protocol Identifier: 
BGB-900-104 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to implementation of this 
sponsor-approved protocol. PRINT your name, title, and the name and address of the center in which the study 
will be conducted.  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: _______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................20 
1. 
INTRODUCTION AND RATIONALES ..................................................................22 
1.1. 
Background Information on Advanced Solid Tumors ................................................22 
1.1.1. 
Hepatocellular Carcinoma ..........................................................................................22 
1.1.2. 
Gastric/Gastroesophageal Junction Cancer ................................................................23 
1.2. 
Sitravatinib as a Receptor Tyrosine Kinase Inhibitor .................................................24 
1.2.1. 
Pharmacology .............................................................................................................24 
1.2.2. 
Toxicology ..................................................................................................................25 
1.2.3. 
Clinical Pharmacology ................................................................................................25 
1.2.4. 
Clinical Experience With Sitravatinib ........................................................................26 
1.2.5. 
Rationale for Selection of Sitravatinib Dose ..............................................................29 
1.3. 
Tislelizumab as a PD-1 Blocker .................................................................................29 
1.3.1. 
Pharmacology .............................................................................................................30 
1.3.2. 
Toxicology ..................................................................................................................30 
1.3.3. 
Clinical Pharmacology ................................................................................................31 
1.3.4. 
Clinical Experience With Tislelizumab ......................................................................31 
1.3.5. 
Rationale for Selection of Tislelizumab Dose ............................................................37 
1.4. 
Rationale for Combination of Sitravatinib and Tislelizumab in the Treatment 
of Advanced Solid Tumors .........................................................................................38 
1.5. 
Benefit-Risk Assessment ............................................................................................39 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Study Objectives for Phase 1 (Dose Escalation) ........................................................40 
2.1.1. 
Primary Objectives .....................................................................................................40 
2.1.2. 
Secondary Objectives .................................................................................................40 
2.1.3. 
Exploratory Objectives ...............................................................................................40 
2.2. 
Study Objectives for Phase 2 (Dose Expansion) ........................................................40 
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2.2.1. 
Primary Objective .......................................................................................................40 
2.2.2. 
Secondary Objectives .................................................................................................40 
2.2.3. 
Exploratory Objectives ...............................................................................................41 
2.3. 
Study Endpoints for Phase 1 (Dose Escalation) .........................................................41 
2.3.1. 
Primary Endpoints ......................................................................................................41 
2.3.2. 
Secondary Endpoints ..................................................................................................41 
2.3.3. 
Exploratory Endpoints ................................................................................................41 
2.4. 
Study Endpoints for Phase 2 (Dose Expansion) .........................................................42 
2.4.1. 
Primary Endpoint ........................................................................................................42 
2.4.2. 
Secondary Endpoints ..................................................................................................42 
2.4.3. 
Exploratory Endpoints ................................................................................................42 
3. 
STUDY DESIGN .......................................................................................................43 
3.1. 
Summary of Study Design ..........................................................................................43 
3.1.1. 
Phase 1 (Dose Escalation for Sitravatinib as Monotherapy and in 
Combination With Tislelizumab) ...............................................................................43 
3.1.2. 
Phase 2 (Dose Expansion for Sitravatinib as Monotherapy and in 
Combination With Tislelizumab) ...............................................................................44 
3.2. 
Screening Period .........................................................................................................45 
3.3. 
Treatment Period ........................................................................................................45 
3.4. 
End-of-Treatment Visit and Safety Follow-up Phone Calls .......................................46 
3.5. 
Survival Follow-up .....................................................................................................46 
3.6. 
Discontinuation From Study Treatment or From the Study .......................................46 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................46 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........47 
3.7. 
End of Study ...............................................................................................................47 
3.8. 
Dose-Limiting Toxicities ............................................................................................48 
3.8.1. 
Assessment of Dose-Limiting Toxicity ......................................................................48 
3.8.2. 
Definition of Dose-Limiting Toxicity ........................................................................48 
4. 
STUDY POPULATION .............................................................................................50 
4.1. 
Inclusion Criteria ........................................................................................................50 
4.1.1. 
Inclusion Criteria for All Patients ...............................................................................50 
4.1.2. 
Phase 1 Inclusion Criteria ...........................................................................................51 
4.1.3. 
Phase 2 Inclusion Criteria ...........................................................................................52 
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4.2. 
Exclusion Criteria for all Patients ...............................................................................53 
5. 
STUDY TREATMENT ..............................................................................................57 
5.1. 
Formulation, Packaging, and Handling ......................................................................57 
5.1.1. 
Sitravatinib ..................................................................................................................57 
5.1.2. 
Tislelizumab ...............................................................................................................57 
5.2. 
Dosage and Administration ........................................................................................57 
5.2.1. 
Sitravatinib ..................................................................................................................57 
5.2.2. 
Tislelizumab ...............................................................................................................58 
5.3. 
Compliance and Accountability .................................................................................58 
5.4. 
Overdose .....................................................................................................................59 
5.4.1. 
Sitravatinib ..................................................................................................................59 
5.4.2. 
Tislelizumab ...............................................................................................................59 
5.5. 
Modification and Dose Delay .....................................................................................59 
5.5.1. 
Dose Modification ......................................................................................................59 
5.5.2. 
Dose Delay ..................................................................................................................60 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................61 
6.1. 
Concomitant Therapy .................................................................................................61 
6.1.1. 
Permitted Concomitant Medications/Procedures .......................................................61 
6.1.2. 
Prohibited Concomitant Medications/Procedures ......................................................61 
6.1.3. 
Restricted Concomitant Medications/Procedures .......................................................62 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................62 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................64 
7.1. 
Screening ....................................................................................................................64 
7.1.1. 
Demographics and Medical History ...........................................................................64 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................65 
7.1.3. 
Informed Consent and Screening Log ........................................................................65 
7.1.4. 
Pulmonary Function Tests ..........................................................................................65 
7.2. 
Enrollment ..................................................................................................................65 
7.3. 
Safety Assessments .....................................................................................................65 
7.3.1. 
Vital Signs ..................................................................................................................65 
7.3.2. 
Physical Examinations ................................................................................................66 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status ........................................66 
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7.3.4. 
Laboratory Safety Test ...............................................................................................66 
7.3.5. 
Hepatitis B and C Testing ...........................................................................................67 
7.3.6. 
Electrocardiograms .....................................................................................................67 
7.3.7. 
Multigated Acquisition Scans or Echocardiograms ...................................................67 
7.3.8. 
Adverse Events ...........................................................................................................67 
7.4. 
Tumor and Response Evaluations ..............................................................................67 
7.5. 
Pharmacokinetic Assessment ......................................................................................69 
7.6. 
Antidrug Antibody Testing .........................................................................................69 
7.7. 
Biomarkers ..................................................................................................................69 
7.8. 
Visit Windows ............................................................................................................70 
7.9. 
Unscheduled Visits .....................................................................................................70 
8. 
SAFETY MONITORING AND REPORTING .........................................................71 
8.1. 
Risks Associated With Sitravatinib and Tislelizumab ................................................71 
8.2. 
General Plan to Manage Safety Concerns ..................................................................71 
8.2.1. 
Eligibility Criteria .......................................................................................................71 
8.2.2. 
Safety Monitoring Plan ...............................................................................................71 
8.3. 
Adverse Events ...........................................................................................................72 
8.3.1. 
Definitions and Reporting ...........................................................................................72 
8.3.2. 
Assessment of Severity ...............................................................................................73 
8.3.3. 
Assessment of Causality .............................................................................................73 
8.3.4. 
Following Adverse Events ..........................................................................................74 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................74 
8.4. 
Definition of a Serious Adverse Event .......................................................................75 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................76 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................76 
8.6.1. 
Adverse Event Reporting Period ................................................................................76 
8.6.2. 
Reporting Serious Adverse Events .............................................................................76 
8.6.3. 
Eliciting Adverse Events ............................................................................................77 
8.6.4. 
Progressive Disease ....................................................................................................77 
8.6.5. 
Deaths .........................................................................................................................77 
8.6.6. 
Pregnancies .................................................................................................................78 
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8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................78 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events ......................................78 
8.7. 
Management of Adverse Events of Special Interest of Tislelizumab .........................78 
8.7.1. 
Infusion-Related Reactions .........................................................................................79 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms .......................................81 
8.7.3. 
Immune-Related Adverse Events ...............................................................................81 
8.8. 
Management of Sitravatinib-Specific Adverse Events ...............................................82 
8.8.1. 
Management of Non-Hematological Toxicities of Sitravatinib .................................82 
8.8.2. 
Management of Hematological Toxicities of Sitravatinib ..........................................83 
8.8.3. 
Dose Modification Guidelines for Sitravatinib-Specific AEs ....................................83 
8.8.4. 
Hypertension ...............................................................................................................85 
8.8.5. 
Palmar-Plantar Erythrodysesthesia .............................................................................85 
8.8.6. 
Diarrhea/Colitis ...........................................................................................................85 
8.8.7. 
Hemorrhagic Events ...................................................................................................85 
8.8.8. 
Thrombotic Events ......................................................................................................86 
8.8.9. 
Thyroid Dysfunction Other Than Immune-Mediated .................................................86 
8.8.10. 
Decreased Left Ventricular Ejection Fraction ............................................................86 
8.8.11. 
Proteinuria ...................................................................................................................86 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................87 
9.1. 
Statistical Analysis ......................................................................................................87 
9.1.1. 
Analysis Sets ...............................................................................................................87 
9.1.2. 
Patient Disposition ......................................................................................................87 
9.1.3. 
Demographic and Other Baseline Characteristics ......................................................88 
9.1.4. 
Prior and Concomitant Medications ...........................................................................88 
9.2. 
Efficacy Analyses .......................................................................................................88 
9.3. 
Safety Analyses ..........................................................................................................89 
9.3.1. 
Extent of Exposure .....................................................................................................89 
9.3.2. 
Adverse Events ...........................................................................................................90 
9.3.3. 
Laboratory Analyses ...................................................................................................90 
9.3.4. 
Vital Signs ..................................................................................................................90 
9.3.5. 
Dose-Limiting Toxicity Analysis ...............................................................................90 
9.4. 
Pharmacokinetic Analysis ..........................................................................................91 
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9.5. 
Immunogenicity Analyses ..........................................................................................92 
9.6. 
Other Exploratory Analyses .......................................................................................92 
9.7. 
Sample Size Consideration .........................................................................................92 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................93 
10.1. 
Safety Monitoring Committee ....................................................................................93 
10.2. 
Communication ...........................................................................................................93 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................94 
11.1. 
Access to Information for Monitoring ........................................................................94 
11.2. 
Access to Information for Auditing or Inspections ....................................................94 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................95 
12.1. 
Regulatory Authority Approval ..................................................................................95 
12.2. 
Quality Assurance .......................................................................................................95 
12.3. 
Study Site Inspections.................................................................................................95 
12.4. 
Drug Accountability ...................................................................................................95 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................97 
13.1. 
Ethical Standard ..........................................................................................................97 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................97 
13.2.1. 
Protocol Amendments ................................................................................................97 
13.3. 
Informed Consent .......................................................................................................97 
13.4. 
Patient and Data Confidentiality .................................................................................98 
13.5. 
Financial Disclosure ...................................................................................................99 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................100 
14.1. 
Data Collection and Management Responsibilities ..................................................100 
14.1.1. 
Data Collection .........................................................................................................100 
14.1.2. 
Data Management/Coding ........................................................................................100 
14.2. 
Study Records Retention ..........................................................................................100 
14.3. 
Protocol Deviations ..................................................................................................101 
14.4. 
Publication and Data Sharing Policy ........................................................................102 
14.5. 
Study and Study Center Closure ...............................................................................102 
14.6. 
Information Disclosure and Inventions ....................................................................103 
15. 
REFERENCES .........................................................................................................104 
16. 
APPENDICES ..........................................................................................................109 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................109 
APPENDIX 2. SCHEDULE OF PK ASSESSMENTS ............................................................115 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................117 
APPENDIX 4. ECOG PERFORMANCE STATUS.................................................................118 
APPENDIX 5. CHILD-PUGH CLASSIFICATION SCORING SYSTEM .............................119 
APPENDIX 6. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................120 
APPENDIX 7. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................121 
APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................123 
APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................124 
APPENDIX 10. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................125 
APPENDIX 11. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................135 
APPENDIX 12. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH SITRAVATINIB ...................144 
APPENDIX 13. BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION ..................................................................................................146 
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LIST OF TABLES 
Table 1 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
 10%) by Preferred Term for Study 516-001 ..........................................................26 
Table 2 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
 10%) by Preferred Term for Study MRTX-500 .....................................................28 
Table 3 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies (Safety Analysis 
Set) ..............................................................................................................................32 
Table 4 
Immune-Related Adverse Events of Any Grade Occurring LQ 1% in Pooled 
Monotherapy Studies (Safety Analysis Set) ...............................................................34 
Table 5 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in 
Pooled Monotherapy Studies (Safety Analysis Set) ...................................................35 
Table 6: 
Sitravatinib Dose Reductions .....................................................................................59 
Table 7: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................76 
Table 8: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab ...............................................................................................................80 
Table 9: 
Immune-Related Adverse Events ...............................................................................82 
Table 10: Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities ....................................................................................................................83 
Table 11: Sitravatinib Dose Modification for Increased Blood Pressure ...................................84 
Table 12: Sitravatinib Dose Modification for Increased Hepatic Transaminase ........................84 
Table 13: Estimates of 95% CI of ORR With 20 Patients ..........................................................92 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................45 
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SYNOPSIS 
Name of Sponsor: 
BeiGene, Ltd. 
Investigational Products:  
Sitravatinib (MGCD516) and Tislelizumab (BGB-A317) 
Title of Study: 
A Phase 1/2 Study to Investigate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Antitumor Activity of Sitravatinib 
as Monotherapy and in Combination With Tislelizumab in Patients 
With Unresectable Locally Advanced or Metastatic Hepatocellular 
Carcinoma or Gastric/Gastroesophageal Junction Cancer 
Protocol Identifier: 
BGB-900-104 
Phase of Development:  
Phase 1/2 
Number of Patients: 
Approximately 18 to 36 DLT evaluable patients enrolled in Phase 1 
and approximately 80 patients enrolled in Phase 2  
Study Centers: 
Approximately 20 centers in Asia Pacific including Australia and 
China 
Study Objectives: 
Phase 1:  
Primary: 
x 
To assess the safety and tolerability of sitravatinib as monotherapy and in combination with 
tislelizumab 
x 
To confirm the recommended Phase 2 dose (RP2D) for sitravatinib as monotherapy and in 
combination with tislelizumab 
Secondary: 
x 
To characterize the pharmacokinetic (PK) profiles of sitravatinib after single dose and at steady 
state as monotherapy and in combination with tislelizumab 
x 
To assess the preliminary antitumor activity of sitravatinib as monotherapy and in combination 
with tislelizumab in hepatocellular carcinoma (HCC) or gastric/gastroesophageal junction 
(G/GEJ) cancer patients  
Exploratory: 
x 
To explore potential biomarkers in association with efficacy, resistance, and/or progressive 
disease (PD) in tumor tissue and in peripheral whole blood 
x 
To explore potential pharmacodynamic biomarkers for sitravatinib as monotherapy and in 
combination with tislelizumab 
x 
To assess PK and immunogenicity of tislelizumab when given in combination with sitravatinib 
x 
To explore the effect of pharmacogenetic (PGx) polymorphisms on PK of sitravatinib 
Phase 2:  
Primary: 
x 
To assess the preliminary antitumor activity as indicated by objective response rate (ORR) per 
Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of sitravatinib as 
monotherapy and in combination with tislelizumab  
Secondary: 
x 
To assess the preliminary antitumor activity as indicated by duration of response (DOR), 
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disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1 as 
monotherapy and in combination with tislelizumab 
x 
To characterize the safety and tolerability of sitravatinib as monotherapy and in combination 
with tislelizumab  
x 
To characterize the PK profile of sitravatinib  
Exploratory: 
x 
To assess potential biomarkers in association with efficacy, resistance, and/or PD in tumor 
tissue and in peripheral whole blood 
x 
To explore potential pharmacodynamic biomarkers for sitravatinib as monotherapy and in 
combination with tislelizumab 
x 
To assess PK and immunogenicity to tislelizumab when given in combination with sitravatinib  
x 
To assess overall survival (OS) 
x 
To explore the effect of pharmacogenetic (PGx) polymorphisms on PK of sitravatinib 
Study Endpoints: 
Phase 1 (Dose Escalation):  
Primary Endpoints: 
x 
Safety and tolerability will be assessed throughout the study by monitoring adverse events 
(AEs) and serious adverse events (SAEs) per National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v5.0, relevant physical examination, 
electrocardiograms (ECGs), and laboratory assessments as needed 
Secondary Endpoints: 
x 
Plasma concentrations and the derived PK parameters of sitravatinib if data permit: 
o Single dose: maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax), area under the plasma or serum concentration-time curve from 
time zero to the last measurable time point (AUC(0-t)), clearance after oral 
administration (CL/F) 
o Repeating dose: Cmax, trough concentration at steady state (CĲ), Tmax, area under the 
plasma concentration-time curve from time zero to 24 hours postdose at steady state 
(AUC(0-Ĳ), CL/F, accumulation ratio (Ro) 
x 
Efficacy evaluations by investigators: ORR, DOR, DCR, and PFS based on RECIST v1.1  
Exploratory Endpoints: 
x 
Potential biomarkers, including, but not limited to, programmed cell death protein ligand-1 
(PD-L1) expression, immune cell profiling, tumor mutation load, and gene expression profiling 
in archival and/or fresh tumor tissue and blood (or blood derivatives) obtained before, during, 
or after treatment or at PD; and the association with disease status and/or the response to 
sitravatinib as monotherapy or in combination with tislelizumab 
x 
Changes of potential pharmacodynamic biomarkers in response to sitravatinib as monotherapy 
and in combination with tislelizumab, such as, but not limited to, soluble vascular endothelial 
growth factor receptor 2 (sVEGFR-2) and immune cell subpopulations in peripheral blood  
x 
Serum concentrations of tislelizumab and anti-tislelizumab antibodies 
x 
Effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, including, 
but not limited to, CYP1A2, 2D6, and 2C8 on the PK of sitravatinib 
Phase 2 (Dose Expansion):  
Primary Endpoint: 
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x 
Efficacy evaluations by investigators: ORR based on RECIST v1.1  
Secondary Endpoints: 
x 
Efficacy evaluations by investigators: DOR, DCR, and PFS based on RECIST v1.1 
x 
Safety and tolerability will be assessed throughout the study by monitoring AEs and SAEs per 
NCI-CTCAE v5.0, relevant physical examination, ECGs, and laboratory assessments as 
needed 
x 
PK: plasma concentrations of sitravatinib predose and postdose at steady state 
Exploratory Endpoints: 
x 
Potential biomarkers, including, but not limited to, PD-L1 expression, immune cell profiling, 
tumor mutation load, and gene expression profiling in archival and/or fresh tumor tissue and 
blood (or blood derives) obtained before, during, or after treatment or at PD; and the 
association with disease status and/or response to sitravatinib as monotherapy or in 
combination with tislelizumab 
x 
Changes of potential pharmacodynamic biomarkers in response to sitravatinib as monotherapy 
and in combination with tislelizumab, such as, but not limited to, sVEGFR-2 and immune cell 
subpopulations in peripheral blood  
x 
Serum concentrations of tislelizumab and anti-tislelizumab antibodies  
x 
OS is defined as the time from date of first dose of study drug(s) to date of death due to any 
cause 
x 
Effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, including, 
but not limited to, CYP1A2, 2D6, and 2C8 on the PK of sitravatinib 
Study Population 
Patients with histologically or cytologically confirmed unresectable locally advanced or metastatic 
HCC or G/GEJ cancer. 
Key Eligibility Criteria 
$GXOWSDWLHQWV 18 years of age at the time of voluntarily signing of informed consent) with 
histologically or cytologically confirmed HCC or G/GEJ cancer. All patients are also required to have 
DQ(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS(&2*SHUIRUPDQFHVWDWXVVFRUHRI 1, and adequate organ 
function. 
Investigational Products, Dose, and Mode of Administration: 
Phase 1 (dose escalation): Sitravatinib capsules will be administered orally, once daily, in a 
continuous regimen in 21-day cycles. The starting dose for sitravatinib in escalation evaluation will be 
80 mg once daily. Depending on safety observations, the sitravatinib dose in the subsequent cohort of 
patients may be escalated to 120 mg once daily. Sitravatinib will be administered either as 
monotherapy or in combination with 200 mg tislelizumab, which will be administered on Day 1 of 
each 21-day cycle (once every 3 weeks). 
Phase 2 (dose expansion): The recommended dose level of sitravatinib will be administered orally, 
once daily, in a continuous regimen in 21-day cycles. Sitravatinib will be administered either as 
monotherapy or in combination with 200 mg tislelizumab, which will be administered on Day 1 of 
each 21-day cycle (once every 3 weeks).  
Study Design 
This is an open-label, multicenter Phase 1/2 clinical study for patients with histologically or 
cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer. All 
patients will receive study treatment(s) until PD, unacceptable toxicity, death, withdrawal of consent, 
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or study termination by sponsor. 
This study consists of the following phases: 
Phase 1 (Dose escalation for sitravatinib as monotherapy and in combination with tislelizumab):  
Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be 
evaluated in patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. A 
modified 3 + 3 design will be used in the dose escalation. Approximately 6 to 12 DLT evaluable 
patients will be treated with sitravatinib as monotherapy.  
The combination dose escalation of sitravatinib (80 mg once daily and 120 mg once daily; modified 
3 + 3 design) with tislelizumab (200 mg once every 3 weeks, in both cohorts) will be evaluated in 
patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. The combination dose 
escalation may start simultaneously with the monotherapy cohort as the dose regimen for all cohorts 
are considered safe based on the totality of available clinical data. There is no interaction anticipated 
between sitravatinib and tislelizumab to influence respective PK profiles. If the combination dose of 
80 mg sitravatinib and 200 mg tislelizumab has been declared tolerable, the dose of sitravatinib will be 
escalated to 120 mg and tislelizumab will remain fixed at 200 mg. Approximately 12 to 24 DLT 
evaluable patients will be treated.  
The Safety Monitoring Committee (SMC) will confirm RP2D of the monotherapy and combination 
treatment based on all available safety, efficacy, PK, and exploratory data. Additional dose levels may 
be evaluated if needed. For the sitravatinib combination therapy, RP2Ds for each tumor type will be 
recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
Phase 2 (Dose expansion for sitravatinib as monotherapy and in combination with tislelizumab): 
Approximately 20 patients will be enrolled in each cohort. There will be a total of 4 cohorts in the 
study. 
Sitravatinib monotherapy 
x 
Cohort A: Anti-PD-1/PD-L1 antibody naïve or refractory/resistant HCC 
Sitravatinib in combination with tislelizumab 
x 
Cohort B: Anti-PD-1/PD-L1 antibody naïve HCC 
x 
Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant HCC 
x 
Cohort D: Anti-PD-1/PD-L1 antibody naïve G/GEJ cancer 
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Study Schema 
Abbreviations: Ab, antibody; G/GEJ, gastric/gastroesophageal junction, HCC, hepatocellular carcinoma; PD-1, programmed 
cell death protein-1; PD-L1, programmed cell death protein ligand-1; PK, pharmacokinetic; QD, once a day; Q3W, once every 
3 weeks; RP2D, recommended Phase 2 dose; R/R, refractory or resistant; Sitra, sitravatinib; SMC, Safety Monitoring 
Committee; Tisle, tislelizumab. 
Note: The combination dose escalation may start simultaneously with the monotherapy cohort. The SMC will confirm RP2D 
of the monotherapy and combination treatment based on all available safety, efficacy, PK, and exploratory data. Additional 
dose levels may be evaluated if needed. For the sitravatinib combination therapy, RP2Ds for each tumor type will be 
recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
Study Assessments 
A table of study assessments is provided in Appendix 1. Patients will be closely monitored for safety 
and tolerability throughout the study. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the first 
dose of study drug(s). For dose escalation decision, only DLTs occurring within 21 days will be 
evaluated. The following patients will not be considered evaluable for DLT, and will be replaced if 
needed to meet the minimum patient number required for dose escalation: 
x 
Patients who withdraw or are withdrawn from the study before completing the DLT assessment 
window for reasons other than a DLT. 
x 
3DWLHQWVUHFHLYLQJPRQRWKHUDS\ZKRGRQRWUHFHLYH 75% of scheduled sitravatinib during the 
DLT assessment window, unless they experience a DLT. 
x 
3DWLHQWVUHFHLYLQJFRPELQDWLRQWKHUDS\ZKRGRQRWUHFHLYH 75% of scheduled sitravatinib and 
 67% (approximately two-thirds) of scheduled tislelizumab during the DLT assessment 
window, unless they experience a DLT. 
Definition of DLT 
A DLT is defined as any of the following toxicities occurring during the DLT assessment window and 
considered by the investigator to be related to sitravatinib and/or tislelizumab. 
Hematologic 
x 
Grade 4 neutropenia lasting > 3 days 
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x 
*UDGH 3 febrile neutropenia 
x 
Grade 3 thrombocytopenia with clinically significant bleeding 
x 
Grade 4 thrombocytopenia 
x 
 Grade 4 anemia 
Non-Hematologic 
x 
*UDGH 4 toxicity 
x 
Grade WR[LFLW\WKDWLVFOLQLFDOO\VLJQLILFDQWDQGGRHVQRWLPSURYHWR Grade 2 within 3 days of 
initiating optimal supportive care 
Note: The following AEs will not be considered DLTs: 
o Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
o Grade 3 hypertension that improves to < 160/100 mmHg, within 7 days of optimal supportive 
care 
o Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
Tumor Assessments 
Radiological assessment of tumor-response status will be performed approximately every 6 weeks 
(± 7 days) in the first year, then every 9 weeks (± 7 days) thereafter.  
Tumor response will be assessed by investigators based on RECIST v1.1.  
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed with 
the medical monitor and documented in the study records. In such cases, patients are also required to be 
reconsented. 
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Statistical Methods 
This study is designed to verify the dose and to establish the safety and tolerability of sitravatinib as 
monotherapy and in combination with tislelizumab and to assess the preliminary antitumor activity in 
selected tumor types. No formal hypothesis testing is planned. Descriptive statistical analyses will be 
performed for all patients in the Safety Analysis Set. The safety and efficacy (eg, ORR, DOR, DCR, 
PFS, and OS) data will be presented by phase and by cohort. 
Analysis Sets 
x 
The Safety Analysis Set includes all patients who received at least 1 dose of any study drug(s) 
(any component for the combination therapy). Patients from either Phase 1 or 2 are eligible for 
inclusion in the Safety Analysis Set. 
x 
The Efficacy Evaluable Analysis Set includes patients who received at least 1 dose of any 
study drug with measurable disease at baseline per RECIST v1.1 who had at least 1 evaluable 
postbaseline tumor assessment unless treatment was discontinued due to clinical progression 
or death before tumor assessment. Patients from either Phase 1 or 2 are eligible for inclusion 
in the Efficacy Evaluable Analysis Set.  
x 
DLT Evaluable Analysis Set for sitravatinib monotherapy includes patients who received at 
least 75% of the assigned total dose of sitravatinib for the DLT assessment window and had 
sufficient safety evaluation. Additionally, patients who had a DLT event will also be 
considered evaluable. Only patients from Phase 1 are eligible for inclusion in the DLT 
Evaluable Analysis Set of sitravatinib monotherapy. 
x 
DLT Evaluable Analysis Set for sitravatinib and tislelizumab combination includes patients 
ZKRUHFHLYHGDWOHDVWRIWKHDVVLJQHGWRWDOGRVHRIVLWUDYDWLQLEDQG 67% (approximately 
two-thirds) of the assigned total dose of tislelizumab for the DLT assessment window. 
Additionally, patients who had a DLT event will also be considered evaluable. Only patients 
from Phase 1 are eligible for inclusion in the DLT Evaluable Analysis Set of sitravatinib and 
tislelizumab combination therapy. 
x 
The PK Analysis Set includes patients who contributed at least 1 quantifiable post-baseline PK 
sample. Patients from either Phase 1 or 2 are eligible for inclusion in the PK Analysis Set.  
x 
The ADA Evaluable Analysis Set includes all patients who received at least 1 dose of 
tislelizumab and for whom both baseline ADA and at least 1 post-baseline ADA results are 
available. Patients from either Phase 1 or 2 are eligible for inclusion in the ADA Evaluable 
Analysis Set. 
Safety Analysis: 
Safety will be determined by the spontaneous reporting of AEs and by laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and ECG findings 
will also be used in determining the safety profile. The severity of AEs will be graded according to the 
CTCAE v5.0. The incidence of DLT events and treatment-emergent adverse events (TEAEs) will be 
reported as the number (percentage) of patients with TEAEs by system organ class (SOC) and 
preferred term. Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n [%] for categorical variables) and changes from baseline will be 
determined for laboratory parameters and vital signs. Safety analyses will be conducted in the Safety 
Analysis Set. 
DLT Analysis:  
DLTs during the DLT assessment window will be used to determine the dose and schedule of 
sitravatinib as monotherapy or in combination with tislelizumab. The DLT events will be summarized 
descriptively by monotherapy and combination dosing level in the DLT Evaluable Analysis Set in dose 
escalation stage. 
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PK Analyses:  
Blood samples for PK analysis of sitravatinib and tislelizumab will be collected at specified time 
points. The actual collection date and time of each blood sample will be recorded. The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points upon sponsor 
approval to ensure thorough PK monitoring.  
All patients enrolled for Phase 1 will provide serial PK samples, and plasma concentrations of 
sitravatinib from these patients will be analyzed using noncompartmental analysis to calculate specified 
PK parameters. For all other sparse samples for sitravatinib, tislelizumab and anti-tislelizumab 
antibody, summary statistics will be provided. 
Efficacy Analysis: 
The efficacy endpoints (ie, ORR, DOR, PFS, and DCR) will be assessed by investigators using 
RECIST v1.1 and will be summarized to evaluate the antitumor activities of sitravatinib as 
monotherapy or in combination with tislelizumab.  
x 
ORR is defined as the proportion of patients who had complete response (CR) or partial 
response (PR) assessed by investigator using RECIST v1.1. ORR, and its 95% confidence 
interval (CI) will be summarized. 
x 
DOR is defined as the time interval between the date of the earliest qualifying response and 
the date of PD or death for any cause (whichever occurs earlier). 
x 
DCR is defined as the proportion of patients with best overall response (BOR) of CR, PR and 
SD (stable disease).  
x 
PFS is defined as the time from the date of the first dose of study drug(s) to the date of the first 
documentation of PD assessed by investigator using RECIST v1.1 or death, whichever occurs 
first.  
x 
OS is defined as the time from date of first dose of study drug(s) to date of death due to any 
cause.  
Descriptive statistics will be used to summarize the efficacy analysis. Exact 95% CI will be calculated 
for the rate variables (ORR and DCR). 
Time-to-event variables DOR, PFS, and OS will be estimated using the Kaplan-Meier (KM) method 
and be plotted over time. Median DOR, PFS, and OS, if possible to estimate, will be presented in each 
arm, along with their 2-sided 95% CIs.  
Waterfall plots of maximum tumor shrinkage per patient will be presented. 
The Efficacy Analysis Set will be the primary analysis set for efficacy analysis.  
Details of statistical analyses will be described in detail in the Statistical Analysis Plan (SAP). 
Sample Size Considerations: 
The study plans to enroll approximately 98 to 116 patients. 
x 
Phase 1 (dose escalation for sitravatinib as monotherapy and in combination with 
tislelizumab): Approximately 18 to 36 DLT evaluable patients with unresectable locally 
advanced or metastatic HCC or G/GEJ cancer will be enrolled.  
x 
Phase 2 (dose expansion for sitravatinib as monotherapy and in combination with 
tislelizumab): Approximately 80 patients will be enrolled in Phase 2 (approximately 
20 patients per cohort). Enrollment into these cohorts will occur simultaneously and 
independent of each other. Each cohort will be evaluated separately. 
 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
BOR 
best overall response 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase cardiac muscle isoenzyme 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
G/GEJ cancer 
gastric/gastroesophageal junction cancer 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
LFT 
liver function testing 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PGx 
pharmacogenetic 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
sVEGFR-2 
soluble vascular endothelial growth factor receptor 2 
TEAE 
treatment-emergent adverse event 
TFT 
thyroid function test 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
VEGFR 
vascular endothelial growth factor receptor 
 
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1. 
INTRODUCTION AND RATIONALES 
1.1. 
Background Information on Advanced Solid Tumors 
1.1.1. 
Hepatocellular Carcinoma  
Liver cancer was the sixth most common type of cancer in 2012, with 782,000 new cases 
worldwide, the fifth most common cancer in men (554,000 cases, 7.5% of the total number of 
7,410,400) and the ninth in women (228,000 cases, 3.4% of the total number of 6,657,500). It 
was also the second most common cause of cancer-related mortality worldwide, according to the 
World Health Organization’s GLOBOCAN 2012 database, responsible for an estimated 
746,000 deaths in 2012 (Ferlay et al 2015). In 2015, there was an estimated 466,100 new liver 
cancer cases and 422,100 liver cancer deaths in China (Chen et al 2016), accounting for 
approximately 50% of the total number of cases and deaths worldwide (Torre et al 2015). In 
2018, it is estimated that there will be 2215 newly diagnosed liver cancer cases in Australia, and 
2088 deaths from liver cancer (AIHW 2017). Hepatocellular carcinoma (HCC) accounts for 80% 
to 90% of primary liver cancer. 
A variety of risk factors are known to cause HCC. These include infection with hepatitis viruses, 
aflatoxin B, tobacco, vinyl chloride, heavy alcohol intake, nonalcoholic fatty liver disease, 
hemochromatosis, and diabetes. Together, hepatitis B virus (HBV) and hepatitis C virus (HCV) 
account for 80% to 90% of all HCC cases worldwide (Bosch et al 2005). Chronic HBV infection 
is the dominant risk factor for the disease in most areas of Asia, with the exception of Japan 
(El-Serag 2012), while chronic infection with HCV is the leading cause of HCC in Western 
countries and in Japan (Choo et al 2016). 
So far, there are only 2 first-line systemic treatments for advanced unresectable HCC approved 
by US Food and Drug Administration (FDA): sorafenib and lenvatinib. Regorafenib has also 
been approved by FDA as the second line of systemic treatment (Bruix et al 2017). However, 
sorafenib is difficult for patients to tolerate. The most common side effects include hypertension, 
hemorrhage, hand-foot skin reaction, diarrhea, sensory neuropathy, weight loss, rash, alopecia, 
anorexia, and pain in abdomen (NEXAVAR prescribing information). Even though lenvatinib 
shows noninferiority to sorafenib, it still has no decrease of adverse events (AEs) rate (Kudo et al 
2018). Nivolumab is the only programmed cell death protein-1 (PD-1) inhibitor approved in US 
as second-line systemic treatment for advanced HCC after treatment with sorafenib (OPDIVO 
prescribing information; El-Khoueiry et al 2017). There were one-third of patients developing 
progressive disease (PD) in nivolumab CheckMate040 trial (El-Khoueiry et al 2017). Oxaliplatin 
in FOLFOX4 chemotherapy is approved in China for unresectable HCC (Chinese hepatocellular 
carcinoma guideline 2017), but more frequent hematological toxicity has been observed, 
including neutropenia, leukopenia, and thrombocytopenia, with especially higher rates in old 
patients (Qin et al 2014; Goldberg et al 2006). 
Due to the unmet medical needs for HCC patients, tolerability issues with currently approved 
treatment options, and the lack of new monotherapy treatment options, combination therapy is 
becoming a major topic in clinical cancer research. Recently 3 studies showed combination 
therapy to have promising activity in HCC. The lenvatinib and pembrolizumab combination 
treatment for unresectable HCC (NCT03006926) showed an objective response rate (ORR) 
including unconfirmed patients of 42.3% in 26 evaluable patients (1/26 complete response [CR], 
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10/26 partial response [PR]) (Ikeda et al 2018). The other combination in HCC, atezolizumab 
and bevacizumab (NCT02715531), presents 65% ORR by independent review facility 
assessment in 23 evaluable patients (1/23 CR, 14/23 PR). The median progression-free survival 
(PFS) and overall survival (OS) have not been reached. The 6-month PFS is 65%. The 6-month 
OS is 86% (Stein et al 2018). No patients developed PD in either of the 2 studies above when the 
data were reported. SHR1210 combination treatment with apatinib showed similar results. Of the 
16 evaluable HCC patients, the ORR was 43.8% (Xu et al 2018). Although the results are 
promising and suggestive of synergistic effects, anti PD-1/programmed cell death protein 
ligand-1 (PD-L1) and multiple kinase inhibitor combination therapy are still under investigation. 
Despite these recent advances in the treatment of HCC, most patients will not show a major 
durable response to approved systemic treatments, including check point inhibition. Progression 
of disease during or after these treatments is common, and little is currently known about optimal 
management of such resistance. Treatment options after prior immunotherapy in HCC remain a 
significant unmet medical need. 
1.1.2. 
Gastric/Gastroesophageal Junction Cancer 
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer 
mortality worldwide. Almost 1 million new cases of stomach cancer were estimated to have 
occurred in 2012 (952,000 cases, 6.8% of the total) according to World Health Organization’s 
GLOBOCAN 2012 database (Ferlay et al 2015). There were 679,100 new diagnosed cases of GC 
and 498,000 deaths in China in 2015 (Chen et al 2016). In 2018, it is estimated that there will be 
2332 newly diagnosed GC cases in Australia, and 1078 deaths from GC (AIHW 2017). 
Patients with newly diagnosed inoperable locally advanced or metastatic disease generally 
receive chemotherapy regimens containing platinum and fluoropyrimidine (Smyth et al 2016; 
NCCN 2017). The duration of first-line chemotherapy typically does not exceed 6 months 
because of PD or due to the toxicities of chemotherapy (Cunningham et al 2008; Van Cutsem et 
al 2006; Hess et al 2016). 
In the second-line setting, the anti-vascular endothelial growth factor receptor 2 (VEGFR-2) 
antibody ramucirumab is an option since it has shown a survival benefit comparable with 
chemotherapy (Fuchs et al 2014; Wilke et al 2014). Apatinib, as monotherapy, is the only 
approved treatment in China. However, according to these study results, monotherapy driven by 
tyrosine kinase inhibitors (TKIs) could not significantly improve patients’ survival (Zhang et al 
2017). More recently, immunotherapy with anti-PD-1 antibodies pembrolizumab and nivolumab 
has resulted in durable remissions for a subset of patients (Le et al 2016; Muro et al 2016). 
Pembrolizumab (Keytruda) has been approved by FDA for the treatment of patients with 
PD-L1–positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or 
more lines of chemotherapy (pembrolizumab label 2014). 
In preclinical models, simultaneous blockade of PD-1 and VEGFR-2 enhanced T cell 
recruitment, activated local immune status, and induced synergistic antitumor effects (Yasuda et 
al 2013). More recent clinical study showed preliminary efficacy results in GC patients treated 
with ramucirumab plus pembrolizumab from a multicohort Phase 1a/b study (NCT02443324). 
For the cohort of  second-line systemic therapy, the ORR was 7% (0/41 CR, 3/41 PR). The 
disease control rate (DCR) was 51%. The median PFS was 2.6 months. The median OS was 
6.2 months. For the cohort of first line, the ORR was 14% (0/28 CR, 4/28 PR), The DCR was 
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64%. The median PFS was 5.6 months. The median OS was not reached when the data was 
reported. (Chau et al 2018, Bendell and Calvo 2018). 
So far, specific application strategies for the combination of anti-PD-1/PD-L1 and TKIs need 
further exploration.  
1.2. 
Sitravatinib as a Receptor Tyrosine Kinase Inhibitor 
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, which bind polypeptide ligands — mainly growth 
factors — play key roles in processes such as cellular 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. 
Sitravatinib 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, 
9(*)59(*)53'*)5Į''575.$DQG75.%6LWUDYDWLQLEWDUJHWVDUHJenetically 
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), providing rationale for combining with PD-1 checkpoint inhibitor 
therapy. Simultaneously to the immunostimulatory effects, sitravatinib may further condition the 
TME in favor of antitumor activity by its immunomodulatory effects mediated through VEGFR 
and KIT inhibition. Preclinical data with sitravatinib indicate that it can increase expression of 
PD-L1 on 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). 
1.2.1. 
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 studies demonstrated that sitravatinib is classified as a highly permeable compound. 
Sitravatinib was more extensively metabolized in dogs than in mice, rats, and humans in vitro. 
In vitro resXOWVIURPWKHK(5*DVVD\GHPRQVWUDWHDQ,&RIȝ0ȝJP/RQWKH
potassium current. At the recommended Phase 2 dose (RP2D) of 150 mg, the mean steady state 
plasma concentrations (adjusted for free fraction) observed in patients are approximately 
290-fold lower than the hERG IC50 concentration. There were no adverse effects on the 
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cardiovascular system, including no effect on the QTc interval, when sitravatinib was 
administered to dogs at doses up to 4 mg/kg (mean 6-KRXUFRQFHQWUDWLRQRIȝJPL). Minor 
increases in blood pressures were observed during the dog cardiovascular study. 
Assessment of the neurological functional observation battery and respiratory evaluations in rats 
did not reveal any sitravatinib-related effects at doses up to 25 mg/kg.  
Please refer to the Sitravatinib Investigator’s Brochure additional details regarding nonclinical 
studies of sitravatinib. 
1.2.2. 
Toxicology 
In repeat-dose toxicity studies in the dog, no target organs were identified, despite overt 
decreases in body weight and food consumption. Daily oral administration of sitravatinib to 
beagle dogs for up to 28 days at a dose level of 3 mg/kg/day was not tolerated and resulted in 
marked body weight loss and anorexia, with 1 female requiring veterinary intervention and 
treatment discontinuation because of general debilitation. Based on the severity of test 
article-related toxicity at 3 mg/kg/day, the no-observed-adverse-effect level (NOAEL) of 
sitravatinib is 1 mg/kg/day.  
In the rat, vascular endothelial growth factor (VEGF)-related target organs were identified, 
including the adrenal gland, Brunner’s glands in the duodenum, femur, and sternum (bone and 
bone marrow), spleen, lymph nodes, thymus, ovary, kidney (glomerulopathy, tubule necrosis, 
increased basophilic tubules), pancreas, and tongue. All effects, except those in the kidney and 
pancreas, either recovered or showed partial recovery. Daily oral administration of sitravatinib to 
Crl:CD (SD) 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 animalVJLYHQ 10 mg/kg/day, the NOAEL is 2.5 mg/kg/day. 
Sitravatinib was evaluated in a standard battery of Good Laboratory Practice (GLP) 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. 
1.2.3. 
Clinical Pharmacology 
The pharmacokinetics (PK) profile of single-agent sitravatinib has been evaluated in 
Study 516-001 after single and repeated dose administration. Plasma samples for PK analyses 
were collected over a 168-hour period following single dose administration and over a 24-hour 
period following repeated dose administration. Plasma drug concentrations were determined 
using a validated, sensitive, liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
assay. The PK of sitravatinib was evaluated using non-compartmental analysis methods. 
After single dose administration, sitravatinib reaches peak concentration in a median time of 
approximately 3 to 8 hours. Exposure parameters (maximum concentration [Cmax] and area under 
the plasma or serum concentration-time curve [AUC]) are approximately dose proportional with 
single doses up to 200 mg. The median elimination half-life varies between approximately 42 
and 58 hours after oral administration. The steady state PK is reached in a mean time of 11 to 
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15 days. Drug accumulation was observed after multiple dose administration and ranged from 
1.8- to 3.5-fold for Cmax and 2.0- to 4.7-fold for AUC0-24. The 150 mg dose was determined to be 
the maximum tolerated dose (MTD) and RP2D; it results in a steady state geometric mean (Cavg), 
Cmax and AUC0-24 of 91.0 ng/mL, 114 ng/mL and 2183 ng·h/mL, respectively. Plasma 
concentrations are overlapping for 120 mg and 150 mg dose levels.  
Pharmacodynamic assessments of sitravatinib are ongoing; however, preliminary analysis shows 
a concentration dependent modulation of VEGF-A, soluble vascular endothelial growth factor 
receptor 2 (sVEGFR-2), and soluble MET ectodomain (sMET) levels in patients’ plasma 
samples. The mean prediction (95% confidence interval [CI]) percent change from baseline in 
biomarker modulation with exposure, approached: VEGF-A (300% increase), sVEGFR-2 
(50% decrease) and sMET (35% increase), consistent with VEGFR and MET inhibition. Mean 
Ctrough at Cycle 1, Day 15 for the 120 mg QD dose level in study MRTX-500 is 68.0 ng/mL. At 
these sitravatinib plasma exposure levels, near optimal modulation of biomarker levels is 
expected.  
Refer to the Sitravatinib Investigator’s Brochure for more detailed information on clinical 
pharmacology of sitravatinib. 
1.2.4. 
Clinical Experience With Sitravatinib 
Sitravatinib monotherapy and sitravatinib in combination with nivolumab are being evaluated in 
ongoing studies. Please refer to the Sitravatinib Investigator’s Brochure and Sitravatinib 
Development Safety Update Report (DSUR) for more detailed information on sitravatinib and 
the currently ongoing studies 
1.2.4.1. 
Study 516-001  
Study 516-001 is a multicenter Phase 1/1b study evaluating the safety, PK, metabolism, PD, and 
clinical activity of sitravatinib in patients with advanced solid tumor malignancies. The study 
determined the 200-mg dose exceeded the MTD and continued to evaluate 150 mg once daily as 
the RP2D for monotherapy. The Phase 1b expansion included patients having tumors with 
selected histological diagnoses and/or molecular markers of solid tumors. As of 26 June 2019, 
among the 186 patients with available safety data, 183 patients (98%) had experienced at least 
one TEAE, and 167 patients (90%) had experienced treatment-related AEs. Treatment-related 
AEVUHSRUWHGLQ 10% of patients are provided in Table 1 . 
Treatment-related Grade 3-5 AEVUHSRUWHGLQ 5% of patients were hypertension (19%), diarrhea 
(10%), fatigue (7%), lipase increased (5%), and palmar-plantar erythrodysesthesia (5%). 
Treatment-related Grade 4 AEs were reported in 3 patients and included lipase increased in 
2 patients (1%) and febrile neutropenia in 1 patient (1%). A treatment-related Grade 5 AE of 
cardiac arrest was reported in 1 patient (1%). 
Table 1 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
 10%) by Preferred Term for Study 516-001 
Adverse Event Term 
Frequency (N=186) 
Diarrhoea 
92 (50%) 
Fatigue 
78 (42%) 
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Adverse Event Term 
Frequency (N=186) 
Hypertension 
73 (39%) 
Nausea 
53 (29%) 
Decreased appetite 
50 (27%) 
Vomiting 
44 (24%) 
Palmar-plantar erythrodysaesthesia syndrome 
37 (20%) 
Alanine aminotransferase increased 
34 (18%) 
Aspartate aminotransferase increased 
34 (18%) 
Hypothyroidism 
31 (17%) 
Stomatitis 
27 (15%) 
Dysphonia 
26 (14%) 
Weight decreased 
26 (14%) 
Abdominal pain 
22 (12%) 
Rash 
21 (11%) 
Constipation 
20 (11%) 
Dry mouth 
20 (11%) 
Lipase increased 
18 (10%) 
Proteinuria 
18 (10%) 
Serious Adverse Events: Among the 186 patients with available safety data, 73 patients (39%) 
had experienced at least one treatment-emergent SAE. Treatment-related SAEs were reported in 
28 patients (15%) and included diarrhea in 6 patients (3%), nausea and vomiting in 5 patients 
each (3%), fatigue in 4 patients (2%), hypertension in 3 patients (2%), and headache, 
pancreatitis, and pulmonary embolism in 2 patients each (1%).  
As of 26 June 2019, 90 deaths were reported in this study, with the primary causes of death being 
the disease under study (n = 61), unknown (n = 17), sepsis (n = 5), respiratory failure (n = 3), and 
aspiration pneumonia, cerebrovascular accident, cardiac arrest, and gastrointestinal (GI) bleed 
(n = 1 each).  
1.2.4.2. 
Study MRTX-500  
Study MRTX-500 is an open-label, parallel Phase 2 evaluation of sitravatinib in the combination 
with the PD-1 inhibitor nivolumab, in patients with locally advanced, unresectable or metastatic 
non-squamous non-small cell lung carcinoma (NSCLC) who have experienced PD either on or 
after prior treatment with a checkpoint inhibitor therapy or after treatment with a platinum-based 
doublet chemotherapy. The study began with a lead-in evaluation of sitravatinib 120 mg once 
daily in combination with nivolumab administered by intravenous infusion, 240 mg every 
2 weeks. No protocol defined dose-limiting toxicities (DLTs) were reported in the first 6 
evaluable patients treated. Based on preliminary long-term tolerability assessments from 
Study 516-001 (Mirati 2018) and data from MRTX-500, Mirati decided to evaluate only the 
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120-mg dose of sitravatinib as this dose level should be adequate to achieve plasma exposure 
required for inhibition of VEGF and TAM receptors necessary to achieve antitumor efficacy in 
the combination setting. The 120-mg dose level was selected as the RP2D.  
As of 26 June 2019, patient data were entered in the clinical trial database for 135 patients 
(63 men/72 women; median age: 66 years; range 37 to 89 years) with advanced or metastatic 
NSCLC. All cohorts have enrolled patients, with 107 patients in the CIT-experienced cohorts 
and 22 patients in the CIT-naïve cohorts. Six patients have enrolled into the PK drug formulation 
substudy. Enrollment is ongoing. 
As of 26 June 2019, among the 135 patients with available safety data, 131 patients (97%) had 
experienced at least one treatment-emergent AE; 126 patients (93%) had experienced 
treatment-related AEs; 125 patients (93%) had experienced sitravatinib-related AEs; and 
91 patients (67%) had experienced nivolumab-related AEs. Treatment-related AEs were reported 
LQ 10% of patients provided in Table 2. 
Treatment-UHODWHG*UDGH$EVUHSRUWHGLQRISDWLHQWVZHUHK\SHUWHQVLRQGLDUUKHD
(11%), and fatigue (7%). Treatment-related Grade 4 AEs were reported in 4 patients and 
included gastric ulcer perforation, hypertensive crisis, lipase increased, and lymphocyte count 
decreased in 1 patient each (1%). A treatment-related Grade 5 AE of cardiac arrest was reported 
in 2 patients (2%). 
Table 2 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
 10%) by Preferred Term for Study MRTX-500 
Adverse Event Term 
Frequency (N=135) 
Diarrhoea 
66 (49%) 
Fatigue 
58 (43%) 
Nausea 
49 (36%) 
Decreased appetite 
45 (33%) 
Weight decreased 
40 (30%) 
Hypertension 
38 (28%) 
Vomiting 
33 (24%) 
Hypothyroidism 
29 (22%) 
Dysphonia 
24 (18%) 
Aspartate aminotransferase increased 
22 (16%) 
Palmar-plantar erythrodysaesthesia syndrome 
22 (16%) 
Stomatitis 
22 (16%) 
Alanine aminotransferase increased 
20 (15%) 
Dehydration 
15 (11%) 
Dry mouth 
13 (10%) 
Dysgeusia 
13 (10%) 
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Serious Adverse Events: Among the 135 patients with available safety data, 60 patients (44%) 
experienced at least one treatment-emergent SAE. Treatment-related SAEs were reported in 
31 patients (23%) and included diarrhea in 5 patients (4%); cardiac arrest, deep vein thrombosis, 
hypertension, pancreatitis, and pneumonitis in 2 patients (2%); and adrenalitis, anemia, cardiac 
failure, colitis, confusional state, dehydration, ejection fraction decreased, embolism, fatigue, 
gastric ulcer perforation, gastritis, hypertensive crisis, hyponatremia, hypothyroidism, hypoxia, 
myocarditis, nausea, palmar-plantar erythrodysesthesia syndrome, pericardial effusion, 
pneumonitis, posterior reversible encephalopathy syndrome, pulmonary embolism, syncope, and 
vomiting in 1 patient each (1%). 
As of 26 June 2019, 57 deaths were reported in this study, with the primary causes of death being 
the disease under study (n=43), unknown (n=4), pneumonia (n=4), ischemic colitis (n=2), and 
aspiration, cardiac arrest, bronchopleural-cutaneous fistula hemorrhage, and pulmonary 
embolism (n=1 each). 
1.2.5. 
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 associated with sitravatinib are 
similar to those observed with other small molecule inhibitors of the VEGFR pathway. 
In Study 516-001, 150 mg once daily was recommended as the RP2D for monotherapy. Based 
on a recent evaluation of the sitravatinib clinical program, it is recommended that the starting 
dose be lowered to 120 mg orally once daily (Mirati 2018). 
In Study MRTX-500, NSCLC patients received sitravatinib 120 mg once daily in combination 
with nivolumab. As recently reported (Mirati 2018), 45 patients have been enrolled in this 
ongoing study as of March 2018 and most AEs reported by investigators were Grade 1 or 2. The 
120-mg dose of sitravatinib is expected to achieve plasma exposure required for inhibition of 
VEGFR and TAM receptors necessary to achieve antitumor efficacy in the combination setting. 
Based on the available data described above, 120 mg once daily is considered safe and is the 
recommended dose in NSCLC patients. Since sitravatinib monotherapy and sitravatinib in 
combination with tislelizumab are being tested for the first time in GC and HCC patients in this 
study, 80 mg once daily is selected as the starting dose. 
1.3. 
Tislelizumab as a PD-1 Blocker 
Immune check point-inhibitory receptor, PD-1 is mainly expressed in activated T cells including 
CD8 + cytotoxic T-lymphocytes and CD4 + T-helper lymphocytes (Topalian et al 2012, 
Bersanelli and Buti 2017). It is believed that PD-1 plays an important role in immune modulation 
of tumor progression by regulating the key inhibitory signaling in the T cells when engaged by 
its ligands. The PD-1 signaling cascade negatively regulates T-cell receptor and attenuate T cell 
proliferation and functional activities, leading to T-cell exhaustion. PD-1 expression is markedly 
up-regulated in tumor-infiltrating lymphocytes, while the expression of PD-1 ligand, PD-L1, is 
significantly increased in tumor cells and tumor-associated immune cells in the presence of 
stimulating cytokines such as IFN-ȖDQG,)1-ĮLQWKHWXPRr microenvironment. Furthermore, the 
increased PD-1 expression in tumor-infiltrating lymphocytes and/or PD-L1 expression in tumor 
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and tumor-associated stromal cells is observed in many types of solid human tumors including, 
but not limited to, melanoma, squamous cell carcinoma, uveal melanoma, NSCLC, head and 
neck squamous cell carcinoma , triple-negative breast cancer, renal cell carcinoma, bladder 
cancer, and ovarian cancer (Jin and Yoon 2016, ONO 2017, Patel and Kurzrock 2015, Van Der 
Kraak et al 2016, McDaniel 2016, Gong et al 2011, Liu et al 2017, Saito et al 2013). Several 
anti-PD-1 agents have been approved for the treatment of several cancers. Thus, PD-1 is an 
established target for cancer immunotherapy. 
1.3.1. 
Pharmacology 
Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against 
PD-1 under clinical development for the treatment of several human malignancies.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD]=0.15 nM). It competitively blocks binding 
efforts by both PD-L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting 
PD-1-mediated negative signaling in T cells. In in vitro cell-based assays, tislelizumab was 
observed to consistently and dose-dependently enhance the functional activity of human T cells 
and preactivated, primary peripheral blood mononuclear cells. In addition, tislelizumab has 
demonstrated antitumor activity in several allogeneic xenograft models, in which peripheral 
blood mononuclear cells were coinjected with human cancer cells (A431 [epidermoid 
carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into immunocompromised mice.  
The IgG4 variant antibody has very low binding affinity to gamma fragment crystallizable region 
)FUHFHSWRU,,,$)FȖ5,,,$DQGcomplement 1q, a subunit of complement 1, by in vitro assays, 
suggesting either low or no antibody-dependent cellular cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC) effects in humans (Labrijn et al 2009). 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.3.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and monkeys and in a 13-week, repeat-dose toxicology study in monkeys. The 
tissue cross-reactivity was evaluated in the normal frozen tissues from both humans and 
monkeys. The cytokine release assays were also evaluated using fresh human whole blood cells. 
The pivotal toxicology studies were conducted following GLP regulations. The single-dosing 
regimens spanned from the intended human doses to 10-fold higher than the maximum of the 
intended human doses, and the repeat-dosing regimens spanned to 3-fold higher than the 
maximum of the intended human doses. Cynomolgus monkey was the only relevant species 
based on the target sequence homology and binding activity  
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in human whole-blood assay. The toxicokinetics profile was well characterized, 
with dose proportional increases in systemic exposure without apparent accumulation or sex 
difference. Immunogenicity was observed without apparent immunotoxicity or effect on the 
systemic exposure. The NOAEL of tislelizumab in the 13-week monkey toxicity study was 
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considered to be 30 mg/kg. The safety profile of tislelizumab is considered adequate to support 
the current study of BGB-900-104.  
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.3.3. 
Clinical Pharmacology 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim PK analysis (data 
cutoff date 28 August 2017) was conducted using noncompartmental methods, using serum 
concentrations from patients who received doses of 0.5, 2.0, 5.0, or 10 mg/kg once every 
2 weeks, and 2.0 mg/kg, 5.0 mg/kg, or 200 mg once every 3 weeks (Phase 1a Parts 1, 2, and 3, 
and Phase 1b in Study BGB-A317_Study_001) and patients who received doses of 200 mg once 
every 3 weeks in Phase 1 of Study BGB-A317-102 (n = 19). Cmax and AUC increased in a nearly 
dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both after single-dose administration and 
at steady state. Preliminary PK data from 27 patients who were administered 200 mg once every 
3 weeks (Phase 1a, Part 3 and Study BGB-A317-102) showed tislelizumab concentrations 
between the range of concentrations observed for patients who were administered 2 mg/kg and 
5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first-order elimination 
shows a systemic clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution (Vd) in 
the central and peripheral compartments of 2.89 and 1.76 L, respectively, and half-life (t1/2) was 
approximately 19 days. Race, gender, and body weight were not significant covariates on the CL 
of tislelizumab, which supports fixed-dosing across different ethnic groups. 
1.3.4. 
Clinical Experience With Tislelizumab 
As of 20 May 2019, there are 22 ongoing studies with tislelizumab with over 1705 patients 
treated. Of these, 13 studies have preliminary data available in the Tislelizumab Investigator’s 
Brochure: 7 monotherapy studies, 2 chemotherapy combination therapy studies, and 
4 investigational agent combination therapy studies. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
safety and efficacy data of tislelizumab when given as monotherapy or in combination with 
chemotherapy. 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies 
A pooled analysis of 7 monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy. Overall, there were 1273 patients in the Pooled 
Monotherapy studies: 1137 patients treated in 5 solid tumor studies and 136 patients treated in 
2 hematologic malignancies studies. Of the 1273 enrolled, 544 patients (42.7%) remained on 
study as of 20 May 2019; 272 patients (21.4%) were still receiving tislelizumab treatment. 
1.3.4.1.1. Pooled Demographics and Baseline Characteristics 
Table 3 shows the demographics and baseline characteristics for the patients treated in the 
Pooled Monotherapy studies. 
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Table 3 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies (Safety Analysis 
Set) 
Measure 
Overall 
N = 1273 
Age (years) 
 
   Median 
59.0 
   Min, Max 
18, 90 
Sex, n (%) 
 
   Male 
852 (66.9) 
   Female 
421 (33.1) 
Race, n (%) 
 
   Asian 
807 (63.4) 
   Black 
11 (0.9) 
   White 
405 (31.8) 
   Missing 
2 (0.2) 
   Other 
48 (3.8) 
Prior systemic anticancer therapy regimens a 
 
   Median 
1.0 
   Min, Max 
0, 12 
Prior systemic anticancer therapy regimens (grouped)a, n (%) 
   0 
271 (21.3) 
   1 
413 (32.4) 
   2 
265 (20.8) 
    
324 (25.5) 
Study treatment exposure duration (months) 
 
   Median 
3.58 
   Min, Max 
0.1, 43.6 
Study follow-up duration (months) 
 
   Median 
8.34 
   Min, Max 
0.1, 47.5 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: N, total number of patients treated; n, number of patients within each category. 
Data cutoff 20 May 2019. 
a Only systemic therapies were selected. 
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Overall, the 1273 patients in the pooled monotherapy analysis had a median treatment exposure 
duration of 3.58 months (range: 0.1 to 43.6) and median study follow-up duration of 8.34 months 
(range: 0.1 to 47.5). Overall, the total pooled monotherapy population had a median age of 
59 years and was 66.9% male. 
1.3.4.1.2. Treatment-Emergent Adverse Events Assessed as Related to Treatment 
Of the 1273 total patients treated in the Pooled Monotherapy studies, 846 (66.5%) experienced at 
least one treatment-related TEAE. The most commonly occurring TEAEs assessed as related to 
tislelizumab were aspartate aminotransferase increased (128 patients, 10.1%), alanine 
aminotransferase increased (123 patients, 9.7%), hypothyroidism (113 patients, 8.9%), rash 
(96 patients, 7.5%), and pyrexia (94 patients, 7.4%). 
Of the 1273 total patients treated in the Pooled Monotherapy studies, 162 (12.7%) experienced at 
OHDVWRQH *UDGH7($(DVVHVVHGDVUHODWHGWRWLVOHOL]XPDE7KHRQO\ Grade 3 TEAEs that 
RFFXUUHGLQ  12 patients) in the total study population were aspartate aminotransferase 
increased (19 patients, 1.5%) and alanine aminotransferase increased (15 patients, 1.2%). 
1.3.4.1.3. Treatment-Emergent Serious Adverse Events 
Of the 1273 total patients treated in the Pooled Monotherapy studies, 424 (33.3%) experienced at 
least one treatment-emergent SAE. The most commonly occurring treatment-emergent SAEs 
were pneumonia (35 patients, 2.7%), pyrexia (22 patients, 1.7%), and ascites (17 patients, 1.3%). 
1.3.4.1.4. Special Categories of Immune-Related Adverse Events 
Immune-related AEs are of special interest in tislelizumab studies because treatment with 
anti-PD-1 therapy can cause autoimmune disorders. As AEs of special interest, irAEs are 
monitored and captured consistently and rapidly. 
Immune-related AEs are consistent with an immune-related mechanism or immune-related 
component for which non-inflammatory etiologies (eg, infection or tumor progression) have 
been ruled out. Immune-related AEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. There is a potential temporal relationship 
between the initiation of treatment with tislelizumab and onset of an irAE that spans a window of 
days to several months. 
All irAEs presented here are assessed as related to study drug by the investigator and categorized 
by the BeiGene Safety/Pharmacovigilance team. Certain irAEs have multiple Medical Dictionary 
for Regulatory Activities (MedDRA) terms associated with the same category. Special categories 
have been created to group patients experiencing these events. 
All irAEs that occurred LQ 1% in the total Pooled Monotherapy studies are shown in Table 4. 
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Table 4 
Immune-5HODWHG$GYHUVH(YHQWVRI$Q\*UDGH2FFXUULQJLQ 1% in Pooled 
Monotherapy Studies (Safety Analysis Set) 
Categories 
   Preferred Term 
Total 
(N = 1273) 
Any Grade 
n (%) a 
Grade  3 
n (%) a 
Patients with at least one potential immune-related AE a 
602 (47.3) 
121 (9.5) 
Immune-related skin adverse reaction 
242 (19.0) 
11 (0.9) 
Rash 
97 (7.6) 
4 (0.3) 
Pruritus 
78 (6.1) 
0 
Pruritus generalised 
29 (2.3) 
0 
Rash maculo-papular 
24 (1.9) 
1 (0.1) 
Immune-related hepatitis 
233 (18.3) 
51 (4.0) 
Aspartate aminotransferase increased 
129 (10.1) 
21 (1.6) 
Alanine aminotransferase increased 
124 (9.7) 
16 (1.3) 
Blood bilirubin increased 
74 (5.8) 
4 (0.3) 
Gamma-glutamyltransferase increased 
45 (3.5) 
17 (1.3) 
Bilirubin conjugated increased 
40 (3.1) 
3 (0.2) 
Immune-related endocrinopathies 
187 (14.7) 
7 (0.5) 
Hypothyroidism 
113 (8.9) 
0 
Hyperthyroidism 
47 (3.7) 
1 (0.1) 
Hyperglycaemia 
17 (1.3) 
4 (0.3) 
Immune-related colitis 
75 (5.9) 
10 (0.8) 
Diarrhoea 
66 (5.2) 
5 (0.4) 
Immune-related pneumonitis 
50 (3.9) 
30 (2.4) 
Pneumonitis 
22 (1.7) 
9 (0.7) 
Lung infection 
13 (1.0) 
8 (0.6) 
Immune-related myositis/rhabdomyolysis/cardiomyopathy 
39 (3.1) 
7 (0.5) 
Blood creatine phosphokinase increased 
30 (2.4) 
4 (0.3) 
Immune-related nephritis and renal dysfunction 
33 (2.6) 
6 (0.5) 
Blood creatinine increased 
25 (2.0) 
2 (0.2) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: AE, adverse event; N, total number of patients treated; n, number of patients within each category; 
NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PT, preferred term; 
SOC, system organ class. 
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Note: All AEs are coded using MedDRA and graded according to NCI CTCAE v4.03. Maximum CTCAE grade was 
selected per patient under each PT. Potential immune-related AE is identified based on a predefined list of AEs and 
assessed as treatment-related by investigators. 
Sorted in descending order of the number of patients in SOC and PT in Any Grade under Total column. 
Data cutoff 20 May 2019. 
a Percentages are based on the total population. 
Of the 1273 total patients for the Pooled Monotherapy studies, 602 (47.3%) experienced at least 
one irAE of any grade. The most commonly occurring irAEs of any grade were aspartate 
aminotransferase increased (129 patients, 10.1%), alanine aminotransferase increased 
(124 patients, 9.7%), hypothyroidism (113 patients, 8.9%), rash (97 patients, 7.6%), and pruritus 
(78 patients, 6.1%). Analysis of the WRWDOSDWLHQWVZLWKDWOHDVWRQHLU$(WKDWDOVRZDV Grade 3 
in severity showed that 121 patients (9.5%) experienced such events. The most commonly 
RFFXUULQJLU$(V Grade 3 in severity were aspartate aminotransferase increased (21 patients, 
1.6%), gamma-glutamyltransferase increased (17 patients, 1.3%), alanine aminotransferase 
increased (16 patients, 1.3%), pneumonitis and pneumonia (9 patients each, 0.7%). 
1.3.4.1.5. Infusion-Related Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
tislelizumab are uncommon. Of the 1273 total patients in the Pooled Monotherapy studies, 
97 (7.6%) experienced at least one infusion-related reaction of any grade. The most commonly 
occurring infusion-related reactions of any grade that occurred in the total pooled analysis were 
pyrexia (50 patients, 3.9%), infusion-related reactions (28 patients, 2.2%), and pruritus 
(11 SDWLHQWV7KHUHZHUHSDWLHQWVZKRUHSRUWHGDWRWDORI Grade 3 infusion-related 
reactions in the Pooled Monotherapy studies (events of back pain, hypotension, infusion-related 
reaction, musculoskeletal chest pain, pyrexia, and rash). 
1.3.4.1.6. Fatal Adverse Events 
Treatment-emergent fatal AEs that occurred in the Pooled Monotherapy studies are shown in 
Table 5. 
Table 5 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in Pooled 
Monotherapy Studies (Safety Analysis Set) 
Category 
Overall 
(N = 1273) 
n (%) 
All deaths at data cutoff 
641 (50.4) 
'HDWK 30 days after last dose 
105 (8.2) 
Primary cause of death 
 
  Adverse event 
21 (1.6) 
  Concurrent illness 
0 
  Disease under study 
22 (1.7) 
  Indeterminate 
0 
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Category 
Overall 
(N = 1273) 
n (%) 
  Progressive disease 
52 (4.1) 
  Other 
10 (0.8) 
Death > 30 days after last dose 
536 (42.1) 
Primary cause of death 
 
  Adverse event 
14 (1.1) 
  Concurrent illness 
0 
  Disease under study 
95 (7.5) 
  Indeterminate 
3 (0.2) 
  Progressive disease 
399 (31.3) 
  Other 
24 (1.9) 
  Missing 
1 (0.1) 
Source: Tislelizumab Investigator’s Brochure. 
Abbreviations: N, total number of patients treated; n, number of patients within each category. 
Data cutoff 20 May 2019. 
Table 5 VKRZVDWRWDORISDWLHQWVRIWKHWRWDOSRSXODWLRQGLHGGD\VDIWHUWKHODVW
study drug dose in the Pooled Monotherapy studies as of 20 May 2019. Of these 105 patients, 
there were 21 patients (1.6% of the total population) who had an AE with a fatal outcome 
 30 days after the last study drug dose. Of the 536 patients (42.1% of the total population) who 
died > 30 days after the last study drug dose, 14 patients (1.1% of the total population) died as a 
result of an AE. 
1.3.4.2. 
Efficacy Assessment of Tislelizumab 
Efficacy data are available from 2 of the ongoing monotherapy studies in solid tumors, 
BGB-A317_Study_001 and BGB-A317-102, which are summarized below (data cutoff 
20 May 2019). 
1.3.4.2.1. Study BGB-A317_Study_001 
BGB-A317_Study_001 is a 2-stage study. Phase 1a consists of a dose escalation and 
dose-finding component, Phase 1b investigates efficacy and safety in select tumor types. 
Responses were assessed by the investigator per the RECIST v1.1 criteria. There were 
451 patients treated in the study and 441 patients were included in the efficacy evaluable set. The 
Efficacy Evaluable Analysis Set includes all treated patients who had at least 1 measurable 
baseline target lesion and had at least 1 evaluable postbaseline tumor assessment.  
Across all disease cohorts, there were 5 patients (1.1%) with a CR. A total of 55 patients (12.5%) 
had a confirmed PR. The resulting overall clinical response rate was 13.6%. Additionally, there 
were 142 patients (32.2%) with a best overall response of stable disease (SD). A total of 
199 patients (45.1%) had a best response of PD in this study.  
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1.3.4.2.2. Study BGB-A317-102 
Study BGB-A317-102 is a two-phase, non-randomized, Phase 1/2 study of tislelizumab 
monotherapy in Chinese patients with advanced solid tumors. Phase 1 includes a dose 
verification substudy and a substudy of PK evaluation of the products derived from 
2 manufacturing processes and scales. Phase 2 is an indication expansion study. 
Responses were assessed by the investigator per the RECIST v1.1 criteria. 
Overall, of the 300 patients treated in Study BGB-A317-102, 249 patients were included in the 
Efficacy Evaluable Analysis Set. The Efficacy Evaluable Analysis Set includes all treated 
patients who had at least 1 measurable baseline target lesion and had at least 1 evaluable 
postbaseline tumor assessment.  
The tumor responses in the Efficacy Evaluable Analysis Set of Study BGB-A317-102 across all 
disease cohorts and study phases was 1 patient (0.4%) with a CR and 44 patients (17.7%) with 
confirmed PR. The resulting overall clinical response rate was 18.1%. Additionally, there were 
91 patients (36.5%) with a best overall response of SD. A total of 113 patients (45.4%) had a 
best response of PD in this study. 
1.3.5. 
Rationale for Selection of Tislelizumab Dose 
The PK, safety, and efficacy data obtained from the first-in-human study 
BGB-A317_Study_001, as well as other clinical study data, were analyzed in aggregate to 
determine the recommended dose for pivotal studies of tislelizumab. The flat dose of 200 mg 
intravenously (IV) once every 3 weeks was selected for further evaluation. The MTD was not 
identified and only 1 DLT was reported in the first-in-human study. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear 
dose-dependence across these regimens. Similarly, confirmed ORRs in patients treated with 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared 
to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender, and the observed serum exposure of a 
200-mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose 
range with comparable safety and efficacy rates).  
No unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n = 13), 3 patients (23%) had a BOR of PR, 4 patients (31%) had a 
BOR of SD, and 6 patients (46%) had a BOR of PD. Therefore, clinical activity with a 
manageable and tolerable safety profile is expected to be maintained in patients receiving 
tislelizumab 200 mg once every 3 weeks. 
Tislelizumab 200 mg once every 3 weeks is the recommended initial dose for combination with 
sitravatinib.  
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1.4. 
Rationale for Combination of Sitravatinib and Tislelizumab in the 
Treatment of Advanced Solid Tumors 
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 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 therapeutic 
challenges that need to be overcome (Syn et al 2017). 
Combining an immunotherapeutic PD-1 checkpoint inhibitor with an agent that has both immune 
modulatory and antitumor properties could enhance the antitumor efficacy observed with either 
agent alone. The use of TKIs to treat cancer is well established based on robust clinical efficacy 
achieved with well tolerated inhibitors directed toward oncogenic tyrosine kinases. In addition, 
selected TKIs 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.  
Monoclonal antibodies that target either PD-1 or PD-L1, checkpoint inhibitors, can block 
binding and boost the immune response against cancer cells. These drugs have been shown to be 
helpful in treating several types of cancer, including melanoma of the skin, non-small cell lung 
cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. Cancer 
cells in most nonresponders to single-agent checkpoint inhibitors escape through innate 
mechanisms that allow the cancer cells to grow and survive. As a result, disease progresses at a 
rate consistent with the natural history. However, unlike intrinsic resistance, late relapses are 
now emerging in patients with prior clinical benefit after longer follow-up of clinical trials, 
suggesting the emergence of acquired resistance (Jenkins et al 2018). Strategies to improve the 
clinical efficacy of checkpoint inhibitors by overcoming innate or acquired resistance are needed. 
Together, sitravatinib and tislelizumab may elicit greater antitumor activity, as sitravatinib is 
predicted to enhance several steps in the cancer immunity cycle that may augment the efficacy of 
tislelizumab. 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 tumor microenvironment 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 interleukin (IL)-12, IL-6, and tumor necrosis 
factor (TNF). 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.  
Combination therapy with agents that target the molecular and cellular mechanisms of resistance 
to checkpoint inhibitor therapy is a rational approach to improving outcomes in patients. In 
summary, selective RTKs inhibit key molecular and cellular pathways strongly implicated in 
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checkpoint inhibitor resistance and therefore represent reasonable strategies to enhance or restore 
antitumor immunity when combined with anti-PD-1 or anti-PD-L1 monoclonal antibodies. 
1.5. 
Benefit-Risk Assessment 
Sitravatinib is being evaluated as monotherapy in the ongoing study 516-001 (NCT02219711). 
In a cohort for clear cell renal cell carcinoma, sitravatinib showed clinical activity with 
4 confirmed PRs in a heavily pretreated patient population (n=20), suggesting that sitravatinib 
may be able to overcome resistance to prior antiangiogenic therapy with VEGF pathway 
inhibitors. 
Combination therapy with a small molecule inhibitor of the VEGFR pathway may improve the 
clinical efficacy of immunotherapies and overcome resistance to checkpoint inhibitor therapy 
(refer to Section 1.2.4.2). For patients with HCC and GC, combination therapy may improve the 
clinical efficacy of single-agent immunotherapies (Section 1.1.1 and Section 1.1.2). Access to 
new treatment options and/or treatment options after prior immunotherapy remain a significant 
unmet medical need. Based on available tislelizumab and sitravatinib data and the publication 
from other PD-1 or PD-L1 inhibitors and other small molecule inhibitors of the VEGFR 
pathway, the combination of sitravatinib and tislelizumab may elicit greater antitumor activity 
and have a manageable safety profile. However, the risk benefit for this combination has not yet 
been established. 
More than 100 patients have been treated with sitravatinib monotherapy and in combination. 
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 of the VEGFR pathway. For further discussion on the safety profile of 
sitravatinib, please refer to the Sitravatinib Investigator’s Brochure. 
More than 1000 patients have been treated with tislelizumab monotherapy at clinically relevant 
GRVHV mg/kg) and in combination. The safety profile is consistent with known class effects 
of anti-PD-1 antibodies and included mostly mild/moderate AEs. Very few Grade 3 or Grade 4 
irAEs have been observed, which are generally reversible and manageable with study drug 
interruption and/or steroid treatment. For further discussion on the safety profile of tislelizumab, 
please refer to the Tislelizumab Investigator’s Brochure. 
A SMC will be established and will monitor the preliminary safety and activity data for 
sitravatinib monotherapy and in combination with tislelizumab in this study. The SMC will be 
tasked with reviewing all available safety, tolerability, PK, and exploratory data and make 
recommendations on safety management.  
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives for Phase 1 (Dose Escalation) 
2.1.1. 
Primary Objectives 
x To assess the safety and tolerability of sitravatinib as monotherapy and in 
combination with tislelizumab 
x To confirm the RP2D for sitravatinib as monotherapy and in combination with 
tislelizumab 
2.1.2. 
Secondary Objectives 
x To characterize the PK profiles of sitravatinib after single dose and at steady state as 
monotherapy and in combination with tislelizumab 
x To assess the preliminary antitumor activity of sitravatinib as monotherapy and in 
combination with tislelizumab in HCC or gastric/gastroesophageal junction (G/GEJ) 
cancer patients  
2.1.3. 
Exploratory Objectives 
x To explore potential biomarkers in association with efficacy, resistance, and/or PD in 
tumor tissue and in peripheral whole blood 
x To explore potential pharmacodynamic biomarkers for sitravatinib as monotherapy 
and in combination with tislelizumab  
x To assess PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib 
x To explore the effect of pharmacogenetic (PGx) polymorphisms on PK of sitravatinib 
2.2. 
Study Objectives for Phase 2 (Dose Expansion) 
2.2.1. 
Primary Objective 
x To assess the preliminary antitumor activity as indicated by ORR per Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of sitravatinib as 
monotherapy and in combination with tislelizumab 
2.2.2. 
Secondary Objectives 
x To assess the preliminary antitumor activity as indicated by duration of response 
(DOR), DCR and PFS per RECIST v1.1 as monotherapy and in combination with 
tislelizumab 
x To characterize the safety and tolerability of sitravatinib as monotherapy and in 
combination with tislelizumab  
x To characterize the PK profile of sitravatinib 
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2.2.3. 
Exploratory Objectives 
x To assess potential biomarkers in association with efficacy, resistance, and/or PD in 
tumor tissue and in peripheral whole blood 
x To explore potential pharmacodynamic biomarkers for sitravatinib as monotherapy 
and in combination with tislelizumab 
x To assess PK and immunogenicity to tislelizumab when given in combination with 
sitravatinib  
x To assess overall survival (OS) 
x To explore the effect of pharmacogenetic (PGx) polymorphisms on PK of sitravatinib 
2.3. 
Study Endpoints for Phase 1 (Dose Escalation) 
2.3.1. 
Primary Endpoints 
x Safety and tolerability will be assessed throughout the study by monitoring AEs and 
SAEs per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) v5.0, relevant physical examination, electrocardiograms 
(ECGs), and laboratory assessments as needed 
2.3.2. 
Secondary Endpoints 
x Plasma concentrations and the derived PK parameters of sitravatinib if data permit: 
o Single dose: Cmax, time to maximum plasma concentration (Tmax), AUC(0-t), 
clearance after oral administration (CL/F) 
o Repeating dose: Cmax, CĲ, Tmax, AUC(0-Ĳ, CL/F, accumulation ratio (Ro) 
x Efficacy evaluations by investigators: ORR, DOR, DCR, and PFS based on 
RECIST v1.1 
2.3.3. 
Exploratory Endpoints 
x Potential biomarkers, including, but not limited to, programmed cell death protein 
ligand-1 (PD-L1) expression, immune cell profiling, tumor mutation load, and gene 
expression profiling in archival and/or fresh tumor tissue and blood (or blood 
derivatives) obtained before, during, or after treatment or at PD; and the association 
with disease status and/or the response to sitravatinib as monotherapy or in 
combination with tislelizumab 
x Changes of potential pharmacodynamic biomarkers in response to sitravatinib as 
monotherapy and in combination with tislelizumab, such as, but not limited to, 
soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) and immune cell 
subpopulations in peripheral blood  
x Serum concentrations of tislelizumab and anti-tislelizumab antibodies 
x Effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, 
including, but not limited to, CYP1A2, 2D6, and 2C8 on the PK of sitravatinib 
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2.4. 
Study Endpoints for Phase 2 (Dose Expansion) 
2.4.1. 
Primary Endpoint 
x Efficacy evaluations by investigators: ORR based on RECIST v1.1 
2.4.2. 
Secondary Endpoints 
x Efficacy evaluations by investigators: DOR, DCR, and PFS based on RECIST v1.1 
x Safety and tolerability will be assessed throughout the study by monitoring AEs and 
SAEs per NCI-CTCAE v5.0, relevant physical examination, ECGs, and laboratory 
assessments as needed 
x PK: plasma concentrations of sitravatinib predose and postdose at steady state 
2.4.3. 
Exploratory Endpoints 
x Potential biomarkers, including, but not limited to, PD-L1expression, immune cell 
profiling, tumor mutation load, and gene expression profiling in archival and/or fresh 
tumor tissue and blood (or blood derives) obtained before, during, or after treatment 
or at PD; and the association with disease status and/or response to sitravatinib as 
monotherapy or in combination with tislelizumab 
x Changes of potential pharmacodynamic biomarkers in response to sitravatinib as 
monotherapy and in combination with tislelizumab, such as, but not limited to, 
sVEGFR-2 and immune cell subpopulations in peripheral blood  
x Serum concentrations of tislelizumab and anti-tislelizumab antibodies  
x OS is defined as the time from date of first dose of study drug(s) to date of death due 
to any cause 
x Effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, 
including, but not limited to, CYP1A2, 2D6, and 2C8 on the PK of sitravatinib 
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design  
This is an open-label, multicenter Phase 1/2 clinical study for patients with histologically or 
cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer. All 
patients will receive study treatment(s) until PD, unacceptable toxicity, death, withdrawal of 
consent, or study termination by sponsor. There will be approximately 20 centers in Asia Pacific 
including Australia and China. 
This study consists of 2 phases. 
3.1.1. 
Phase 1 (Dose Escalation for Sitravatinib as Monotherapy and in Combination 
With Tislelizumab) 
Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be 
evaluated in patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. A 
modified 3 + 3 design will be used in the dose escalation. Approximately 6 to 12 DLT evaluable 
patients will be treated with sitravatinib as monotherapy.  
The combination dose escalation of sitravatinib (80 mg once daily and 120 mg once daily; 
modified 3 + 3 design) with tislelizumab (200 mg once every 3 weeks, in both cohorts) will be 
evaluated in patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. 
The combination dose escalation may start simultaneously with the monotherapy cohort as the 
dose regimen for all cohorts are considered safe based on the totality of available clinical data. 
There is no interaction anticipated between sitravatinib and tislelizumab to influence respective 
PK profiles. If the combination dose of 80 mg sitravatinib and 200 mg tislelizumab has been 
declared tolerable, the dose of sitravatinib will be escalated to 120 mg and tislelizumab will 
remain fixed at 200 mg. Approximately 12 to 24 DLT evaluable patients will be treated.  
DLT Observation Period and the Modified 3 + 3 Scheme 
For Phase 1 dose escalation, a 21-day DLT assessment window will be utilized for initial dose 
confirmation recommendations. DLTs will be assessed among evaluable patients within 21 days 
after the first dose of study drug(s). For dose escalation decisions, only DLTs occurring within 
21 days will be evaluated. 
Dose escalation in sitravatinib monotherapy or sitravatinib in combination with tislelizumab will 
occur in accordance with the following modified 3 + 3 dose escalation rules. 
A minimum of 3 DLT evaluable patients will be initially enrolled per cohort. 
x If none of the first 3 evaluable patients enrolled in a given cohort experience a DLT, 
dose escalation may proceed. 
x If one of the first 3 evaluable patients enrolled in a given cohort experiences a DLT, 
additional patients (for a minimum of 6 evaluable patients) will be enrolled in that 
cohort.  
 If less than one-third of evaluable patients in a given cohort experiences a DLT 
(eg, DLTs in fewer than two of 6 evaluable patients), escalation will proceed to 
the next higher dose level. 
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If a DLT is observed in at least one-third or more of evaluable patients (eg, two or more of up to 
6 evaluable patients), the dose escalation will be stopped. A lower dose level or an intermediate 
dose level may be evaluated if recommended by the SMC. 
The SMC will confirm RP2D of the monotherapy and combination treatment based on all 
available safety, efficacy, PK and exploratory data. Additional dose levels may be evaluated if 
needed. For the sitravatinib combination therapy, RP2Ds for each tumor type will be 
recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
3.1.2. 
Phase 2 (Dose Expansion for Sitravatinib as Monotherapy and in Combination 
With Tislelizumab) 
Approximately 20 patients will be enrolled in each cohort. There will be a total of 4 cohorts in 
the study (Figure 1). 
Sitravatinib monotherapy 
x Cohort A: Anti-PD-1/PD-L1 antibody naïve or refractory/resistant HCC 
Sitravatinib in combination with tislelizumab 
x Cohort B: Anti-PD-1/PD-L1 antibody naïve HCC 
x Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant HCC 
x Cohort D: Anti-PD-1/PD-L1 antibody naïve G/GEJ cancer 
Sitravatinib will be administered orally, once daily continuously, tislelizumab will be 
administered sequentially starting on Cycle 1 Day 1 and every 21 days (ie, once every 3 weeks) 
thereafter. The study drug(s) will be administered until they meet a discontinuation criterion. 
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Figure 1: 
Study Schema 
 
Abbreviations: Ab, antibody; G/GEJ, gastric/gastroesophageal junction, HCC, hepatocellular carcinoma; PD-1, 
programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; PK, pharmacokinetic; QD, once a 
day; Q3W, once every 3 weeks; RP2D, recommended Phase 2 dose; R/R, refractory or resistant, Sitra, sitravatinib; 
SMC, Safety Monitoring Committee; Tisle, tislelizumab. 
Note: The combination dose escalation may start simultaneously with the monotherapy cohort. The SMC will 
confirm RP2D of the monotherapy and combination treatment based on all available safety, efficacy, PK and 
exploratory data. Additional dose levels may be evaluated if needed. For the sitravatinib combination therapy, 
RP2Ds for each tumor type will be recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
3.2. 
Screening Period 
Screening evaluations will be performed within 28 days prior to the first dose of study drug(s). 
Patients who agree to participate will sign the informed consent form (ICF) prior to undergoing 
any screening procedure. Patients who are suspected or known to have serious respiratory 
concurrent condition or exhibit significant respiratory symptoms unrelated to underlying cancer 
will have a pulmonary function test (refer to Appendix 1 for details). Repeating screening 
assessments within the original screening window is allowed if the patient did not previously 
meet certain eligibility criteria (eg, when a patient narrowly misses a laboratory criterion and it is 
correctable and not due to rapidly deteriorating condition or PD) after consultation with the 
medical monitor; the investigator is to assess patient eligibility according to the latest screening 
assessment results. Refer to Section 7.1 for additional details. 
3.3. 
Treatment Period 
After completing all screening activities, patients confirmed to be eligible by the sponsor or 
designee will be enrolled to receive either sitravatinib monotherapy or sitravatinib in 
combination with tislelizumab. The patients will be enrolled according to their tumor type and by 
prior anti-PD-1/PD-L1 treatment. All patients will receive study drug(s) until occurrence of PD, 
unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. 
Study procedures of each clinic visit are outlined in Appendix 1 and Appendix 2. 
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On days with PK assessments, study drug(s) should be administered in the clinic in accordance 
with the schedule for the PK samples. Assessments should be obtained before study drug(s) 
administration unless stated otherwise in Appendix 1 and Appendix 2 and should be performed 
in order of least invasive to most invasive assessment. All safety-related assessments must be 
reviewed and dose modifications, if necessary, must be made by the investigator or 
subinvestigator before study drug(s) administration. 
3.4. 
End-of-Treatment Visit and Safety Follow-up Phone Calls 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
EOT Visit within 30 days after last dose of the study drug(s) or before initiation of a new 
anticancer treatment, whichever occurs first. If routine laboratory tests (eg, hematology, clinical 
chemistry) were performed  7 days before the EOT Visit, these tests do not need to be repeated. 
A tumor assessment is not required at the EOT Visit if  6 weeks have passed since the last 
assessment. If the study drug(s) were initially interrupted due to AEs and then permanently 
discontinued, the EOT Visit may occur later, but no later than the permitted time of dose delay 
plus 7 days. 
See Appendix 1 for assessments to be performed for the EOT Visit. 
Telephone contact with patients should be conducted to assess irAEs and concomitant 
medications (if appropriate; eg, if associated with an irAE or is a new anticancer therapy) at 
60 days and 90 days (± 14 days) after the last dose of tislelizumab regardless of whether or not 
the patient starts a new anticancer therapy. If patient reports a suspected irAE at a telephone 
follow-up contact, the investigator should arrange an unscheduled visit if further assessment is 
indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
Patients who discontinue study treatment prior to PD will have their tumors assessed as outlined 
in Section 7.4. 
3.5. 
Survival Follow-up 
In Phase 2 (dose expansion), patients will be followed for survival and further anticancer therapy 
information after discontinuation of study treatment via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months (± 14 days) after the EOT Visit until death, 
loss to follow-up, withdrawal of consent, or study completion by the sponsor. 
3.6. 
Discontinuation From Study Treatment or From the Study 
3.6.1. 
Patient Discontinuation From Study Treatment 
Patients have the right to discontinue study treatment at any time for any reason. Patients who 
discontinue study treatment for reasons other than PD, should be followed for assessments of 
antitumor activity (Section 7.4), safety (Section 7.3) and survival (Section 3.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons which include, but are not limited to, the following:  
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x Patient withdrawal of consent 
x Pregnancy 
x 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 
x Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicines] for the treatment of cancer) 
x Patient noncompliance 
x PD 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) 
Patients may discontinue study for reasons which include, but are not limited to, the following:  
x Patient withdrawal of consent 
x Death 
x Lost to follow up  
x Patients have completed all study assessments 
x Sponsor termination of study 
3.7. 
End of Study 
The end of study is defined as the date when the last patient’s last visit (LPLV) occurs or the date 
at which the last data point required for statistical analysis or safety follow-up is collected for the 
last patient, whichever occurs later. 
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:  
x The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients  
x Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
The sponsor has the right to close a site at any time. The decision will be notified to the site in 
advance. Reasons for closing a site may include, but are not limited, to the following:  
x Excessively slow recruitment  
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x Poor protocol adherence  
x Inaccurate or incomplete data recording  
x Noncompliance with Good Clinical Practice (GCP), applicable laws, and regulations 
x Study activity is completed (ie, all patients have completed and all obligations have 
been fulfilled) 
3.8. 
Dose-Limiting Toxicities 
3.8.1. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the 
first dose of study drug(s). For dose escalation decision, only DLTs occurring within 21 days 
will be evaluated. The following patients will not be considered evaluable for DLT, and will be 
replaced if needed to meet the minimum patient number required for dose escalation: 
x Patients who withdraw or are withdrawn from the study before completing the DLT 
assessment window for reasons other than a DLT. 
x 3DWLHQWVUHFHLYLQJPRQRWKHUDS\ZKRGRQRWUHFHLYH 75% of scheduled sitravatinib 
during the DLT assessment window, unless they experience a DLT. 
x 3DWLHQWVUHFHLYLQJFRPELQDWLRQWKHUDS\ZKRGRQRWUHFHLYH 75% of scheduled 
VLWUDYDWLQLEDQG 67% (approximately two-thirds) of scheduled tislelizumab during 
the DLT assessment window, unless they experience a DLT. 
3.8.2. 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any of the following toxicities occurring during the DLT assessment 
window and considered by the investigator to be related to sitravatinib and/or tislelizumab. 
Hematologic 
x Grade 4 neutropenia lasting > 3 days 
x  Grade 3 febrile neutropenia 
x Grade 3 thrombocytopenia with clinically significant bleeding 
x Grade 4 thrombocytopenia 
x  Grade 4 anemia 
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Non-Hematologic 
x  Grade 4 toxicity 
x Grade 3 toxicity that is clinically significant and does not improve WR Grade 2 
within 3 days of initiating optimal supportive care 
Note: The following AEs will not be considered DLTs: 
 Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
 Grade 3 hypertension that improves to < 160/100 mmHg, within 7 days of 
optimal supportive care 
 Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), 
will be reviewed with input from other functional representatives as appropriate. On the basis of 
a review of these data and in consultation with the investigators, a determination will be made 
regarding dose confirmation decisions and/or safety management.  
SMC will be established and includes both the sponsor and investigators. The SMC will review 
all available safety, efficacy, PK, and exploratory data. Additional dose levels may be evaluated 
if needed. For the sitravatinib combination therapy, RP2Ds for each tumor type will be 
recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
4.1.1. 
Inclusion Criteria for All Patients 
Each patient eligible to participate in this study must meet all the following criteria: 
1. 
Able to provide written informed consent and can understand and agree to comply with the 
requirements of the study and the schedule of assessments 
2. 
$JH 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. 
To provide archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] block with 
tumor tissue or unstained slides)  
Note: If archival tumor tissue is not available or of sufficient quantity, a fresh biopsy is 
recommended. Patients who cannot provide archival tumor tissue or biopsy samples are 
eligible for the study if other enrollment criteria are satisfied. 
x Tumor tissue needs to originate from core or punch biopsy. 
x Tumor tissue from fine-needle aspiration is not acceptable. 
4. 
Eastern Cooperative Oncology Group (ECOG) 3HUIRUPDQFH6WDWXV 1 (Appendix 4) 
5. 
Adequate organ function as indicated by the IROORZLQJODERUDWRU\YDOXHV 7 days before the 
first dose of study drug(s): 
a. Patients must not have required a blood or platelet transfusion or growth factor 
VXSSRUW 14 days before sample collection at Screening for the following 
i. 
$1& 1.5 x 109/L 
ii. 
PlatelHWV 75 x 109/L 
iii. 
+HPRJORELQ 90 g/L 
b. 6HUXPFUHDWLQLQH 1.5 x upper limit of normal (ULN), or estimated glomerular 
ILOWUDWLRQUDWH*)5 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (Appendix 9) 
c. $67DQG$/7 3 x ULN for patients with G/GEJ cancer. AST DQG$/7 5 x ULN 
for patients with HCC 
d. 6HUXPWRWDOELOLUXELQ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome), total bilirubin < 5 x ULN for patients with HCC and 
cirrhosis 
e. ,QWHUQDWLRQDOQRUPDOL]HGUDWLR,15 1.5 or pURWKURPELQWLPH37 1.5 x ULN 
f. $FWLYDWHGSDUWLDOWKURPERSODVWLQWLPHD377 1.5 x ULN 
g. 6HUXPDOEXPLQ 30 g/L 
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6. 
Females of childbearing potential must be willing to use a highly effective method of birth 
control (Appendix 7IRUWKHGXUDWLRQRIWKHVWXG\DQG 120 days after the last dose of 
VWXG\GUXJVDQGKDYHDQHJDWLYHVHUXPSUHJQDQF\WHVW 7 days of first dose of study 
drug(s) 
7. 
Nonsterile males must be willing to use a highly effective method of birth control 
(Appendix 7IRUWKHGXUDWLRQRIWKHVWXG\DQGIRU 120 days after the last dose of study 
drug(s) 
4.1.2. 
Phase 1 Inclusion Criteria 
8. 
Failed current standard-of-care treatment, or standard-of-care treatment is considered not 
appropriate at present 
For HCC patients 
9. 
Histologically or cytologically confirmed, unresectable, locally advanced, or metastatic 
HCC 
Note: Fibrolamellar, sarcomatoid, or mixed cholangiocarcinoma histology is excluded 
10. Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease 
(Appendix 13) that is not amenable to or has progressed after loco-regional therapy and is 
not amenable to a curative treatment approach 
11. Child-Pugh A classification for liver function (Appendix 5) assessed within 7 days of first 
dose of study drug(s) 
12. No tumor thrombus involving main trunk of portal vein or inferior vena cava 
13. No loco-regional therapy to the liver (ie, transarterial chemoembolization [TACE], 
transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, or 
ablation) within 28 days before the first dose of study drug(s) 
14. 1RSULRUKLVWRU\RI*UDGH 2 hepatic encephalopathy before the first dose of study drug(s) 
15. No clinical evidence of portal hypertension with bleeding esophageal or gastric varices 
within 6 months before the first dose of study drug(s) 
For G/GEJ cancer patients 
16. Histologically or cytologically proven adenocarcinoma of the stomach or gastroesophageal 
junction, inoperable locally advanced or with metastatic disease 
17. No history of gastrointestinal (GI) perforation and/or fistulae within 6 months before the 
first dose of study drug(s) 
18. No clinically significant GI bleeding within 3 months before the first dose of study drug(s) 
19. No clinically significant bowel obstruction 
20. No complete gastric resection  
21. 1RZHLJKWORVVof total body weight within 2 months before the first dose of study 
drug(s) 
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4.1.3. 
Phase 2 Inclusion Criteria 
22. At least 1 measurable lesion as defined by RECIST v1.1 
Note: Selected target lesion(s) must meet 1 of 2 criteria: 1) not previously treated with local 
therapy or 2) within the field of prior local therapy but with documented subsequent 
progression as per RECIST v1.1 
Cohorts A, B, and C: HCC 
23. Histologically or cytologically confirmed unresectable locally advanced or metastatic HCC 
Note: Fibrolamellar, sarcomatoid, or mixed cholangiocarcinoma histology is excluded 
24. Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease 
(Appendix 13) that is not amenable to or has progressed after loco-regional therapy and is 
not amenable to a curative treatment approach 
25. Child-Pugh A classification for liver function (Appendix 5) assessed within 7 days of first 
dose of study drug(s) 
26. No tumor thrombus involving main trunk of portal vein or inferior vena cava 
27. No loco-regional therapy to the liver (ie, transarterial chemoembolization [TACE], 
transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, or 
ablation) within 28 days before the first dose of study drug(s) 
28. 1RSULRUKLVWRU\RI*UDGHKHSDWLFHQFHSKDORpathy before the first dose of study drug(s) 
29. No clinical evidence of portal hypertension with bleeding esophageal or gastric varices 
within 6 months before the first dose of study drug(s) 
Cohort A: Anti-PD-1/PD-L1 Antibody Naïve or Refractory/Resistant HCC  
30. Failed current standard-of-care treatment, or standard-of-care treatment is considered not 
appropriate at present 
31. 5HFHLYHG 2 lines of systemic treatment 
Cohort B: Anti-PD-1/PD-L1 Antibody Naïve HCC 
32. Failed current standard-of-care treatment, or standard-of-care treatment is considered not 
appropriate at present 
33. No other prior immunotherapies, including but not limited to, anti-PD-1/PD-L1, 
anti-CTLA-4, anti-OX40, and anti-CD137 
34. 5HFHLYHG 2 lines of systemic treatment 
Cohort C: Anti-PD-1/PD-L1 Antibody Refractory/Resistant (R/R) HCC 
35. 5HFHLYHG 2 lines of systemic treatment 
36. Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1 therapy as the 
most recent treatment for unresectable locally advanced or metastatic HCC 
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x Anti-PD-1/PD-L1 antibody refractory is defined as radiographic progression on or 
after anti-PD-1/PD-L1 therapy with best response to anti-PD-1/PD-L1 of PD or SD 
IRU 6 weeks (+ 2 weeks permitted for radiographic scheduling) 
x Anti-PD-1/PD-L1 antibody resistant is defined as best response to anti-PD-1/PD-L1 
therapy of CR or PR or SD lasting for > 6 weeks (+ 2 weeks permitted for 
radiographic scheduling) 
37. No other prior immunotherapies, including but not limited to, anti-CTLA-4, anti-OX40, and 
anti-CD137  
38. No unacceptable toxicity from prior anti-PD-1/PD-L1 treatment, defined as: 
x *UDGH$(UHODWHGWRDQWL-PD-1/PD-L1 treatment 
x *UDGH2 irAE associated with anti-PD-1/PD-L1 unless the AE resolved or was well 
controlled by withholding anti-PD-1/PD-L1 and/or treatment with steroids, with the 
exception of prior colitis, encephalitis, myocarditis, hepatitis, uveitis, and 
pneumonitis, which are exclusionary 
x Central nervous system (CNS) or ocular AE of any grade related to anti-PD-1/PD-L1 
Note: Patients with a prior endocrine AE are allowed if they are stably maintained on 
appropriate replacement therapy and are asymptomatic 
Cohort D: Anti-PD-1/PD-L1 Antibody Naïve G/GEJ Cancer 
39. Failed current standard-of-care treatment, or standard-of-care treatment is considered not 
appropriate at present 
40. Histologically or cytologically proven adenocarcinoma of the stomach or gastroesophageal 
junction, inoperable locally advanced or with metastatic disease 
41. Radiographic progression per RECIST v1.1 on or after systemic treatment for unresectable 
locally advanced or metastatic G/GEJ cancer 
42. No prior immunotherapies, including but not limited to, anti-PD-1/PD-L1, anti-CTLA-4, 
anti-OX40, and anti-CD137  
43. No history of gastrointestinal (GI) perforation and/or fistulae within 6 months before the 
first dose of study drug(s) 
44. No clinically significant GI bleeding within 3 months before the first dose of study drug(s) 
45. No clinically significant bowel obstruction 
46. No complete gastric resection 
47. 1RZHLJKWORVVof total body weight within 2 months before the first dose of study 
drug(s) 
4.2. 
Exclusion Criteria for all Patients 
Patients who meet any of the following criteria are not eligible to enroll: 
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1. 
Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal 
findings or with confirmed brain metastases are eligible for enrollment provided that they 
are asymptomatic and radiologically stable without the need for therapy such as radiation, 
surgery or corticosteroid therapy to control symptoms from brain metastases for  28 days 
before first dose of study drug(s). 
2. 
Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 6) 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening:  
a. Controlled Type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors  
3. 
$Q\DFWLYHPDOLJQDQF\ 2 years before the first dose of study drug(s) except for 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) 
4. 
Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednLVRQHRUHTXLYDOHQWRURWKHULPPXQRVXSSUHVVLYHPHGLFDWLRQ 14 days before the first 
dose of study drug(s) 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dosH 10 mg daily of prednisone or equivalent)  
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. 6KRUWFRXUVH 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) 
5. 
Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
calcium despite standard medical management, or *UDGH K\SRDOEXPLQHPLD 14 days 
before the first dose of study drug(s) 
6. 
History of interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases 
including pulmonary fibrosis, acute lung diseases, etc 
7. 
Severe chronic or active infections (including tuberculosis infection, etc) requiring systemic 
antibacterial, antifungal, or antiviral therapy within 14 days prior to first dose of study 
drug(s). Note: antiviral therapy is permitted for patients with viral hepatitis 
8. 
Known history of human immunodeficiency virus (HIV) infection 
9. 
Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV 
DNA > 500 IU/mL or active HCV carriers with detectable HCV RNA. Note: Inactive 
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hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA 
< 500 IU/mL) can be enrolled 
10. $Q\PDMRUVXUJLFDOSURFHGXUHUHTXLULQJJHQHUDODQHVWKHVLD 28 days before the first dose of 
study drug(s) 
11. Prior allogeneic stem cell transplantation or organ transplantation 
12. Any of the following cardiovascular criteria  
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
GDLO\OLYLQJ 28 days before the first dose of study drug(s) 
b. 6\PSWRPDWLFSXOPRQDU\HPEROLVP 28 days before the first dose of study drug(s) 
c. $Q\KLVWRU\RIDFXWHP\RFDUGLDOLQIDUFWLRQ 6 months before the first dose of study 
drug(s) 
d. Any history of heart failure meeting New York Heart Association Classification 
(NYHA) III or IV (Appendix 8 6 months before the first dose of study drug(s) 
e. $Q\HYHQWRIYHQWULFXODUDUUK\WKPLD*UDGHLQVHYHULW\ 6 months before the first 
dose of study drug(s) 
f. Any histor\RIFHUHEURYDVFXODUDFFLGHQW 6 months before the first dose of study 
drug(s) 
g. QT corrected (QTc) interval (corrected by Fridericia’s method) > 450 msec  
Note: If QTc interval is > 450 msec on initial ECG, a follow up ECG will be 
performed to exclude result 
h. Current left ventricular ejection fraction (LVEF) < institutional LLN as assessed by 
echocardiography (ECHO). The same modality used at baseline must be applied for 
subsequent evaluations 
i. $Q\HSLVRGHRIV\QFRSHRUVHL]XUH 28 days before the first dose of study drug(s)  
13. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg)  
14. Hypersensitivity to tislelizumab or sitravatinib, to any ingredient in the formulation, or to 
any component of the container 
15. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents 
requiring therapeutic INR monitoring within 6 months before the first dose of study drug(s) 
16. Any systemic chemotherapy within 28 days of the first dose of study drug(s) or 
immunotherapy (eg, interleukin, interferon, thymoxin, etc.), hormone therapy, targeted 
therapy, or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) 
of first dose of study drugs  
17. Any Chinese herbal or Chinese patent medicine with anticancer activity approved by the 
China National Medical Product Administration (NMPA) (regardless of the type of cancer) 
used within 14 days before the first administration of study drug(s)  
18. 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) 
19. $GPLQLVWUDWLRQRIOLYHYDFFLQH 28 days before the first dose of study drug(s) 
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Note: seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed 
20. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse 
or dependence that will be unfavorable for the administration of study drug(s) or affect the 
explanation of drug toxicity or AEs or result in insufficient or might impair compliance with 
study conduct 
21. Concurrent participation in another clinical study, unless it is an observation 
(non-interventional) clinical study or during the follow-up period of an interventional study. 
Prior randomization in a tislelizumab study regardless of the treatment arm, until the 
primary and key secondary endpoints of the study have read out 
22. Inability to swallow capsules or disease significantly affecting gastrointestinal function such 
as malabsorption syndrome, resection of the complete stomach or small bowel, bariatric 
surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction 
23. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage 
or medical intervention (clinically significant recurrence requiring an additional intervention 
within 2 weeks of intervention; cytological confirmation of any effusion permitted) within 
7 days before first dose of study drug(s) 
24. Pregnant or breastfeeding woman 
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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling 
5.1.1. 
Sitravatinib 
Sitravatinib will be provided as 10 mg and 40 mg unit dose strength capsules. 
Sitravatinib drug product is packaged in 30-count, high-density polyethylene (HDPE), opaque 
white, round 60 cc bottles. A tamper proof heat induction seal and a child resistant closure are 
used. The provided bottles may be labeled for specific patient use and given to the patient if the 
capsule count is the needed number. The contents of the label will be in accordance with all 
applicable local regulatory requirements. 
The bottles of sitravatinib must be stored in labeled carton at refrigerated conditions (2oC to 8oC) 
in the study site Pharmacy. Once dispensed to patients, the bottles will be removed from the 
carton and can be stored at room temperature as specified on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
Please also refer to the Sitravatinib Investigator’s Brochure for other details regarding 
sitravatinib. 
5.1.2. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab has been aseptically filled in single-use vials with a 
Flurotec-coated butyl rubber stopper and an aluminum cap. Each vial is packaged into a single 
carton box. The contents of the label will be in accordance with all applicable local regulatory 
requirements. 
Tislelizumab must be stored at temperatures between 2oC and 8oC and protected from light as 
specified on the label. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the Tislelizumab Investigator’s Brochure for other details 
regarding tislelizumab. 
5.2. 
Dosage and Administration 
On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of 
sitravatinib should precede tislelizumab infusion. 
5.2.1. 
Sitravatinib 
In Phase 1, sitravatinib capsules will be administered orally, once daily, in a continuous regimen 
in 21-day cycles. The starting dose for sitravatinib in escalation evaluation will be 80 mg once 
daily. Depending on safety observations, the sitravatinib dose in the subsequent cohort of 
patients may be escalated to 120 mg once daily. 
In Phase 2, SMC will confirm RP2D of the monotherapy and combination treatment dosing of 
sitravatinib, which can be withheld for up to approximately 28 days consecutively.  
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The following guidelines should be followed for sitravatinib administration: 
x Dosing in the morning is preferred. 
x Capsules should be taken in the fasted state, at least 2 hours after the previous meal 
and 1 hour before the next meal. For once daily dosing, capsules should be taken 
during the morning hours, for instance, at least 1 hour before breakfast or lunch. 
x Capsules should be taken with at least 200 mL (1 cup) of water. 
x Patients should swallow the capsules whole and not chew them. 
x If vomiting occurs after dosing, sitravatinib doses should not be replaced.  
x If a patient forgets to take sitravatinib for more than 12 hours, he/she should skip the 
dose and resume taking the drug the next day. 
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 and administration are provided in the 
Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a  30-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion. Tislelizumab must not be concurrently administered with any 
other drug (refer to Section 6). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of irAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 10. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or appropriately delegated study personnel 
at each patient visit and information provided by the patient. Patients enrolled in the study will 
be provided with patient diaries. The patient is responsible for maintaining the patient diary and 
will record the number of capsules of sitravatinib taken and if any were missed. The site 
personnel responsible for drug accountability will record the quantity of drug dispensed and 
quantity of drug received after the cycle visit. The patient diaries and the pharmacist record of 
drug will be assessed by the investigator/study personnel at each visit. 
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The study drugs required for completion of this study (sitravatinib and tislelizumab) will be 
provided by the sponsor, as required by local or country-specific guidance. The investigational 
site will acknowledge receipt of study drugs. Any damaged shipments will be replaced.  
Accurate records of all study drugs received, dispensed, returned, and disposed should be 
recorded on the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of study 
drug(s) management. 
5.4. 
Overdose 
5.4.1. 
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. 
5.4.2. 
Tislelizumab 
$Q\RYHUGRVHRIWLVOHOL]XPDEGHILQHGDV 600 mg in a 24-hour period) or incorrect 
administration of tislelizumab 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. 
5.5. 
Modification and Dose Delay 
5.5.1. 
Dose Modification 
There will be no dose reductions for tislelizumab in this study. Dose reductions for sitravatinib 
are presented in Table 6. Once the dose has been reduced, re-escalation is generally not 
recommended but may be considered on a case-by-case basis. 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. Criteria for treatment modifications and suggested guidelines for the 
management of some toxicities related to sitravatinib are presented in Section 8.8. 
Table 6: 
Sitravatinib Dose Reductions 
Starting Dose 
80 mg once daily 
120 mg once daily 
Dose Level -1 
60 mg once daily 
80 mg once daily 
Dose Level -2 
40 mg once daily 
60 mg once dailya 
a Dose reduction below 60 mg once daily may be undertaken after discussion with the sponsor. 
If one study drug is interrupted or discontinued, administration of the other study drug may 
continue at the discretion of the investigator. 
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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 Delay 
Every effort should be made to administer the study drugs according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided. Reasons for dose modifications or delays, the supportive measures 
taken, and the outcome will be documented in the patient's chart and recorded in the eCRF. 
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 
soon as possible after the AEs recover to baseline or Grade 1 (whichever is more severe) and 
within 4 weeks for sitravatinib or 12 weeks for tislelizumab after last dose of the respective study 
drug. Sitravatinib should be resumed at a reduced dose level as outlined in Table 6. 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. 
The following dose delays or interruptions will be permitted: 
x Sitravatinib can be interrupted for up to approximately 28 consecutive days. If 
WUHDWPHQWZLWKVLWUDYDWLQLELVGHOD\HGIRU 14 days, then resumption at a reduced 
GRVHVKRXOGEHFRQVLGHUHG,IGUXJLVSODQQHGWREHLQWHUUXSWHG 28 days, the medical 
monitor should be contacted before permanent patient discontinuation from the study 
drug. 
x Tislelizumab can be delayed or interrupted for up to 12 weeks. If a dose is delayed for 
 10 days for a planned dosing cycle (eg, Cycle 3, Day 1), tislelizumab should be 
administered (on the same day with sitravatinib, if applicable) and all assessments 
should be conducted according to the original cycle (ie, Cycle 3). If the delay 
is > 10 days, the patient should skip the tislelizumab, and tislelizumab will be 
administered on Day 1 of the next planned cycle (ie, Cycle 4, Day 1). 
The tumor assessment schedule will not be altered even if the administration of study drug(s) is 
delayed. 
If the patient is unable to resume sitravatinib or tislelizumab within the permitted timeframe after 
the last dose of study drug(s), then the patient should be discontinued from the study drug(s). 
Dose modification related to irAEs and infusion-related reactions for tislelizumab are described 
in Appendix 10 and Section 8.7, respectively. 
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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Concomitant Therapy 
6.1.1. 
Permitted Concomitant Medications/Procedures 
Most concomitant medications and therapies deemed necessary in keeping with the local 
standards of medical care at the discretion of the investigator for supportive care (eg, antiemetics, 
antidiarrheals) and in a patient’s interest are allowed.  
Proton pump inhibitors and H2 antagonists should be avoided during treatment on study but are 
not exclusionary. Switching from use of proton pump inhibitors or H2 antagonists to use of 
antacids is preferred. Use of antacids should be avoided 4 hours before and 2 hours after 
administration of investigational study treatment. 
Systemic corticosteroids given for the control of irAEs must be tapered gradually (see 
Appendix 10DQGEHDWQRQLPPXQRVXSSUHVVLYHGRVHV 10 mg/day of prednisone or equivalent) 
before the next administration of study drug(s). The short-term use of steroids as prophylactic 
treatment (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted.  
Patients with active hepatitis B, defined as either detectable HBsAg or HBV DNA at baseline, 
must initiate treatment 2 weeks prior to first dose of study drug(s) and continue until 6 months 
after the last dose of study drug(s). Patients should continue effective antiviral treatment during 
the study to decrease potential viral re-activation risk. Tenofovir and entecavir are recommended 
in the American Association for the Study of Liver Disease (AASLD) guideline because they 
lack resistance with long-term use (Terrault et al 2016; AASLD/IDSA HCV Guidance Panel, 
2015). The investigator might use other antiviral agents, if appropriate, following local 
guidelines. Management of antiviral therapy is at the discretion of the Investigator; however, 
reason(s) must be provided in the CRF if a patient with active hepatitis B is not treated with 
antiviral prophylaxis. 
Palliative (limited-field) radiation therapy is permitted for pain control or prophylaxis of bone 
fracture to sites of bone disease present at baseline. The lesion being considered for palliative 
radiation should not be a target lesion for RECIST v1.1. The case should be discussed with the 
medical monitor; the therapy will be used if the medical monitor agrees that the conditions 
required to receive palliative radiation are met. Additionally, palliative radiation or other focally 
ablative therapy for other nontarget sites of the disease is permitted if clinically indicated per 
investigators’ discretion and after consultation with the medical monitor. Whenever possible, 
these patients should undergo a tumor assessment of the lesion(s) before receiving the 
radiotherapy in order to rule out PD. 
6.1.2. 
Prohibited Concomitant Medications/Procedures 
The following medications are prohibited during the study: 
x Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicine] for the treatment of cancer) is not allowed. 
Chinese herbal and Chinese patent medicines with anticancer activity are defined as 
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medication with approval by the China NMPA for use as anticancer treatment 
(regardless of the type of cancer). 
x Live vaccines within 28 days before first dose of study drug(s) and 60 days following 
the last dose of study drug(s). 
x Anticoagulants such as warfarin or similar agents requiring therapeutic INR 
monitoring. 
6.1.3. 
Restricted Concomitant Medications/Procedures 
The following medications are restricted during the study: 
x Immunosuppressive agents (except to treat a drug-related AE). 
x 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. 
x Patients should avoid alcohol completely and should avoid other addictive drugs 
during the study. 
x Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored. 
x Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.1.1.  
x Herbal remedies are not recommended for use during the study treatment. Patients 
must notify the investigators of all herbal remedies used during the study. 
x Opiates and other medication required for palliative management of patients are 
allowed. Patients must notify the investigator of all concurrent medications used 
during the study. 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications 
Sitravatinib was not considered as a high-risk compound as a victim drug-drug interaction (DDI) 
because multiple enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, and 3A4, are 
involved in its metabolism. 
Based on the in vitro CYP inhibition/induction assay results, high plasma protein binding and 
lesVWKDQȝ0SRWHQF\VLWUDYDWLQLESHUSHWUDWRUULVNDWSURMHFWHGFOLQLFDOGRVHDQGH[SRVXUH
levels are considered to be low. 
Per the International Council for Harmonisation (ICH) E14 guidance, it is recommended to avoid 
medications with potential to prolong QT/QTc or cause torsades de pointes. Please refer to 
Appendix 12 for a list of medications or substances to be avoided or used with caution during 
treatment with sitravatinib. 
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Potential Interaction Between Sitravatinib and 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 therapeutic administered orally. Like most therapeutic proteins, tislelizumab is 
not expected to be metabolized by CYP or other drug-metabolizing enzymes and is unlikely to 
have an effect on CYPs or other metabolizing enzymes in terms of inhibition or induction. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
The study-specific assessments and procedures with allowed time windows are outlined 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. 
All assessments will be performed on the day of the specified visit unless an acceptable time 
window is specified. Assessments scheduled on the day of study treatment administration 
(Day 1) of each cycle should be performed prior to study treatment unless otherwise noted. 
Laboratory results are required to be reviewed prior to dosing. Dosing will occur only if the 
clinical assessment and local laboratory test values (that must be available before any dosing) 
have been reviewed and found to be acceptable per protocol guidelines.  
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date, with subsequent visits 
conducted according to the planned schedule every 3 weeks from Cycle 1 Day 1. 
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to the first dose of study drug(s). 
Patients who agree to participate will sign the ICF prior to undergoing any screening procedure. 
The Screening period begins on the first day a screening procedure is conducted. Patients who 
are suspected or known to have serious respiratory concurrent illness or exhibit significant 
respiratory symptoms unrelated to underlying cancer should take a pulmonary function test (refer 
to Appendix 1 for details). Screening evaluations may be repeated as needed within the 
Screening period; the investigator is to assess patient eligibility according to the latest screening 
assessment results.  
Results of standard-of-care tests or examinations performed prior to obtaining informed consent 
DQG 28 days prior to the first dose of study drug(s) may be used for the purposes of screening 
rather than repeating the standard-of-care tests unless otherwise indicated. 
Procedures conducted during the Screening Visit only are described in this section. For the 
description of other assessments that are conducted during Screening, as well as throughout the 
study, refer to Safety Assessments (Section 7.3), Tumor and Response Evaluations (Section 7.4), 
and Biomarkers (Section 7.7) sections. The PK sampling schedule is shown in Appendix 2. 
Rescreening under limited conditions may be allowed after consultation with BeiGene, eg, when 
a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or progressive disease. Rescreening is allowed only once. 
7.1.1. 
Demographics and Medical History 
Demographic data will include gender, date of birth (or age), and race/ethnicity. 
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before the first dose of study drug. 
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Cancer history will include an assessment of prior surgery, prior radiotherapy, and prior drug 
therapy, including start and stop dates, best response, and reason for discontinuation. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator. 
Archival tumor tissues (if available) will be collected for biomarker analysis. In addition to 
archival tumor tissues, a fresh tumor biopsy at baseline is recommended. Refer to Section 7.7 for 
details. 
7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 7 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential”  
7.1.3. 
Informed Consent and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. 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 the first dose of study drug(s). The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
7.1.4. 
Pulmonary Function Tests 
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit 
significant respiratory symptoms unrelated to the underlying cancer will undergo pulmonary 
function testing, which may include, but is not limited to, spirometry and assessment of diffusion 
capacity done during the Screening period to assist the determination of suitability on the study. 
7.2. 
Enrollment 
The investigator will assess, and the sponsor or designee will confirm the eligibility of each 
patient. All screening procedure results and relevant medical history must be available before 
eligibility can be determined. All inclusion criteria must be met and none of the exclusion criteria 
may apply. No eligibility waivers will be granted.  
After a patient is screened and the investigator determines the patient is eligible for enrollment, 
study site personnel will complete an Eligibility Authorization Packet and send it to the medical 
monitor or designee to approve the enrollment. Study site personnel should ensure that a medical 
monitor’s confirmation has been received before the study drug(s) administration. 
7.3. 
Safety Assessments 
7.3.1. 
Vital Signs 
9LWDOVLJQVZLOOLQFOXGHPHDVXUHPHQWVRIWHPSHUDWXUHÛ&SXOVHUDWHDQGEORRGSUHVVXUH 
(systolic and diastolic) after resting for 10 minutes. 
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7.3.2. 
Physical Examinations 
At Screening and EOT Visit, a complete physical examination will be conducted including an 
evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) 
musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during Screening will be graded according to NCI-CTCAE v 5.0 and 
recorded on the eCRF with appropriate disease/condition terms.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations will be performed. Changes from baseline will be recorded. New or worsened 
clinically significant abnormalities are to be recorded as AEs on the Adverse Event eCRF. Refer 
to Section 8.3 regarding AE definitions and reporting and follow-up requirements. 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (refer to Appendix 4) will be assessed during the study. 
7.3.4. 
Laboratory Safety Test 
Local laboratory assessments of hematology, clinical chemistry, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Appendix 1.  
If laboratory tests at Screening are not performed within 7 days before administration of study 
drug(s) on Cycle 1 Day 1, these tests (hematology, clinical chemistry, and urinalysis) should be 
repeated and reviewed before study drug(s) administration. In Phase 1, hematology and clinical 
chemistry, as specified in Appendix 3, should be performed weekly for the first 2 cycles. For all 
patients in Phase 1 and Phase 2, hematology, clinical chemistry, and urinalysis should be 
performed at the beginning of each cycle and at the EOT Visit. After Cycle 1, laboratory safety 
tests should be performed, and the results should be reviewed within 48 hours before study 
drug(s) administration. For creatine kinase (CK) and creatine kinase cardiac muscle isoenzyme 
(CK-MB) tests and coagulation tests, refer to Appendix 3. 
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. 
In addition, the following tests will be conducted in this study:  
x Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) must be performed and documented as negative within 
7 days prior to first administration of study drug(s). Urine or serum pregnancy tests 
will be performed during treatment before study drug(s) administration at each cycle 
and the EOT Visit. A serum pregnancy test must be performed if the urine pregnancy 
test is positive or equivocal. A negative pregnancy test (by urine or blood) must be 
completed and recorded before administration of study drug(s) at each cycle. 
x Thyroid function tests (TFTs) (thyroid-stimulating hormone [TSH], free T3, free T4) 
will be performed at Screening, every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc) and 
the EOT Visit. The test does not need to be repeated at the EOT Visit within 63 days 
after last test. 
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x CK and CK-MB testing will be performed for all patients receiving tislelizumab as 
part of clinical chemistry (see Appendix 3). Troponin I and/or T may be performed if 
the local laboratory does not provide CK-MB analysis. If tislelizumab has been 
permanently discontinued, CK and CK-MB testing is no longer required. Patients 
with a history of cardiological disease receiving sitravatinib monotherapy, either in 
Cohort A or after discontinuation of tislelizumab, may receive CK and CK-MB 
testing if clinically indicated. 
7.3.5. 
Hepatitis B and C Testing 
Testing will be performed by the local laboratory at Screening and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], 
and HCV antibody) and viral load assessment (HBV DNA and HCV RNA).  
Patients who have detectable HBV DNA at Screening will receive a viral load test every 4 cycles 
and at the EOT Visit. 
7.3.6. 
Electrocardiograms 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's study file at the 
site.  
When coinciding with blood draws, ECG assessment should be performed prior to blood draws. 
Patients should rest in semirecumbent supine position for at least 10 minutes prior to ECG 
collection (refer to Appendix 1). 
7.3.7. 
Multigated Acquisition Scans or Echocardiograms 
Evaluations of cardiac function will be performed at Screening and every 12 weeks during 
treatment. For study purposes, evaluation by multigated acquisition (MUGA) scan is preferred. 
Evaluation by echocardiogram is an acceptable alternative if necessary. The method used for 
individual patients should be consistent throughout study participation.  
7.3.8. 
Adverse Events 
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0 
(NCI-CTCAE 2017). 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. 
Tumor and Response Evaluations 
Tumor imaging will be performed within 28 days prior to the first dose of study drug(s). Results 
of standard-of-care tests or examinations performed prior to obtaining informed consent and 
 28 days prior to the first dose of study drug(s) may be used for the purposes of screening rather 
than repeating the standard-of-care tests. During the study, tumor imaging will be performed 
approximately every 6 weeks (± 7 days) in the first year and thereafter approximately every 
9 weeks (± 7 days).  
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Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral/intravenous contrast, unless contraindicated) or contrast-enhanced 
magnetic resonance imaging (MRI), with preference for CT, of the chest, abdomen, and pelvis. 
Other known or suspected sites of disease must be included in the imaging assessments (neck, 
brain, etc). 
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). All known sites of disease 
must be documented at Screening and reassessed at each subsequent tumor evaluation. 
x ,PDJLQJRIWKHEUDLQ05,RU&7DWEDVHOLQH 28 days of informed consent) should 
be performed at Screening if clinically indicated. 
x If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed. 
x If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
x Bone scans (Technetium-99m [TC-99m]) or PET should be performed at Screening if 
clinically indicated. If bone metastases are present at Screening and cannot be seen on 
CT or MRI scans afterwards, or clinically indicated, TC-99m or PET bone scans 
should be repeated when a CR is suspected in target lesion or when progression in 
bone is suspected. 
x CT scans of the neck or extremities should also be performed if clinically indicated 
and followed throughout the study, if there is evidence of metastatic disease in these 
regions at Screening.  
x At the investigator’s discretion, other methods of assessment of target lesion and 
nontarget lesions per RECIST v1.1 may be used. 
Tumor response will be assessed using RECIST v1.1 (refer to Appendix 11). The same evaluator 
should perform assessments, if possible, to ensure internal consistency across visits.  
After the first documentation of response (CR or PR), confirmation of tumor response should 
occur at 4 weeks or later after the first response or at the next scheduled assessment time point.  
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic PD is suspected by the investigator to 
reflect pseudoprogression, patients may continue treatment with tislelizumab until PD is 
FRQILUPHGE\UHSHDWHGLPDJLQJ 4 weeks later (but not exceeding 6 to 8 weeks from the date of 
initial documentation of PD). The following criteria must be met in order to treat patients with 
suspected pseudoprogression: 
x Absence of clinical symptoms and signs of PD (including clinically significant 
worsening of laboratory values) 
x 6WDEOH(&2*3HUIRUPDQFH6WDWXV 1 
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x Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, cord 
compression) that requires urgent alternative medical intervention 
x Investigators must obtain written informed consent for treatment beyond initial 
radiologic PD and inform patients that this practice is not considered standard in the 
treatment of cancer 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed 
with the medical monitor and documented in the study records. In such cases, patients are also 
required to be reconsented. 
Patients who discontinue study treatment early for reasons other than PD (eg, toxicity) will 
continue to undergo tumor assessments following the original plan until the patient begins a 
subsequent anticancer treatment, experiences PD, withdraws consent, is lost to follow-up, death, 
or until the study terminates, whichever occurs first.  
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. 
7.5. 
Pharmacokinetic Assessment  
The PK concentrations will be determined using plasma (sitravatinib) or serum (tislelizumab) 
samples collected at specified time points within a reasonable variation window (refer to 
Appendix 1 and Appendix 2). The actual collection date and time of each sample collection will 
be recorded on the source document and eCRF.  
In the event of a DLT or significant toxicity, it is recommended that an unscheduled PK blood 
sample be drawn as soon as possible. 
Shipping, storage, and handling of samples will be managed through a central laboratory. 
Analysis of samples will be performed using specific validated bioanalytical methods. Full 
details on sample collection, processing, storage, and shipment will be provided in the Study 
Laboratory Manual. 
7.6. 
Antidrug Antibody Testing 
The anti-tislelizumab antibody concentrations will be determined using serum samples collected 
at specified time points within a reasonable variation window (refer to Appendix 1 and 
Appendix 2). Shipping, storage, and processing of samples will be managed through a central 
laboratory. 
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.  
Archival/biopsy tumor tissue (FFPE with tumor tissue or approximately 15 unstained slides) will 
be sent to central laboratory for biomarker analysis, including but not limited to 
immunohistochemistry assay of PD-L1 status, tumor infiltrating lymphocytes, and tumor 
mutation load. Submission of < 15 unstained slides is not a protocol deviation. 
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For all patients, in addition to archival tumor tissue, a fresh biopsy of a tumor lesion within 
28 days before Cycle 1 Day 1 and/or after 2 cycles of treatment (Cycle 3 Day 1) is recommended 
to obtain tumor samples for evaluating pharmacodynamic effects. For patients with confirmed 
PD during the study, an optional biopsy is recommended for exploration of the resistance 
mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion 
as the baseline biopsy. Written patient informed consent is required before obtaining fresh tumor 
biopsies. 
For fresh biopsy specimens, acceptable samples include core needle biopsies for deep tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. Tumor tissue should be of good quality based on total and viable tumor content. 
Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable. 
Blood samples will be collected at specified time points as described in the schedule of 
assessments to be used for the evaluation of pharmacodynamic biomarkers and exploratory 
biomarkers, including but not limited to cytokines, plasma proteins, immune cell populations, 
and circulating tumor DNA (ctDNA).  
7.8. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion/dose 
unless otherwise noted. Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Cycle 1 Day 1. 
7.9. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; ECOG Performance status; AE 
review; concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation.  
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests 
may be performed based on the investigator assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 
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8. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated With Sitravatinib and Tislelizumab 
Sitravatinib and tislelizumab are investigational agents that are currently in clinical development. 
Limited safety data for sitravatinib and tislelizumab in patients are available, and the full safety 
profiles have not been characterized. The following recommendations are based on results from 
nonclinical and clinical studies of sitravatinib or tislelizumab and published data on other 
molecules within the same biologic classes. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of irAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7. 
The guidelines for management of potential AEs more specific to treatment with sitravatinib or 
agents in the same class of cancer treatment are presented in Section 8.8. 
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, 
such events should be recognized early and treated promptly to avoid potential major 
complications. Suggested workup procedures for suspected irAEs are provided in Appendix 10. 
8.2. 
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 of sitravatinib and tislelizumab, clinical data with sitravatinib and 
tislelizumab, as well as the nonclinical/clinical data from other RTK inhibitors and PD-L1/PD-1 
inhibitors, were considered. Specifically, patients at risk for study-emergent active autoimmune 
diseases or with a history of autoimmune diseases that may relapse, patients who have undergone 
allogenic stem cell or organ transplantation, and patients who have received a live vaccine within 
28 days before the first dose of study drug(s) are excluded from the study (see Section 4.2). 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to 
the start of each cycle. 
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 
measurements (hematology, chemistry, etc.), and other assessments. In addition, patients will be 
closely monitored for the development of any signs or symptoms of autoimmune conditions and 
infection. 
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Serum samples will be drawn for determination of antidrug antibody (ADA) to tislelizumab in 
patients for both Phase 1 and Phase 2 portions of the study. Administration of tislelizumab will 
be performed in a setting where emergency medical equipment and staff who are trained to 
respond to medical emergencies are available (see Section 5.2). 
All AEs will be recorded during the study (AE from the time of the first dose of study drug(s) 
and SAEs from the time of signing of informed consent) and for up to 30 days after the last dose 
of study treatment or until the initiation of another anticancer therapy, whichever occurs first. At 
the EOT, ongoing AEs considered related to study treatment will be followed until the event has 
UHVROYHGWREDVHOLQHRU Grade 1, the event is assessed by the investigator as stable, the patient is 
lost to follow-up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the AE. 
Immune-related AEs will be recorded until up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new anticancer therapy. All drug-related SAEs will be 
recorded by investigator after treatment discontinuation until patient death, withdrawal of 
consent, or loss to follow up, whichever occurs first. 
Investigators are instructed to report all AEs (including pregnancy-related AEs).  
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections.  
8.3. 
Adverse Events 
8.3.1. 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug(s) or not.  
Examples of AEs include:  
x Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome  
x New conditions detected or diagnosed after study drug(s) administration even though 
it may have been present before the start of the study  
x Signs, symptoms, or the clinical sequelae of a suspected interaction  
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug(s) or a concurrent medication (overdose per se should not be reported as an AE 
or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor.  
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8.3.2. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
x Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
x Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)  
x Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL  
x Grade 4: Life-threatening consequences; urgent intervention indicated  
x Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, Grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug(s) and the 
occurrence of each AE or SAE, using best clinical judgment. Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the AE or SAE to the study drug(s) should be considered and investigated. The 
investigator should refer to the Investigator’s Brochures of sitravatinib and tislelizumab in the 
determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always makes an assessment of causality for every SAE prior to transmission of the 
SAE report to the sponsor, since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements. The investigator may change his/her opinion of 
causality considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment, 
including:  
x Temporal relationship of the AE to the administration of study treatment/study 
procedure 
x Whether an alternative etiology has been identified 
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x Mechanism of action of the study drug 
x Biological plausibility 
An AE should be considered “related” to study drug if any of the following criteria are met, 
otherwise the event should be assessed as not related: 
x There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
x There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely 
x There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs). 
8.3.4. 
Following Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow up, or the patient 
withdraws consent. The investigator will ensure that follow up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that:  
x are associated with clinical signs or symptoms, or  
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x require active medical intervention, or  
x lead to dose interruption or discontinuation, or 
x require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
Abnormalities in liver function tests (ALT, AST, total bilirubin) that are Grade 3 or higher need 
to be reported to the sponsor within 24 hours of occurrence via SAE reporting process as 
described in Section 8.6.2.1. Repeat liver function testing (LFT) should be performed according 
to the schedule in Appendix 10. 
8.4. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose:  
x Results in death 
x Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE, 
which hypothetically might have caused death, if it were more severe 
x Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting 
x Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions, but do not constitute a substantial 
disruption 
x Is a congenital anomaly/birth defect 
x Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are NOT considered to be SAEs: 
x Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
x Hospitalization for social/convenience considerations 
x Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
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8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.6.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study drug(s) or initiation of new anticancer 
therapy, whichever occurs first. Immune-related AEs (serious or nonserious) should be reported 
until 90 days after the last dose of tislelizumab, regardless of if the patient starts a new anticancer 
therapy. 
The investigator should report any SAEs that are assessed as related to study drug treatment, at 
any time after treatment discontinuation. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 7. 
Table 7: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe 
for Making 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs 
Within 24 h of 
first knowledge 
of the SAE 
SAE form 
As 
expeditiously 
as possible 
SAE report 
Email or 
fax SAE 
form 
Abbreviations: h, hours; SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE report 
will always be completed as thoroughly as possible with all available details of the SAE, and 
forwarded to the sponsor or designee within the designated time frames.  
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If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1 and Section 8.6.2.2. 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 sitravatinib and tislelizumab studies. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
8.6.3. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions: 
x How are you feeling?  
x Have you had any medical problems since your last visit?  
x Have you taken any new medicines since your last visit?  
8.6.4. 
Progressive Disease 
PD, which is expected in this study population and measured as an efficacy endpoint, should not 
be reported 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 PD should not 
be recorded. However, if there is any uncertainty as to whether a nonserious AE is due to PD, it 
should be recorded as an AE. All SAEs and deaths regardless of relatedness to PD should be 
recorded and reported (see Section 8.6.2). 
8.6.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death,” 
“death of unknown cause,” or “death unexplained.” 
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8.6.6. 
Pregnancies 
If a female patient or the partner of a male patient receiving investigational therapy becomes 
pregnant within 120 days after the last dose of tislelizumab or sitravatinib, a pregnancy report 
form is required to be completed and expeditiously submitted to the sponsor to facilitate outcome 
follow-up. Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, follow up will be no longer than 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug(s) should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug(s) experience to 
identify and expeditiously communicate new safety findings to regulatory authorities, 
investigators, IRBs, and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
x Sitravatinib Investigator’s Brochure and Tislelizumab Investigator’s Brochure 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related (see Section 8.7.3) should be classified as irAEs and identified 
as such in the eCRF AE page until 90 days after the last dose of tislelizumab. 
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 10. 
An extensive list of potential irAEs appears in Table 9. All conditions similar to those listed 
should be evaluated to determine whether they are irAEs, based on a similar diagnostic process 
to those reactions that are presented in more detail in Appendix 10. 
8.7. 
Management of Adverse Events of Special Interest of Tislelizumab 
As a routine precaution, after infusion of tislelizumab on Cycle 1 and Cycle 2 Day 1, patients 
must be monitored for at least 1 hour afterward in an area with resuscitation equipment and 
emergency agents. From Cycle RQZDUGD-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents.  
The management of infusion-related reactions, severe hypersensitivity reactions and irAEs 
according to the NCI-CTCAE criteria are outlined below. 
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8.7.1. 
Infusion-Related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Patients should be closely monitored 
for such reactions. Immediate access to an Intensive Care Unit (ICU) or equivalent environment 
and appropriate medical therapy (including epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen) must be available to treat infusion-related 
reactions.  
Treatment modification for symptoms of infusion-related reactions due to tislelizumab is 
provided in Table 8. 
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Table 8: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as 
needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, intravenous 
fluids); prophylactic medications indicated for 
 24 h. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions have 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described 
below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended 
Abbreviations: h, hours; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event; 
NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the patient has a second infusion-UHODWHGUHDFWLRQ Grade 2) on the slower 
infusion rate, infusion should be discontinued, and the patient should be withdrawn from 
tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or intravenous glucocorticoids, epinephrine, bronchodilators, and 
oxygen. In the next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
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oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and 
oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the patient 
discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the patient should be placed on monitor 
immediately and ICU should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.7.3. 
Immune-Related Adverse Events 
While sitravatinib may have immunostimulatory effects, autoimmune AEs have not been 
reported in clinical trials, including to date in combination with nivolumab, nor are they 
recognized as class effects for this agent. However, the potential for sitravatinib to exacerbate or 
promote these AEs when administered in combination with a PD-1 inhibitor should be noted. 
Immune-related AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, PD, metabolic, toxin, or other neoplastic causes) with appropriate diagnostic 
tests which may include but are not limited to serologic, immunologic, and histologic (biopsy) 
data. If alternative causes have been ruled out; the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy and is consistent with an immune-mediated 
mechanism of action, the irAE indicator in the eCRF AE page should be checked. A clinically 
relevant overlap in toxicity may arise between an irAE attributed to tislelizumab and the 
nonspecific, most often mild to moderate AE (eg, rash and colitis) observed with sitravatinib. 
The time to onset may be helpful in distinguishing an AE that may be attributed to autoimmune 
effects versus nonspecific toxicity. 
A list of potential irAEs is shown below in Table 9. All conditions similar to those listed should 
be evaluated in patients receiving tislelizumab to determine whether they are immune-related.  
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Recommendation for diagnostic evaluation and management of irAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017, Brahmer et al 2018) and common immune-related toxicities are 
detailed in Appendix 10. For any AEs not included in Appendix 10 please refer to ASCO 
Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-related toxicities.  
Table 9: 
Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase 
(ALT/AST) elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent 
diabetes mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing irAEs are detailed in Appendix 10. 
In the event of an immune-related AE during study treatment, administration of sitravatinib and 
WLVOHOL]XPDEVKRXOGEHLQWHUUXSWHGXQWLOWKHHYHQWVWDELOL]HVWR Grade 1. If a toxicity does not 
UHVROYHWR Grade 1 within 4 weeks for sitravatinib or 12 weeks, study drug(s) should be 
discontinued after consultation with the sponsor. Patients who experience a recurrence of the any 
event at the same or higher severity grade with rechallenge should permanently discontinue 
treatment.  
8.8. 
Management of Sitravatinib-Specific Adverse Events 
8.8.1. 
Management of Non-Hematological Toxicities of Sitravatinib 
Patients experiencing symptomatic Grade 2 non-hematological sitravatinib-related adverse 
events are recommended to have a dose reduction to the next lower dose level at the discretion of 
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the investigator, per the reduction schedule (Table 10). Dose reductions are expected to improve 
treatment tolerability. 
Non-KHPDWRORJLFDOWR[LFLWLHV Grade 3 and considered to be related to sitravatinib treatment 
VKRXOGEHPDQDJHGZLWKVLWUDYDWLQLELQWHUUXSWLRQXQWLOUHVROXWLRQRIWR[LFLW\WR 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 elevation treatment may be resumed at the same 
dose; if not, treatment may be resumed at a reduced dose as outlined in Table 10. Recurrence of 
the toxicity may be managed similarly. If treatment is interrupted IRU 28 days, permanent 
discontinuation from study treatment should be considered. 
Table 10: 
Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities 
Toxicity 
Drug Interruption 
Dose Modification 
Grade 1 
May be implemented based on investigator and patient discretion 
Grade 2 - Asymptomatic 
May be implemented based on investigator and patient discretion 
Grade 2 - Symptomatic 
May be implemented based on 
investigator and patient discretion 
Recommend dose reduction to next 
lower dose level 
Grade 3 or 4 
Hold until  Grade 1 or return to 
baseline 
Resume at dose one or more levels 
below that inducing the toxicity. 
Exceptions presented in footnotes 
Notes:  
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:  
x 
Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with 
conventional medical treatment within 72 hours 
x 
Grade 3 amylase or lipase elevation that is not associated with symptoms or the clinical manifestations of 
pancreatitis 
8.8.2. 
Management of Hematological Toxicities of Sitravatinib 
Hematological toxicities are not a frequent cause of treatment interruption or discontinuation of 
VLWUDYDWLQLEWUHDWPHQW2EVHUYHG Grade 3 hematological events that are considered to be 
causally related to sitravatinib should initially be managed using treatment interruption. In 
addition, dose reduction at the discretion of sitravatinib should be implemented in the following 
cases:  
x Grade 3 or 4 febrile neutropenia 
x Grade 4 neutropenia persisting for > 7 days  
x Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
clinically significant bleeding 
8.8.3. 
Dose Modification Guidelines for Sitravatinib-Specific AEs 
Dose modification guidelines for increased blood pressure and increased hepatic transaminase 
not likely to be immune-mediated are presented in Table 11 and Table 12 below. Guidance for 
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management of Hy’s Law cases is also provided below. Additional management guidelines for 
sitravatinib-specific AEs are also described below. 
Table 11: 
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 8.8.4 
Grade 3 hypertension with clinically 
significant increases in BP defined as either 
DQLQFUHDVHRIPP+JLQV\VWROLF%3WR
PP+Jor LQFUHDVHRIPP+JLQ
GLDVWROLF%3WRPP+JFRQILUPHG
with repeated testing after at least 5 minutes  
+ROGXQWLO Grade 2 or 
return to baseline  
Investigator discretion  
Grade 4 hypertension  
Discontinue sitravatinib  
Discontinue sitravatinib  
Abbreviation: BP, blood pressure. 
For cases where transaminase increases are not likely to be immune-mediated, treatment 
management decisions should be made per investigator discretion in consideration of clinical 
factors. Recommended treatment modifications for sitravatinib are provided in Table 12. 
Table 12: 
Sitravatinib Dose Modification for Increased Hepatic Transaminase 
Toxicity  
Drug Interruption 
Dose Modification  
Grade 1 (> ULN - 3.0 x ULN if baseline 
was normal; 1.5 - 3.0 x baseline if 
baseline was abnormal)  
May be implemented based on investigator and patient 
discretion  
Grade 2 (> 3.0 - 5.0 x ULN if baseline 
was normal; > 3.0 - 5.0 x baseline if 
baseline was abnormal) 
Not required 
Decrease by 1 dose level 
Grade 3 or 4 (> 5.0 x ULN if baseline 
was normal; > 5.0 x baseline if baseline 
was abnormal) 
+ROGXQWLO 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. 
Abbreviation: ULN, upper limit of normal. 
Management of Hy’s Law Cases 
,QWKHHYHQWDSDWLHQWGHYHORSVFRQFXUUHQWLQFUHDVHLQ$67DQGRU$/7 x ULN, bilirubin 
 2 x ULN but without concurrent increases in alkaline phosphatase (ie, alkaline phosphatase 
< 2 x ULN), that is not attributable to liver metastases or biliary obstruction, sitravatinib and 
tislelizumab should be permanently discontinued and steroids administered. 
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8.8.4. 
Hypertension 
Hypertension, including Grade 3 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 blood pressure (BP) (see Table 11). In 
cases of Grade 3 hypertension with clinically significant increases in blood pressure, temporary 
suspension of sitravatinib dosing is recommended until blood pressure 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 11). 
8.8.5. 
Palmar-Plantar Erythrodysesthesia 
Palmar plantar erythrodysesthesia (PPE) has been reported as a DLT in the Phase 1 study of 
sitravatinib. Measures that can be taken to manage PPE 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, 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. 
8.8.6. 
Diarrhea/Colitis 
Diarrhea has been reported with sitravatinib treatment, though the mechanism remains unclear, 
as with other small molecule RTK inhibitors. Patients should be counseled that diarrhea is a 
possible side effect and advised to take loperamide or a similar medication as needed if diarrhea 
develops. Any patients developing dehydration or clinically significant electrolyte abnormalities 
should interrupt treatment, but treatment may be restarted once diarrhea is controlled. 
Investigators should also evaluate whether diarrhea may be attributable to the irAE 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 treatment-associated diarrhea. The diarrhea observed with sitravatinib generally 
improves within several days of interrupting study medication, with close observation may help 
establish the most likely causality.  
8.8.7. 
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 suspension of treatment is recommended for patients developing 
clinically significant bleeding.  
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8.8.8. 
Thrombotic Events 
Though thrombotic events (eg, pulmonary embolism) have been reported with sitravatinib and 
with inhibitors of VEGFR, the risk of such events with sitravatinib is unknown. Precautions 
should be taken in patients with recent, clinically significant thrombotic events, and treatment 
should be discontinued in patients who develop clinically significant thromboembolic 
complications such as acute myocardial infarction or severe pulmonary embolism. 
8.8.9. 
Thyroid Dysfunction Other Than Immune-Mediated 
Hypothyroidism and increases in TSH have been reported in patients taking sitravatinib. Patients 
diagnosed with hypothyroidism should be treated with hormone replacement therapy and may 
continue treatment with sitravatinib at the Investigator’s discretion. 
8.8.10. 
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 multigated acquisition (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 
(CHF).  
8.8.11. 
Proteinuria 
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
LQKLELWRUVRIWKH9(*)5SDWKZD\3DWLHQWVZKRGHYHORS 2 + proteinuria should undergo 
24-hour urine collection for assessment of urine protein; treatment with sitravatinib should be 
GLVFRQWLQXHGLQWKHSUHVHQFHRI 2 g of proteinuria/24 hours and may restart when protein levels 
decrease to less than 2 g/24 hours. Patients who develop nephrotic syndrome should be 
withdrawn from treatment with sitravatinib. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released. Details of the statistical analyses will be included in a 
separate Statistical Analysis Plan (SAP). 
In general, data from Phase 1 part will be summarized by dose level and schedule, while data 
from Phase 2 part will be summarized by cohort, unless otherwise specified. 
9.1. 
Statistical Analysis 
9.1.1. 
Analysis Sets 
x The Safety Analysis Set includes all patients who received at least 1 dose of any 
study drug (any component for the combination therapy). Patients from either Phase 1 
or 2 are eligible for inclusion in the Safety Analysis Set. 
x The Efficacy Evaluable Analysis Set includes all patients who received at least 1 dose 
of any study drug with measurable disease at baseline per RECIST v1.1 and who had 
at least 1 evaluable postbaseline tumor assessment unless treatment was discontinued 
due to clinical progression or death before tumor assessment. Patients from Phase 1 or 
2 are eligible for inclusion in the Efficacy Evaluable Analysis Set. 
x DLT Evaluable Analysis Set for sitravatinib monotherapy includes patients who 
received at least 75% of the assigned total dose of sitravatinib for the DLT assessment 
window and had sufficient safety evaluation. Additionally, patients who had a DLT 
event will also be considered evaluable. Only patients from Phase 1 are eligible for 
inclusion in the DLT Evaluable Analysis Set of sitravatinib monotherapy. 
x DLT Evaluable Analysis Set for sitravatinib and tislelizumab combination includes 
patients who received at least 75% of the assigned total dose of sitravatinib and 
 67% (approximately two-thirds) of the assigned total dose of tislelizumab for the 
DLT assessment window. Additionally, patients who had a DLT event will also be 
considered evaluable. Only patients from Phase 1 are eligible for inclusion in the 
DLT evaluable analysis set of sitravatinib and tislelizumab combination therapy. 
x The PK Analysis Set includes patients who contributed at least 1 quantifiable 
post-baseline PK sample. Patients from either Phase 1 or 2 are eligible for inclusion 
in the PK Analysis Set. 
x The ADA Evaluable Analysis Set includes all patients who received at least 1 dose of 
tislelizumab and for whom both baseline ADA and at least 1 post-baseline ADA 
results are available. Patients from either Phase 1 or 2 are eligible for inclusion in the 
ADA Evaluable Analysis Set. 
9.1.2. 
Patient Disposition 
The number of patients treated, discontinued from study drug(s) and/or study, and those with 
major protocol deviations will be counted. The primary reason for study drug(s) discontinuation 
will be summarized according to the categories in the eCRF. The end of study status (alive, dead, 
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withdrew consent, or lost to follow-up) at the data cutoff date will be summarized using the data 
from the eCRF.  
Major protocol deviations will be summarized and listed by each category. 
9.1.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics of the Safety Analysis Set will be summarized 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis, and time since advanced/metastatic disease diagnosis; categorical 
variables include prior number of systemic treatment, gender, ECOG, country, race, and 
metastatic site. 
9.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
drug codes. Concomitant medications will be further coded to the appropriate Anatomical 
Therapeutic Chemical (ATC) code indicating therapeutic classification. Prior and concomitant 
medications will be summarized and listed by drug and drug class in the Clinical Study Report 
(CSR) for this protocol. Prior medications will be defined as medications that stopped before the 
day of first dose of study drug(s). Concomitant medications will be defined as medications that 
1) started before the first dose of study drug(s) and were continuing at the time of the first dose 
of study drug(s), or 2) started on or after the date of the first dose of study drug(s) up to 30 days 
after the patient’s last dose. In addition, telephone contacts with patients should be conducted to 
assess irAEs and concomitant medications (if appropriate, eg, associated with an irAE or is a 
new anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizumab 
regardless of whether or not the patient starts a new anticancer therapy.  
9.2. 
Efficacy Analyses 
The efficacy endpoints (ie, ORR, DOR, PFS, and DCR) will be assessed by investigators using 
RECIST v1.1 and will be summarized to evaluate the antitumor activities of sitravatinib as 
monotherapy or in combination with tislelizumab. 
Details of statistical analyses will be described in detail in the SAP. 
Objective Response Rate (ORR) 
The number and proportion of patients who achieve objective tumor response (CR or PR) 
according to RECIST v1.1 will be summarized. The ORR will be estimated along with Clopper 
Pearson 2-sided 95% confidence interval (CI). 
Analyses for ORR will be presented by tumor expansion cohort. 
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with BOR of CR, PR, and SD in accordance with 
RECIST v1.1 criteria. DCR will be reported with the 95% CI. 
Progression-Free Survival (PFS) 
PFS is defined as the time from the date of first dose of study drug(s) to the date of the first 
documentation of PD as assessed by the investigator using RECIST v1.1 or death, whichever 
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occurs first. Kaplan-Meier methodology will be used to estimate median PFS and 95% CI. 
Kaplan-Meier curves will be constructed to provide a visual description of the PFS change with 
time. 
Duration of Response (DOR) 
DOR for responders (CR or PR) is defined as the time interval between the date of the earliest 
qualifying response and the date of PD or death for any cause (whichever occurs earlier). DOR 
analysis will only include responders. Censoring rule for DOR will follow PFS censoring rule. 
Kaplan-Meier curve will be used to estimate median time and 95% CI for DOR. The censoring 
rule for PFS and DOR will follow FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (FDA 2007). 
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesion. The 
maximum tumor shrinkage based on target lesion used in the plots will be listed. The 
postbaseline nadir will be summarized using descriptive statistics. These analyses will be 
performed based on RECIST v1.1. 
Analyses for DCR, PFS, and DOR will be presented by tumor expansion cohort. 
Overall Survival (OS) 
OS is defined as the time from date of first dose of study drug(s) to date of death due to any 
cause. Patients who remained alive before data cutoff or discontinuation of the study 
(discontinued study due to reasons other than “Death”) will be censored at the time of data cutoff 
or the last date the patient was known to be alive. Kaplan-Meier curve will be used to estimate 
OS at different time points.  
9.3. 
Safety Analyses 
Safety will be determined by the spontaneous reporting of AEs and by laboratory values 
(hematology, clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, 
and ECGs findings will also be used in determining the safety profile. The severity of AEs will 
be graded according to the CTCAE v5.0. The incidence of DLT events and TEAEs will be 
reported as the number (percentage) of patients with TEAEs by system organ class (SOC) and 
preferred term (PT). Descriptive summary statistics (eg, n, mean, standard deviation, median, 
minimum, maximum for continuous variables; n [%] for categorical variables), and changes from 
baseline will be determined for laboratory parameters and vital signs. Safety analyses will be 
conducted in the Safety Analysis Set. 
9.3.1. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), 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. 
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9.3.2. 
Adverse Events 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA (v18.1 or higher) by lower-level term, preferred term, 
and primary SOC. 
DLT will be summarized at each dose cohort in Phase 1. 
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(s) and up to 30 days following study 
drug(s) discontinuation or initiation of new anticancer therapy, whichever occurs first. TEAE 
classification also applies to irAEs recorded up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new anticancer therapy. Only those AEs that were 
treatment-emergent will be included in summary tables. All AEs, treatment-emergent or 
otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and preferred term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v.5.0 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 drug. TEAEs include those events 
considered by the investigator to be related to study treatment or with missing assessment of the 
FDXVDOUHODWLRQVKLS6$(VGHDWKV7($(ZLWK Grade 3 severity, irAE, 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, clinical chemistry, urinalysis) values will be evaluated for 
each laboratory parameter as appropriate. Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be included in the CSR for this protocol. Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n[%] for categorical variables) for laboratory parameters and their changes from 
baseline will be calculated. Laboratory values will be summarized by visit and by worst 
postbaseline visit. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 or higher will be summarized 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 
Specific vital signs, eg, blood pressure and temperature, will be summarized and listed. The 
change from baseline will also be presented.  
9.3.5. 
Dose-Limiting Toxicity Analysis  
DLTs during the DLT assessment window will be used to determine the dose and schedule of 
sitravatinib as monotherapy or in combination with tislelizumab. The DLT events will be 
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summarized descriptively by monotherapy and combination dosing level in the DLT Evaluable 
Analysis Set in dose escalation stage. 
9.4. 
Pharmacokinetic Analysis  
Blood samples for PK analysis of sitravatinib and tislelizumab will be collected at specified time 
points (Appendix 2). The actual collection date and time of each blood sample will be recorded. 
The timing of PK samples may be altered and/or PK samples may be obtained at additional time 
points upon sponsor approval to ensure thorough PK monitoring.  
For the PK analysis set that contributed serial plasma samples for sitravatinib on Cycle 1 Day 1 
and Day 21, plasma concentration-time data of each patient will be tabulated and graphically 
presented on linear and semilogarithmic scales. Plots of sitravatinib concentration-time data will 
be presented for Cycle 1 Day 1 (after single dose) and Day 21 (at steady state). Pharmacokinetic 
parameters will be determined using standard noncompartmental method. A listing of patients 
excluded from the analysis set and individual data points excluded from the analysis will be 
provided. The final analysis of PK parameters will be calculated based on actual sample 
collection time, rather than scheduled times. The parameters will be summarized with descriptive 
statistics (eg, N, arithmetic mean, standard deviation, minimum, median, maximum, geometric 
mean, and coefficient of variation [CV] % associated to the geometric mean).  
PK parameters will include, but are not limited to, the following as allowed by data: 
Cmax ȝJP/  
Observed maximum plasma concentration during a sample interval.  
CĲ ȝJP/  
Observed trough concentration at steady state. 
Tmax (hr)  
Observed time to maximum plasma concentration during a sampling interval.  
Ȝ]KU-1)  
Elimination rate constant, determined by linear regression of the terminal points of the 
log-linear plasma concentration-time curve. Visual assessment will be used to identify 
the terminal linear phase of the concentration-time profile. A minimum of 3 data points 
will be used for determination (Cmax excluded).  
t1/2 (h)  
Terminal elimination half-OLIHGHWHUPLQHGIURPWKHTXRWLHQWȜ]  
AUC(0-t) ȝJKP/  
Area under the plasma concentration-time curve from time zero to the last measurable 
time point calculated by log-linear trapezoidal summation. 
AUC(0-Ĳ (ȝJKP/) 
Area under the plasma concentration-time curve from time zero to 24 h postdose at 
steady state; calculated by log-linear trapezoidal summation. 
CL/F (L/hr)  
Apparent clearance after oral administration. 
Ro  
Observed accumulation ratio determined by AUC(0-ĲVV /AUC(0-24), Day1. 
The sitravatinib and tislelizumab concentration data collected sparsely at predose and around 
Tmax will be tabulated and summarized by visit/cycle. Descriptive statistics will include means, 
standard deviations, medians, and ranges as appropriate. 
Additional PK, including population PK analyses, may be conducted as appropriate, and the 
results of such analysis may be reported separately from the CSR. 
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9.5. 
Immunogenicity Analyses 
Samples to assess anti-tislelizumab antibodies will be collected. The immunogenicity results will 
be summarized using descriptive statistics by the number and percentage of patients who develop 
detectable ADA. The incidence of positive ADA and neutralizing ADA will be reported for 
evaluable patients. The effect of immunogenicity on PK, efficacy, and safety may be evaluated if 
data allow. 
9.6. 
Other Exploratory Analyses 
Summary statistics will be provided for pharmacodynamic biomarkers, including, but not limited 
to, plasma protein, cytokine, and immune cell subtypes in blood. An exploratory analysis on a 
potential correlation of these pharmacodynamic markers with PK parameters, safety, and 
antitumor activity will be performed as appropriate. 
Exploratory biomarker analyses will be performed in an effort to understand the association of 
these markers with study drug(s) response, such as efficacy and treatment resistance.  
For potential PGx analysis of genes that may affect the PK of sitravatinib, a blood sample for 
DNA isolation will be collected from patients predose on Cycle 1 Day 1. If needed, these 
samples will be analyzed together with PGx samples from other studies to assess the impact of 
genetic polymorphisms on the PK of sitravatinib, and these results may be reported separately.  
9.7. 
Sample Size Consideration 
The study plans to enroll approximately 98 to 116 patients. 
x Phase 1 (sitravatinib as monotherapy and in combination with tislelizumab dose 
escalation): Approximately 18 to 36 DLT evaluable patients with unresectable locally 
advanced or metastatic HCC or G/GEJ cancer will be enrolled.  
x Phase 2 (sitravatinib as monotherapy and in combination with tislelizumab 
combination dose expansion): Approximately 80 patients will be enrolled in Phase 2 
(approximately 20 patients per cohort). Enrollment into these cohorts will occur 
simultaneously and independent of each other. Each cohort will be evaluated 
separately. 
Estimates of the 95% CI of the observed ORR for several potential outcomes using the sample 
size of 20 patients are provided in Table 13. 
Table 13: 
Estimates of 95% CI of ORR With 20 Patients 
Number of Observed Responses  
ORR 
95% CI 
4 
20% 
5.7%, 43.7% 
6 
30% 
11.9%, 54.3% 
8 
40% 
19.1%, 63.9% 
10 
50% 
27.2%, 72.8% 
12 
60% 
36.1%, 80.9% 
Abbreviations: CI, confidence interval; ORR, objective response rate. 
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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Safety Monitoring Committee 
An SMC will be established consisting of the sponsor’s clinical, safety, and medical team 
representatives (eg, medical monitor, Clinical Pharmacology, and Drug Safety) and investigators. 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), 
will be reviewed with input from other functional representatives as appropriate. On the basis of 
a review of these data and in consultation with the investigators, a determination will be made 
regarding dose and/or safety management. 
10.2. 
Communication 
Sponsor plans to have regular communications with all study sites (study investigators and 
coordinators) regarding: 
x Study enrollment status  
x Decisions on dose escalation  
x Any significant safety findings  
x Considerations for protocol amendments 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data.  
11.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct study with the investigational drug from the 
appropriate regulatory agency in accordance with applicable country-specific regulatory 
requirements or file the protocol to the appropriate regulatory agency before the study is initiated 
at a study center in that country. 
12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be made periodically by the sponsor’s or the contract research organization’s 
(CRO’s) qualified compliance auditing team, which is an independent function from the study 
team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
12.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product. Dispensation records will document quantities received from BeiGene’s 
designated depot or its designee and quantities dispensed to patients, including batch/lot number, 
date dispensed, patient identifier number, 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(s) disposal/destruction to ensure that it complies with BeiGene’s requirements specified in 
the Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study, the study site will dispose of and/or destroy all unused study drug(s) supplies following 
drug inventory reconciliation by the monitor. These including empty containers, according to 
these procedures. If the site cannot meet BeiGene’s requirements specified in the Pharmacy 
Manual for disposal, arrangements will be made between the site and BeiGene or its 
representative for destruction or return of unused study drug(s) supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. A patient diary will be provided to each patient to 
record the sitravatinib dose taken each day. Any missed doses with explanation should be 
recorded in the diary. The diary should be returned to the site personnel for review by the 
investigator/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 ICH E6 guideline for GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will comply with the requirements of 
the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted to the IRB/IEC by the principal investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IRB/IEC.  
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
investigational new drug (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 
All protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming willingness to remain in the study. 
13.3. 
Informed Consent 
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements.  
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The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.  
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality 
The sponsor will maintain confidentiality and privacy standards by coding each patient enrolled 
in the study through assignment of a unique patient identification number. This approach ensures 
that patients’ names are not included in any data set transmitted to any sponsor location.  
Patient medical information obtained by this study is confidential and may be disclosed only to 
third parties as permitted by the signed ICF (or a separate authorization for the use and disclosure 
of personal health information that has been signed by the patient), unless permitted or required 
by law.  
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated by this study must be available for inspection upon request by representatives of 
the US FDA, 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 must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the Investigator’s Brochure, this protocol, 
eCRFs, the IND, and any other study information, remain the sole and exclusive property of the 
sponsor during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor. The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
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13.5. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient and accurate financial 
information, in accordance with regulations to allow the sponsor to submit complete disclosure 
or certification to the absence of certain financial interest of the clinical investigators and/or 
disclose those financial interests, as required, to the appropriate health authorities. This is 
intended to ensure financial interests and arrangements of the clinical investigators with BeiGene 
that could affect reliability of data submitted to health authorities are identified and disclosed by 
the sponsor. Investigators are responsible for providing information about their financial interests 
before participation in the study, and to update this information if any relevant changes occur 
during the study and for 1 year after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Collection and Management Responsibilities 
14.1.1. 
Data Collection 
Data required by the protocol will be entered into an electronic data capture (EDC) system.  
Data collection in the eCRF must follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The investigator or designee must provide an e-signature in the 
EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities.  
14.1.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored by BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs 
for completeness, clarity, and cross checking with source documents is required to monitor the 
progress of the study. Direct access to source data is also required for inspections and audits and 
will be carried out giving due consideration to data protection and medical confidentiality. 
AEs will be coded using the MedDRA v18.1 or higher. Concomitant medications will be coded 
using the World Health Organization Drug Dictionary. Concomitant diseases/medical history 
will be coded using the MedDRA v18.1 or higher. 
14.2. 
Study Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following categories: 1) investigator’s study file, and/or 2) 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF, IRB/IEC, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
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Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to the 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 the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
14.3. 
Protocol Deviations 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the Sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures.  
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14.4. 
Publication and Data Sharing Policy 
A clinical study report will be prepared and provided to the regulatory agency(ies). BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the study. The data generated in this clinical study are the exclusive 
property of the sponsor and are confidential. As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors 2018) 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation in 
accordance with the clinical study agreement. This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. Each investigator agrees 
that, in accordance with the terms of clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings in advance 
of the publication/presentation.  
14.5. 
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: 
x Return of all study data to the sponsor 
x Resolution and closure of all data queries 
x Accountability, reconciliation, and arrangements for unused study drug(s) 
x Review of study records for completeness 
x Return of treatment codes to the sponsor 
x Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study or suspend enrollment either at a single study center or at all study centers at any time 
for reasons including, but not limited to, safety or ethical issues or severe noncompliance. If the 
sponsor determines such action is needed, the sponsor will discuss this with the investigator 
(including the reasons for taking such action) at that time. When feasible, the sponsor will 
provide advance notification to the investigator of the impending action prior to it taking effect. 
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The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated and will also inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the 
suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
14.6. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study are the sole property of the sponsor, and are hereby 
assigned to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept 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.  
These restrictions do not apply to: 
x Information that becomes publicly available through no fault of the investigator or 
study center personnel 
x Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
x Information that is necessary to disclose to provide appropriate medical care to a 
patient 
x Study results that may be published as described in Section 14.4 
If a written contract for the conduct of the study (which includes confidentiality provisions 
inconsistent with this section) is executed, that contract’s provisions shall apply to the extent 
they are inconsistent with this section. 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
ONO Submits Supplemental Application of OPDIVO® (Nivolumab) for Unresectable Advanced 
or Recurrent Gastric Cancer for a Partial Change in Approved Items of Manufacturing and 
Marketing Approval in Japan [press release]. Ono Pharmaceutical, Ltd. December 27, 2016. 
Accessed 01 February 2017. 
Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2018. 
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Patel SP, Kurzrock, R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. 
Mol Cancer Ther. 2015;14(4):847–56. 
Qin S, Cheng Y, Liang J, et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin 
in Chinese patients with advanced hepatocellular carcinoma: A subgroup analysis of the EACH 
study. Oncologist. 2014;19(11):1169-78. 
Saito H, Kuroda H, Matsunaga T, et al. Increased PD-1 expression on CD4+ and CD8+ T cells is 
involved in immune evasion in gastric cancer. J Surg Oncol. 2013;107(5):517-22. 
Smyth EC, Verheij M, Allum W, et al. ESMO Guidelines Committee. Gastric cancer: ESMO 
clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 
5):38-49. 
Soar J, Pumphrey R, Cant A, et al. Emergency treatment of anaphylactic reactions--guidelines 
for healthcare providers. Resuscitation. 2008;77(2):157-69. 
Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + 
bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). 2018 ASCO annual 
meeting, Abstract 4074. 
Syn NL, Teng MWL, Mok TSK, et al. De-novo and acquired resistance to immune checkpoint 
targeting. Lancet Oncol. 2017;18(12): e731–41. 
Terrault NA, Bzowej NH, Chang K-M, et al. AASLD guidelines for treatment of chronic 
hepatitis B. Hepatology. 2016;63:261-83. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
DQWLERG\LQFDQFHU1(QJO-0HGí 
Torre LA, Bray F, Siegel RL, et al. Global Cancer Statistics, 2012. CA Cancer J Clin. 2015 
Mar;65(2):87-108. 
Van Cutsem E, Moiseyenko V, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus 
fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric 
cancer: A report of the V325 Study Group. J Clin Oncol. 2006;24 (31):4991-7. 
Van Der Kraak L, Goel G, Ramanan K, et al. 5-Fluorouracil upregulates cell surface B7-H1 
(PD-L1) expression in gastrointestinal cancers. J Immunoth Cancer. 2016;4(1):65. 
Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus 
paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 
2014;15(11):1224-35. 
Xu JM, Zhang Y, Jia R, et al. Anti-programmed death-1 antibody SHR-1210 (S) combined with 
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esophagogastric junction (EGJ) cancer refractory to standard therapy: A phase 1 trial. 2018 
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Clin Exp Immunol. 2013;172(3):500-6. 
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Zhang Y, Han C, Li J et al. Efficacy and safety for Apatinib treatment in advanced gastric 
cancer: A real world study. Sci Rep. 2017;7(1):13208.
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16. 
APPENDICES 
APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety 
Follow-up 
Phone Call5 
Survival 
Follow-up6 
Cycle 1 and 2 
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
12 
8 
(±1) 3 
15 
(±2) 3 
1(±3) 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 
(± 14) Days 
After Last 
Dose of 
Tislelizumab 
Approximately 
Every 3 
Months 
(± 14 days) 
(Phase 2) 
Informed consent1 
x 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
Demographics/medical 
history/prior medications 
x 
 
 
 
 
 
 
 
Child-Pugh 
classification score7 
x 
(-7 to -1) 
 
 
 
 
 
 
 
Height  
x 
 
 
 
 
 
 
 
Vital signs/weight8 
x 
x 
x 
x 
x 
x 
 
 
Complete physical 
examination9 
x 
 
 
 
 
x 
 
 
Limited physical 
examination9 
 
x 
x 
x 
x 
 
 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
x 
 
 
12-Lead ECG10 
x 
x 
 
 
x 
x 
 
 
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Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety 
Follow-up 
Phone Call5 
Survival 
Follow-up6 
Cycle 1 and 2 
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
12 
8 
(±1) 3 
15 
(±2) 3 
1(±3) 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 
(± 14) Days 
After Last 
Dose of 
Tislelizumab 
Approximately 
Every 3 
Months 
(± 14 days) 
(Phase 2) 
AEs11 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant 
medications12 
x 
x 
x 
x 
x 
x 
x 
 
Hematology13 
x 
x13 
x13 
x13 
x 
x13 
 
 
Clinical chemistry13 
x 
x13 
x13 
x13 
x 
x13 
 
 
Coagulation 
parameters13 
x 
 
As clinically indicated 
 
 
 
Urinalysis13 
x 
x13 
 
 
x 
x13 
 
 
AFP (for HCC patients 
only) 14 
x 
x14 
 
 
x 
x14 
 
 
Pregnancy test15 
x 
x15 
 
 
x 
x 
 
 
Thyroid function16 
x 
Cycles 4, 7, 10, and 
every 3 cycles thereafter 
 
 
HBV/HCV tests17 
x 
As clinically indicated 
 
 
Tumor assessment18 
x 
In the first year, every 6 weeks (± 7 days) 
every 9 weeks (± 7 days) 
thereafter 
 
 
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Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety 
Follow-up 
Phone Call5 
Survival 
Follow-up6 
Cycle 1 and 2 
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
12 
8 
(±1) 3 
15 
(±2) 3 
1(±3) 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 
(± 14) Days 
After Last 
Dose of 
Tislelizumab 
Approximately 
Every 3 
Months 
(± 14 days) 
(Phase 2) 
Archival tumor tissue19 
x 
 
 
 
 
 
 
 
Fresh tumor tissue 
(optional)20 
x 
 
 
 
x 
C3D1 only 
 
 
 
Pulmonary function 
test21 
As clinically indicated 
 
 
Sitravatinib 
administration22 
 
Daily 
 
 
 
Tislelizumab 
administration23 
 
x 
 
 
x 
 
 
 
Patient diary 
 
x 
x 
x 
x 
x 
 
 
Survival status6 
 
 
 
 
 
 
 
x 
MUGA/echo-
cardiogram24 
x 
Every 12 weeks (± 7 days) 
 
 
PK sampling for 
sitravatinib25 
 
See Appendix 2 
 
 
 
PK sampling for 
tislelizumab25 
 
 
 
ADA sampling for 
tislelizumab25 
 
 
 
PGx25 
 
 
 
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Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety 
Follow-up 
Phone Call5 
Survival 
Follow-up6 
Cycle 1 and 2 
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
12 
8 
(±1) 3 
15 
(±2) 3 
1(±3) 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 
(± 14) Days 
After Last 
Dose of 
Tislelizumab 
Approximately 
Every 3 
Months 
(± 14 days) 
(Phase 2) 
Pharmacodynamic 
biomarker26 
x 
C1D1, 
C2D1 and C3D1 (within 30 min before dosing of sitravatinib) 
 
 
ctDNA26 
x 
Confirmed PR or CR (± 14 days) or PD at EOT (± 14 days) 
 
 
Abbreviations: ADA, antidrug antibody, AE, adverse event; AFP, alpha fetoprotein; CR, complete response; ctDNA, circulating tumor DNA; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; FFPE, formalin-fixed paraffin-embedded; HBcAb, hepatitis B core 
antibody; HBsAb , hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; MUGA, multigated 
acquisition; PD, progressive disease; PGx, pharmacogenetic; PK, pharmacokinetic; PR, partial response; SAE, serious adverse event; x, to be performed. 
Note: On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of sitravatinib should precede tislelizumab infusion. 
1. During Screening, written informed consent must be signed before performing any study-specific tests or procedures. Results of standard-of-care tests or 
examinations performed before obtaining informed consent and within 28 days before the first dose of study drug(s) may be used for screening assessments 
rather than repeating such tests.  
2. All assessments on Cycle 2 Day 1 may be performed within a time window of ± 3 days. 
3. In Cycle 1 and Cycle 2, only patients in Phase 1 will return to study sites for assessments on Days 8 and 15. 
4. The EOT Visit is conducted within 30 days after last dose of the study drug(s) or before initiation of a new anticancer treatment, whichever occurs first. If 
routine laboratory tests (eg, hematology, clinical chemistry) have been performed  7 days before the EOT Visit, these tests do not need to be repeated. A 
WXPRUDVVHVVPHQWLVQRWUHTXLUHGDWWKH(279LVLWLI 6 weeks have passed since the last assessment. If the study drug (s) were initially interrupted due to 
AEs and then permanently discontinued, the EOT Visit may occur later, but no later than the permitted time of dose delay plus 7 days. 
5. The Safety Follow-up Phone calls. Telephone contacts with patients should be conducted to assess irAEs and concomitant medications (if appropriate, ie, 
associated with an irAE or is a subsequent anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizumab, regardless of whether or not 
the patient starts a new anticancer therapy. Safety Follow-up Phone Call is not required for patients with sitravatinib monotherapy. 
6. Survival follow-up information will be collected via telephone calls only in Phase 2 (dose expansion), patient medical records, and/or clinic visits 
approximately every 3 months (± 14 days) after the EOT Visit until death, loss to follow-up, withdrawal of consent, or study termination by sponsor. All 
patients will be followed for survival and subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
7. Child-Pugh classification for liver function (Appendix 5) is required to be assessed for HCC patients only within 7 days before the first dose of study 
drug(s). 
8. Vital signs collected on study include temperature, pulse, and blood pressure (systolic and diastolic) after patient resting for 10 minutes. The patient’s vital 
signs are required to be recorded within 60 minutes before; during; and within 30 minutes after the first infusion of tislelizumab. For subsequent infusions, 
vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and within 30 minutes after the infusion. Vital signs should 
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also be recorded prior to administration of sitravatinib; recorded values may be used for pre-tislelizumab assessment if vital signs are collected within 
60 minutes before tislelizumab infusion.  
9. Complete physical examination including an evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 
5) respiratory, 6) gastrointestinal, and 7) neurological systems is required to be performed at Screening and EOT Visit. Limited physical examination: At 
subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations will be performed.  
10. 12-Lead ECG: The ECG should be performed during Screening, C1D1, at the beginning of every subsequent cycle, EOT Visit, and as clinically indicated at 
other time points. Patients should be resting for at least 10 minutes before each ECG collection. If ECG has been performed within 3 days before first dose 
of study drug(s) and EOT Visit, the test does not need to be repeated on C1D1 and the EOT Visit. 
11. AEs will be graded and recorded throughout the study according to NCI-CTCAE, v5.0.  
12. All concomitant medications received within 30 days before the first dose of study drug(s) and 30 days after the last dose of study treatment should be 
recorded.  
13. Hematology, clinical chemistry, coagulation and urinalysis (Appendix 3): If laboratory tests at Screening are not performed within 7 days before 
administration of study drug on Cycle 1 Day 1, these tests (hematology, clinical chemistry and urinalysis) should be repeated and reviewed before study drug 
administration. In Phase 1, hematology and clinical chemistry, as specified in Appendix 3, should be performed weekly for the first 2 cycles. For all patients 
in Phase 1 and Phase 2, hematology, clinical chemistry and urinalysis should be performed at the beginning of each cycle and the EOT Visit. After Cycle 1, 
laboratory safety tests should be performed, and the results should be reviewed within 48 hours before study drug(s) administration. For CK and CK-MB 
tests and coagulation tests, refer to Appendix 3. 
14. If AFP test has been performed at Screening and within 21 days before EOT Visit, the test does not need to be repeated on C1D1 and the EOT Visit. 
15. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days before administration of study drug(s). Urine or serum pregnancy tests will be performed during treatment before study drug(s) 
administration at each cycle and EOT Visit. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. A negative 
pregnancy test (by urine or blood) must be completed and recorded before administration of study drug(s) at each cycle. 
16. TFTs by analysis of FT3, FT4, and TSH will be performed at Screening, every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc) and EOT Visit. The test does not 
need to be repeated at the EOT Visit within 63 days after last test. 
17. HBV/HCV tests: Testing will be performed by the local laboratory at Screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV 
antibody) and viral load assessment (HBV DNA and HCV RNA). Testing at Screening is mandatory for patients. Additionally, for patients who have 
detectable HBV DNA at Screening, the respective viral load test will be performed every 4 cycles starting at Cycle 5 (ie, Day 1 of Cycles 5, 9, 13, etc), and 
EOT Visit. 
18. Tumor imaging: Radiological images captured as standard of care before obtaining written informed consent and within 28 days before the first dose of 
study drug(s) may be used rather than repeating tests. All measurable and evaluable lesions are required to be assessed and documented. At Screening, an 
MRI (or CT scan if MRI is contraindicated or not readily available) of the head may be required based on clinical judgement; bone scan or PET is required if 
clinically indicated. The same radiographic procedure must be used throughout the study for each patient. 
The investigator must review radiograph results before dosing at the next cycle. During the study, tumor imaging will be performed within 28 days prior to 
C1D1 and while on study approximately every 6 weeks ± 7 days in the first 12 months and approximately every 9 weeks ± 7 days thereafter. The 
investigator may perform additional scans or more frequent assessments if clinically indicated. Patients who discontinue study treatment early for reasons 
other than PD (eg, toxicity) will continue to undergo tumor assessments following the original plan until the patient experiences PD, withdraws consent, is 
lost to follow-up, dies, or until the study terminates, whichever occurs first. Patients who continue tislelizumab treatment beyond radiographic PD will be 
monitored with a follow-up scan no more than 6 to 8 weeks beyond the initial diagnosis of radiographic PD before discontinuation of tislelizumab. 
19. Archival tumor tissue (FFPE blocks or approximately 15 unstained FFPE slides) will be collected; if archival samples are not available, a fresh biopsy is 
recommended.  
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20. Fresh biopsy: In addition to archive tumor tissue, a fresh biopsy of a tumor lesion within 28 days before Cycle 1 Day 1 and/or after 2 cycles of treatment 
(approximately Cycle 3 Day 1) is recommended to obtain tumor samples for the evaluation of pharmacodynamic effects. An optional biopsy will also be 
taken from patients who have confirmed PD during the study from accessible tumor sites to obtain samples to explore resistance mechanism. If feasible, post 
treatment biopsy should be ideally taken from the same tumor lesion as the screening biopsy. Written informed consent is required before obtaining fresh 
tumor biopsies. 
21. Pulmonary function test: Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms 
unrelated to the underlying cancer will have pulmonary function testing which may include, but is not limited to, spirometry and assessment of diffusion 
capacity done during the Screening period to assist the determination of suitability on the study. 
22. Sitravatinib administration orally once daily without food (capsules should be taken in the fasted state, at least 2 hours after the previous meal and 1 hour 
before the next meal. For once daily dosing, capsules should be taken during the morning hours, for instance, at least 1 hour before breakfast or lunch.). 
23. Tislelizumab administration (not for patients in sitravatinib monotherapy arm) on Day 1 of every cycle after sitravatinib administration.  
24. MUGA/Echocardiogram: Evaluations of cardiac function will be performed at Screening and every 12 weeks (± 7 days). For study purposes, evaluation by 
MUGA scan is preferred. Evaluation by echocardiogram is an acceptable alternative if necessary. The method used for individual patients should be 
consistent throughout study participation.  
25. See Appendix 2 for PK sampling for sitravatinib, PK sampling for tislelizumab, ADA sampling for tislelizumab, and blood sampling for PGx 
analysis while on study treatment. 
26. Blood sampling for biomarker analysis: Peripheral blood samples will be collected for biomarker assessments, including, but not limited to cytokines, 
immune cell subpopulation, plasma protein and ctDNA. Approximately 15 mL of peripheral blood samples will be collected at Screening and on Day 1 
(within 30 min before dosing of sitravatinib) of Cycles 1, 2, and 3. For the patients who have confirmed CR/PR or PD (at EOT Visit) as assessed by the 
investigator, additional blood samples (approximately 10 mL) will be collected at each time. Instructions for the processing, storage, and shipping of samples 
will be provided in the laboratory manual. 
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APPENDIX 2. SCHEDULE OF PK ASSESSMENTS 
 
Collection Time and 
Allowable Window 
PK-Sitrac 
PK-Tisled 
ADA-Tislee 
PGxf 
Phase 1 
Phase 2 
Phase 1 and Phase 2 
C1D1, C1D21 
Predose - 30 min 
x 
x 
(C1D1 only) 
x 
(C1D1 only, Pre-tisle-dose 
[-30 min]) 
x 
(C1D1 only, Pre-tisle-dose 
[-30 min]) 
x 
(C1D1 only) 
0.5 h ± 10 min 
x 
 
x 
(C1D1 only, Post-tisle 
infusion + 30min) 
 
 
1 h ± 10 min 
x 
 
 
 
 
2 h ± 15 min 
x 
 
 
 
 
4 h ± 20 min 
x 
 
 
 
 
6 h ± 20 min 
x 
x 
(C1D1 only) 
 
 
 
8 h ± 30 min 
x 
 
 
 
 
10 h ± 1 h 
x 
 
 
 
 
12 h ± 2 hb 
x 
 
 
 
 
C1D2, C2D1 
24h ± 2 h  
(Pre-C1D2 dose and 
Pre-C2D1 dose)b 
x 
 
 
 
 
C2D1 
Predose - 30 min 
 
x 
x 
(Pre-tisle-dose [-30 min]) 
x 
(Pre-tisle-dose [-30 min]) 
 
6 h ± 20 min 
 
x 
 
 
 
C5D1 
Predose - 30 min 
 
x 
x 
(Pre-tisle-dose [-30 min]) 
x 
(Pre-tisle-dose [-30 min]) 
 
0.5 h 
 
 
x 
(Post-tisle infusion + 30min) 
 
 
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Collection Time and 
Allowable Window 
PK-Sitrac 
PK-Tisled 
ADA-Tislee 
PGxf 
Phase 1 
Phase 2 
Phase 1 and Phase 2 
6 h ± 20 min 
 
x 
 
 
 
C9D1, C17D1a 
Predose - 30 min 
 
 
x 
(Pre-tisle-dose [-30 min]) 
x 
(Pre-tisle-dose [-30 min]) 
 
EOT 
Within 30 Days After 
Last Dose of Study 
Drug(s) 
 
 
x 
x 
 
Abbreviations: ADA, antidrug antibody; irAE, immune-related adverse event; PGx, pharmacogenetic PK; pharmacokinetic; Sitra, sitravatinib; Tisle, tislelizumab; x, to 
be performed 
a. 
Samples for tislelizumab PK and ADA will be collected if these cycles are achieved in this study.  
b. Postdose samples for sitravatinib at 12 h and 24 h are optional and depend on site feasibility. 
c. 
PK sampling for sitravatinib: Serial PK samples will be collected from all patients per cohort after single dose (C1D1) and at steady state (C1D21) in 
Phase 1. For patients enrolled in Phase 2 samples at predose (within 30 min before administration of sitravatinib) and 6 hours post dose will be collected 
on Day 1 of Cycles 1, 2, and 5. In the following situations additional PK sample may be collected: when a DLT event or SAE occurs, when a dose 
reduction happens, or when hepatic impairment status proceeds from mild to moderate in HCC patient cohorts. 
d. PK sampling for tislelizumab: In Phase 1 and Phase 2, predose (within 30 min before starting tislelizumab infusion) samples should be collected on 
Day 1 of Cycles 1, 2, 5, 9, and 17 (if achieved); two postdose (within 30 min after the end of tislelizumab infusion) samples should be collected at C1D1 
and C5D1; and an additional blood PK sample should be collected at the EOT Visit (See Appendix 1). Should a patient present with DLT event or 
 Grade 3 or above irAE, additional blood PK samples may be taken to determine the serum concentration of tislelizumab. 
e. 
ADA sampling for tislelizumab: In Phase 1 and Phase 2, samples should be collected before start of Day 1 tislelizumab infusion of Cycles 1, 2, 5, 9 
and 17 (if achieved) and at the EOT Visit (See Appendix 1). All samples should be drawn at the same time as blood collection for predose PK samples. 
f. 
PGx: A blood sample for DNA isolation will be collected from patients predose on C1D1. 
 
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
Hematology 
Coagulationa 
Urinalysis 
Alkaline phosphatase 
Hematocrit 
Prothrombin time or INR Glucose  
Alanine aminotransferase  
Hemoglobin 
aPTT 
Protein 
Aspartate aminotransferase  Platelet count 
 
Blood 
Albumin  
WBC count 
 
Ketones 
Total bilirubin  
Lymphocyte count 
 
24-hour proteinb 
Direct bilirubin  
Neutrophil count 
 
 
Blood urea nitrogen or urea   
 
 
Potassium  
 
 
 
Sodium 
Corrected calciumc  
 
 
 
Creatinine  
 
 
 
Glucose  
 
 
 
Lactate dehydrogenase  
 
 
 
Total protein  
 
 
 
CKd 
CK-MBd,e 
 
 
 
Abbreviations: aPTT, activated partial thromboplastin time; CK, creatine kinase; CK-MB, creatine kinase cardiac 
muscle isoenzyme; INR, International Normalized Ratio; WBC, white blood cell. 
a. 
Coagulation tests are required at Screening, and subsequently as clinically indicated. 
b. 2QURXWLQHXULQDO\VLVLIXULQHSURWHLQLV 2+ by dipstick, then obtain a 24-hour urine sample for total 
protein or a random urine sample for total protein and creatinine to determine a protein to creatinine ratio. 
c. 
If testing for corrected calcium is not feasible at the local laboratory, total calcium may be performed 
instead. 
d. Patients receiving tislelizumab will receive CK and CK-MB testing. If tislelizumab has been permanently 
discontinued, CK and CK-MB testing is no longer required. Patients with a history of cardiological disease 
receiving sitravatinib monotherapy, either in Cohort A or after discontinuation of tislelizumab, may receive 
CK and CK-MB testing if clinically indicated. 
e. 
In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
In addition, the following tests will be conducted in this study: 
x 
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal 
ligation) must be performed and documented as negative within 7 days prior to administration of study 
drug(s). Urine or serum pregnancy tests will be performed during treatment before study drug(s) 
administration at each cycle and the EOT Visit. A serum pregnancy test must be performed if the urine 
pregnancy test is positive or equivocal. A negative pregnancy test (by urine or blood) must be completed 
and recorded before administration of study drug(s) at each cycle 
x 
Thyroid function tests (thyroid-stimulating hormone [TSH], free T3, free T4) will be performed at 
Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and EOT Visit (see Section 7.3.4 for 
details). TFT is not required at the EOT VLVLWLI 63 days have passed since the last test. 
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APPENDIX 4. ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX 5. CHILD-PUGH CLASSIFICATION SCORING SYSTEM 
The information presented here has been obtained from the Washington University Medical 
Center, with sources as follows: 
x Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-37. 
x Pugh RNH, Murray-Lyon IN, Dawson DL, et al. Transection of the esophagus for 
bleeding esophageal varices. Brit J Surgery. 1973;60:646-64. 
x Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood 
transfusion. N Engl J Med. 1966;274(9):473-81. 
Child-Pugh classification is either Grade A (mild: score 5 to 6 points), B (moderate: from 7 to 9 
points), or C (severe: from 10 to 15 points) and is determined by both clinical and biochemical 
parameters (as shown below). 
Clinical/Biochemical Parameter 
Score (Anomaly Severity) 
1 
2 
3 
Hepatic encephalopathy (NCI-CTCAE grade)a 
0b 
1c or 2d 
3e or 4f 
Ascites (presence and severity) 
None 
Mild 
Moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prolonged prothrombin time (seconds) 
or 
INRg 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events. 
a. 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion.  
N Engl J Med. 1996;274(9):473-481. 
b. Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c. 
Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5CPS waves. 
d. Grade 2: Lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e. 
Grade 3: Drowsiness, coma, orientation disorder, over-reflection, stiff/slow wave. 
f. 
Grade 4: Cannot wake up from coma, no independent personality/behavior, irrational, slow 2-3CPS Delta 
activity. 
g. Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of 
adults on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637. 
 
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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.  
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 7. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control. 
These methods include the following: 
x Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
x Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
x Intrauterine device (IUD) 
x Intrauterine hormone-releasing system (IUS) 
x Bilateral tubal occlusion 
x Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
x Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment) 
 Note: Total sexual abstinence should only be used as a contraceptive method if it 
is in line with the patient’s usual and preferred lifestyle. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and if used, this method must be 
combined with a highly effective form of birth control, listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
x Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
x Postmenopausal, defined as: 
  \HDUVRIDJHZLWKQRVSRQWDQHRXVPHQVHVIRU 12 months OR 
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 < \HDUVRIDJHZLWKQRVSRQWDQHRXVPHQVHVIRU 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
DOWHUQDWLYHPHGLFDOFDXVHVIRUWKHODFNRIVSRQWDQHRXVPHQVHVIRU 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG) Recommendations related to contraception and 
pregnancy testing in clinical trials. 
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APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity 
(eg, no shortness of breath when walking, climbing stairs, et cetera). 
II 
Mild symptoms (eg, mild shortness of breath and/or angina).  
Slight limitations during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, eg, walking short distances (20-100 meters). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound. 
Adapted from Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 
9th ed.  
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 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation and the Modification of Diet in Renal Disease (MDRD) Study equation. NKDEP’s 
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.  
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. 
This equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr țĮ × max(Scr ț-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
țLVIRUIHPDOHVDQGIRUPDOHV 
ĮLV-0.329 for females and -0.411 for males, 
min indicates the minimum of Scr țRUDQG 
max indicates the maximum of Scr țRU 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found on the National Institute of Diabetes and 
Digestive and Kidney Diseases webpage (https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators) 
Classification of Renal Impairment Using FDA Guidance for Industry  
The renal impairment classification scale provided in the guidance document considers eGFR 
and Estimated Creatinine Clearance (CLcr). It allows for the fact that equations to calculate 
eGFR are evolving. In this study, eGFR will be calculated using the CKD-EPI equation. 
Classification of Renal Function Based on Estimated GFR or Estimated Creatinine Clearance 
Stage 
Description 
eGFR 
(mL/min/1.73m2) 
CLcr 
(mL/min) 
1 
Control (Normal) GFR 
 90 
 90 
2 
Mild Decrease in GFR 
60-89 
60-89 
3 
Moderate Decrease in 
GFR 
30-59 
30-59 
4 
Severe Decrease in GFR 
15-29 
15-29 
5 
End Stage Renal Disease 
< 15 not on dialysis or requiring 
dialysis 
< 15 not on dialysis or requiring 
dialysis 
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APPENDIX 10. IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE are intended as a 
guidance. This document should be used in conjunction with expert clinical judgement (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies. 
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, PD, and adverse 
effects of concomitant drugs. In addition to the results of these tests, the following factors should 
be considered when making an irAE diagnosis:  
x What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
x How did the patient respond to withdrawal of tislelizumab? 
x Did the event recur when tislelizumab was reintroduced? 
x Was there a clinical response to corticosteroids? 
x Is the event an autoimmune endocrinopathy? 
x Is PD or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field 
associated with the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of Possible  
Immune-related Adverse Events 
Immune-Related Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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Immune-Related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a patient 
experiences bleeding, pain, or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.  
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a hepatologist. A 
liver biopsy is encouraged. 
Renal toxicity 
Review hydration status and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to nephrology for further management assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology 
referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK, CK-MB, troponin I and T analysis, 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 muscle 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 testing; LKM, liver kidney microsomal antibody; LP, liver pancreas antigen; MRA, 
magnetic resonance angiogram; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; 
SMA, smooth muscle antibody; T4, thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea 
electrolytes and creatinine. 
Treatment of Immune-Related AEs 
x An irAEs can escalate quickly; study treatment interruption, close monitoring, timely 
diagnostic work-up and treatment intervention, as appropriate, with patients is 
required 
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x An irAEs should improve promptly after introduction of immunosuppressive therapy. 
If this does not occur, review the diagnosis, seek further specialist advice, and contact 
the medical monitor 
x For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the medical monitor 
x Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
x Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with 
a beta blocker, and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 μg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
μg/kg/day). Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker and 
may require carbimazole until 
thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month. If there is no improvement 
in 48 hours, treat as Grade 3-4. 
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. 
Initiate pulse 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 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until 
resolved/improved to 
Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if 
symptoms/appearance persist for 48 
hours or worsen. Consider 
Pneumocystis infection prophylaxis. 
Taper corticosteroids over at least 
6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or 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. 
Colitis/Diarrhea 
1 
Mild symptoms: < 3 liquid 
stools per day over 
baseline and feeling well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day over 
baseline, or abdominal 
pain, or blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
 
Initiate intravenous 
methylprednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, hepatitis, 
NYHA grade III/IV CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and 
after discussion with 
the medical monitor. 
 
4 
Life-threatening symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
2 
Rash covers 10%-30% of 
BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch. Consider a 
short course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with substantial 
symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: 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 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 - 3 X ULN if 
baseline was normal; 
1.5 - 3 X baseline if 
baseline was abnormal 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or 
AST > 3 - 5 X ULN if 
baseline was 
normal; > 3 - 5 X baseline 
if baseline was abnormal 
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 
WR 10 mg. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
ALT or 
AST > 5 - 20 X ULN if 
baseline was 
normal; > 5 - 20 X baseline 
if baseline was abnormal 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
intravenous (methyl)prednisolone 
2 mg/kg/day. When LFTs improve 
to Grade 2 or lower, convert to oral 
prednisolone and taper over at least 
4 weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
medical monitor. 
4 
ALT or AST > 20 X ULN 
if baseline was 
normal; > 20 X baseline if 
baseline was abnormal 
Initiate intravenous 
methylprednisolone 2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 6 weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
x 
If on oral prednisolone, change to pulsed intravenous methylprednisolone 
x 
If on intravenous, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
x 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered 
to < 10 mg 
prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate 
intravenous (methyl)prednisolone 
1-2 mg/kg. Taper corticosteroids 
over at least 4 weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug 
suspected: Discontinue 
study treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
replacement therapy is available. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value ULN 
to 160 mg/dL; ULN to 8.9 
mmol/L 
Monitor closely and treat according 
to local guideline. Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and 
islet cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 160-
250 mg/dL; 8.9- 13.9 
mmol/L 
Obtain a repeat blood glucose level 
at least every week. Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 250-
500 mg/dL; 13.9- 27.8 
mmol/L 
Admit patient to hospital and refer 
to a diabetologist for hyperglycemia 
management. Corticosteroids may 
exacerbate hyperglycemia and 
should be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline 
or Grade 0-1. 
4 
Fasting glucose 
value > 500 mg/dL; > 27.8 
mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. Refer the patient to a 
diabetologist for insulin 
maintenance and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment. Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; reintroduce 
only after discussion 
with the medical 
monitor. 
4 
Blindness (at least 20/200) 
in the affected eyes 
Initiate intravenous 
(methyl)prednisolone 2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Admit to hospital for urgent 
Hold study treatment; 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Abdominal pain, nausea, 
and vomiting 
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. 
reintroduce only after 
discussion with the 
medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate 
referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental (fine 
motor) activities 
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or permanent 
joint damage, daily living 
activity limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments, and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage 
as a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food 
and fluid intake, daily 
living activity limited 
Admit to hospital for appropriate 
management. Initiate intravenous 
(methyl)prednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone when symptoms 
improved to Grade 2 and taper over 
at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider 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 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
steroids and treat as Grade 2  
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1 
3-4 
Severe weakness, limiting 
self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus intravenous 
(methyl)prednisolone and1-
2 mg/kg/day maintenance for severe 
activity restriction or dysphagia. If 
symptoms do not improve add 
immunosuppressant therapy. Taper 
oral steroids over at least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1. 
Discontinue if any 
evidence of 
myocardial 
involvement 
Myocarditis 
1 
Asymptomatic but 
abnormal CK-MB, cardiac 
troponin, or 
intraventricular conduction 
delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac symptoms 
or any increase in cardiac serum 
markers to the coronary care unit. 
Initiate oral prednisolone or 
intravenous (methyl)prednisolone at 
1-2 mg/kg/day. Manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of 
(methyl)prednisolone 1g/day and 
add MMF, infliximab or 
antithymocyte globulin 
Hold study treatment 
until completely 
resolved or 
myocarditis has been 
ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
has been excluded and 
symptoms have 
completely resolved 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; 
CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle isoenzyme; INR, international 
normalized ratio; LFT, liver function testing; MMF, mycophenolate mofetil; NYHA, New York Heart Association; T4, 
thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, 
upper limit of normal. 
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APPENDIX 11. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following Eisenhauer et al 2009.  
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria.  
Note: Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
x 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 
x 10 mm caliper measurement by clinical exam (when superficial). 
x 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
QRGHPXVWEH 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. 
Non-measurable Disease 
$OORWKHUOHVLRQVRUVLWHVRIGLVHDVHLQFOXGLQJVPDOOOHVLRQVORQJHVWGLDPHWHU 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
x Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions 
x Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
x Blastic bone lesions are non-measurable. 
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Cystic lesions: 
x Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
x Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
x Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as tarJHWOHVLRQVPXVWPHHWWKHFULWHULRQRIDVKRUWD[LVRI
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, saggital, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological noGHVWKRVHZLWKVKRUWD[LV mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
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progression” (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
x 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. 
x CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (eg, for body scans). 
x 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. 
x Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint. 
x Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. Because tumor 
markers are disease specific, instructions for their measurement should be 
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incorporated into protocols on a disease specific basis. Specific guidelines for both 
CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response 
(in recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer. 
x Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and PD. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
x Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
x Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
x Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
1 or more new lesions is also considered progression). 
x Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
x 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 complete response criteria are met, since a normal lymph 
node is defined as having a short axis of < 10 mm. Case report recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis 
<10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
x 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 
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become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the eCRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value 
will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm. 
x Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
x CR: Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
x PD: Unequivocal progression (as detailed below) of existing non-target lesions. 
(Note: the appearance of 1 or more new lesions is also considered progression.) 
x Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
x When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of 1 or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
x When the patient has only non-measurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of trial entry to have measurable disease. The 
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same general concept applies here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden. Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). 
Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy”. If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
New Lesions 
The appearance of new malignant lesions denotes PD; 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 trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the patient who has 
visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals 
metastases. The patient’s brain metastases are considered to be evidence of PD even if he/she did 
not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While 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. 
x 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 
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PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drugs until the end of 
treatment taking into account any requirement for confirmation. On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR. Protocols must specify how any new 
therapy introduced before progression will affect best response designation. The patient’s BOR 
assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions. Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement. Specifically, 
in nonrandomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “BOR”. 
The BOR is determined once all the data for the patient is known. Best response determination in 
trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all time points (for example, a patient who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a BOR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline. If the minimum time is not met when SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments. For example, a 
patient who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after the first SD 
assessment would be considered inevaluable. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
SD 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all evaluated 
Non-PD or not all evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
No 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
SD 
NE 
PD 
PD 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
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based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as “symptomatic deterioration”. 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response: it is a reason 
for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDGPET 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 FDGPET 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 
FDGPET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
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The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
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APPENDIX 12. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
SITRAVATINIB 
The text below was obtained from the followings https://crediblemeds.org/ and 
https://drug-interactions.medicine.iu.edu/Main-Table.aspx. 
Bold font indicates medications or substances that might be relatively commonly used. 
Italic font indicates medications for indications that are exclusionary for the current study or 
would likely result in discontinuation from study treatment with sitravatinib for management of a 
concurrent illness. 
MEDICATIONS THAT SHOULD BE AVOIDED 
Drugs with a Known Risk of QT Prolongation/Torsades de Pointes 
Amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), azithromycin, bepridil 
(off US market), chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride (off US 
market), citalopram, clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on 
US market), donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, 
fluconazole, gatifloxacin (off US market), grepafloxacin (not on US market), halofantrine (not 
on US market), haloperidol, ibogaine (not on US market), ibutilide, levofloxacin, 
levomepromazine / methotrimeprazine (not on US market), levomethadyl (off US market), 
levosulpiride (not on US market), mesoridazine (off US market), methadone, moxifloxacin, 
ondansetron, oxaliplatin, pentamidine, pimozide, probucol (off US market), procainamide, 
propofol, quinidine, roxithromycin (not on US market), sevoflurane, sotalol, sparfloxacin (off 
US market), sulpiride (not on US market), sultopride (non on US market), terfenadine (off US 
market), terlipressin (not on US market), terodiline (not on US market), thioridazine, 
vandetanib. 
CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS 
Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and BCRP 
Transporters 
Enzyme 
 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, 
fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, 
saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan. 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan. 
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CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS (CONTINUED) 
Sensitive Substrates and Substrates With Narrow Therapeutic Index for the Indicated 
CYP Enzymes  
Enzyme 
 
CYP2B6 
Bupropion. 
CYP2C8 
Repaglinide.  
CYP2D6 
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, 
perphenazine, tolterodine, 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, vardenafil.  
Drugs with Conditional Risk of Torsades de Pointes 
Amantadine, amisulpride (not on US market), amitriptyline, amphotericin B, atazanavir, 
bendroflumethiazide / bendrofluazide (not on US market), chloral hydrate, diphenhydramine, 
doxepin, esomeprazole, famotidine, fluoxetine, fluvoxamine, furosemide / frusemide, 
galantamine, garenoxacin (not on US market), hydrochlorothiazide, hydroxychloroquine, 
hydroxyzine, indapamide, itraconazole, ivabradine, ketoconazole, lansoprazole, loperamide, 
metoclopramide, metolazone, metronidazole, nelfinavir, olanzapine, omeprazole, 
pantoprazole, paroxetine, piperacillin/tazobactam, posaconazole, propafenone, quetiapine, 
quinine sulfate, ranolazine, sertraline, solifenacin, telaprevir, torsemide / torasemide, 
trazodone, voriconazole, ziprasidone. 
 
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APPENDIX 13. BARCELONA CLINIC LIVER CANCER (BCLC) 
STAGING CLASSIFICATION 
The Barcelona Clinic Liver Cancer (BCLC) system has been widely validated and is the most 
commonly used staging system for HCC. It determines cancer stage and patient prognosis based 
on tumor burden, severity of liver disease, and the patient’s ECOG Performance Status. 
The staging according to the BCLC classification assigns prognoses based on clinical and tumor 
parameters and is summarized as follows: 
BCLC Stagea, b 
Very early stage (0) 
Early stage (A) 
Intermediate 
stage (B) 
Advanced stage (C) Terminal stage (D) 
Single nodule <2 cm 
Carcinoma in situ 
Child–Pugh A, 
ECOG PS 0 
Single or 3 
nodules 
<3 cm 
Child–Pugh A-B, 
ECOG PS 0 
Multinodular, 
Child–Pugh A-B, 
ECOG PS 0 
Portal invasion, 
Extrahepatic spread, 
Child–Pugh A-B, 
ECOG PS 1-2 
Child–Pugh C 
ECOG PS 3-4 
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group 
Performance Status. 
a. 
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with 
hepatocellular carcinoma. Gastroenterology. 2016;150:835-53. 
b. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin 
Liver Dis 1999;19:329-38. 
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STATISTICAL AALYSIS PLA
Study Protocol umber: 
BGB-900-10
Study Protocol Title: 
A Phase 1/2 Study to Investigate the Safety, Tolerability, 
Pharmacokinetics, 
and 
Preliminary 
Antitumor 
Activity 
of 
Sitravatinib as Monotherapy and in Combination With Tislelizumab 
in Patients With Unresectable Locally Advanced or Metastatic 
Hepatocellular Carcinoma or Gastric/Gastroesophageal Junction 
Cancer 
Date: 
 07 April 2023 
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1.0 
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SIGATURE PAGE 
 
Author:
              
              
 
 
 
___
_______ 
Signature 
 
Date: ______________ 
 
Approval 
 
 
 
 
____
__________ 
Signa
 
Date: ______________ 
 
 
 
____
__________ 
Signa
 
Date: ______________ 
 
 
 
_____
________ 
Signat
 
Date: ______________ 
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TABLE OF COTETS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7
1.INTRODUCTION ........................................................................................................8
2.STUDY OVERVIEW ...................................................................................................8
2.1.Study Design .................................................................................................................8
2.1.1.Phase 1 (Dose Escalation for Sitravatinib as Monotherapy and in 
Combination With Tislelizumab) .................................................................................8
2.1.2.Phase 2 (Dose Expansion for Sitravatinib as Monotherapy and in 
Combination With Tislelizumab) .................................................................................9
2.2.Study Assessments......................................................................................................10
3.STUDY OBJECTIVES ..............................................................................................11
3.1.Study Objective for Phase 1 (Dose Escalation) ..........................................................11
3.1.1.Primary Objectives .....................................................................................................11
3.1.2.Secondary Objectives .................................................................................................11
3.1.3.Exploratory Objective .................................................................................................11
3.2.Study Objective for Phase 2 (Dose Expansion) ..........................................................11
3.2.1.Primary Objective .......................................................................................................11
3.2.2.Secondary Objectives .................................................................................................11
3.2.3.Exploratory Objectives ...............................................................................................12
4.STUDY ENDPOINTS ................................................................................................12
4.1.Primary Endpoints for Phase 1 (Dose Escalation) ......................................................12
4.1.1.Primary Endpoints ......................................................................................................12
4.1.2.Secondary Endpoints ..................................................................................................12
4.1.3.Exploratory Endpoints ................................................................................................12
4.2.Primary Endpoints for Phase 2 (Dose Expansion) .....................................................12
4.2.1.Primary Endpoint ........................................................................................................12
4.2.2.Secondary Endpoints ..................................................................................................12
4.2.3.Exploratory Endpoints ................................................................................................13
5.SAMPLE SIZE CONSIDERATIONS .......................................................................13
6.STATISTICAL METHODS .......................................................................................13
6.1.Analysis Sets ...............................................................................................................14
6.2.Multiplicity Adjustment..............................................................................................15
6.3.Data Analysis General Considerations .......................................................................15
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6.3.1.Definitions and Computations ....................................................................................15
6.3.2.Conventions ................................................................................................................15
6.3.3.Handling of Missing Data ...........................................................................................16
6.4.Patient Characteristics ................................................................................................16
6.4.1.Patient Disposition ......................................................................................................16
6.4.2.Protocol Deviations ....................................................................................................16
6.4.3.Demographic and Other Baseline Characteristics ......................................................17
6.4.4.Disease History ...........................................................................................................17
6.4.5.Prior Anticancer Drug Therapies and Surgeries .........................................................18
6.4.5.1Prior Anticancer Drug Therapies ................................................................................18
6.4.5.2Prior Anticancer Surgeries/ Procedures with Therapeutic Intent ...............................18
6.4.5.3Prior Radiotherapies ...................................................................................................19
6.4.6.Prior and Concomitant Medications ...........................................................................19
6.4.7.Medical History ..........................................................................................................19
6.5.Efficacy Analysis ........................................................................................................19
6.5.1.Primary Efficacy Endpoints ........................................................................................19
6.5.2.Secondary Efficacy Endpoints ....................................................................................19
6.5.3.Exploratory Efficacy Endpoints .................................................................................22
6.6.Safety Analysis ...........................................................................................................22
6.6.1.Extent of Exposure .....................................................................................................22
6.6.2.Adverse Events ...........................................................................................................23
6.6.2.1Treatment Emergent Adverse Event ...........................................................................23
6.6.2.2Immune- Mediated Adverse Event .............................................................................25
6.6.2.3Infusion-related Adverse Event ..................................................................................26
6.6.2.4Death ...........................................................................................................................26
6.6.3.Laboratory Values ......................................................................................................26
6.6.4.Vital Signs ..................................................................................................................28
6.6.5.Electrocardiograms (ECG) .........................................................................................28
6.6.6.Eastern Cooperative Oncology Group (ECOG) Performance Status .........................28
6.7.Pharmacokinetic Analysis ..........................................................................................28
6.7.1.Pharmacokinetic Analysis of Sitravatinib ..................................................................28
6.7.2.Pharmacokinetic Analysis of Tislelizumab ................................................................29
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6.8.Immunogenicity Analysis ...........................................................................................30
7.INTERIM ANALYSIS ...............................................................................................30
8.CHANGES IN THE PLANNED ANALYSIS ...........................................................30
9.REFERENCES ...........................................................................................................32
APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES ...............33
1.1 Prior/Concomitant Medications/Procedures ............................................................................33
1.2 Adverse Events ........................................................................................................................33
1.3 Disease history and prior therapy (Drug, surgery/procedure, radiotherapy) ...........................34
1.4 Subsequent anti-cancer therapy ...............................................................................................35
APPENDIX 2. RULES FOR IDENTIFYING MISSING TUMOR ASSESSMENTS ...............36
 
 
 
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LIST OF TABLES 
Table 1: Estimates of 95% CI of ORR With 20 Patients ...............................................................13
Table 2: Layout for tables by indication ........................................................................................14
Table 3: Layout for tables by dosage .............................................................................................14
Table 4: Censoring Rules for Progression-free Survival Per RECIST Version 1.1 ......................20
Table 5: Clinical Laboratory Assessment ......................................................................................26
Table 6: Statistical Analysis Plan Changes ....................................................................................31
Table 7: Example of scheduled tumor assessments with time window .........................................36
 
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LIST OF ABBREVIATIOS AD DEFIITIOS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug Antibody  
AEs  
Adverse Events 
ATC 
Anatomical Therapeutic Chemical  
CA-125 
Cancer Antigen 125 
CBR 
Clinical Benefit Rate  
CIs 
Confidence Intervals 
CR  
Complete Response 
DCR 
Disease Control Rate 
DOR 
Duration of Response  
ECG 
Electrocardiograms  
ECOG 
Eastern Cooperative Oncology Group  
GCIG  
Gynecologic Cancer Intergroup 
imAEs 
Immune-mediated AEs  
MedDRA 
Medical Dictionary for Regulatory Activities  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NSCLC 
Non-Small Cell Lung Cancer  
ORR 
Objective Response Rate  
OS 
Overall Survival  
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein-1 
PD-L1  
Programmed Cell Death Protein-Ligand 1 
PFS 
Progression-Free Survival 
PGx 
Pharmacogenetic 
PK 
Pharmacokinetic(s)  
PR  
Partial Response 
PT 
Preferred Term  
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAEs 
Serious Adverse Events 
SD 
Stable Disease 
SFD 
Study Follow-up Duration  
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event  
TTR 
Time to Response 
WHO DD 
World Health Organization Drug Dictionary  
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1. 
ITRODUCTIO 
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-900-10: A Phase 1/2 study to 
investigate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of 
sitravatinib as monotherapy and in combination with tislelizumab in patients with unresectable 
locally advanced or metastatic hepatocellular carcinoma or gastric/gastroesophageal junction 
cancer. This SAP is based on BGB-900-104 Protocol Amendment 4.0, dated on April 28, 2020. 
The focus of this SAP is for the planned final analysis specified in the study protocol. The analysis 
details for Pharmacodynamics, Pharmacogenomics and Biomarker are not described within this 
SAP.  
2. 
STUDY OVERVIEW 
2.1. 
Study Design 
This is an open-label, multicenter Phase 1/2 clinical study for patients with histologically or 
cytologically confirmed unresectable locally advanced or metastatic hepatocellular carcinoma 
(HCC) or gastric/gastroesophageal junction (G/GEJ) cancer. All patients will receive study 
treatment(s) until PD, unacceptable toxicity, death, withdrawal of consent, or study termination by 
sponsor. 
This study consists of 2 phases. 
2.1.1. 
Phase 1 (Dose Escalation for Sitravatinib as Monotherapy and in Combination 
With Tislelizumab) 
Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be 
evaluated in patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. A 
modified 3 + 3 design will be used in the dose escalation. Approximately 6 to 12 DLT evaluable 
patients will be treated with sitravatinib as monotherapy.  
The combination dose escalation of sitravatinib (80 mg once daily and 120 mg once daily; 
modified 3 + 3 design) with tislelizumab (200 mg once every 3 weeks, in both cohorts) will be 
evaluated in patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer. 
Approximately 12 to 24 DLT evaluable patients will be treated. 
DLT assessment will be performed for HCC, G/GEJ cancer respectively. 
DLT Observation Period and the Modified 3 + 3 Scheme 
For Phase 1 dose escalation, a 21-day DLT assessment window will be utilized for initial dose 
confirmation recommendations. DLTs will be assessed among evaluable patients within 21 days 
after the first dose of study drug(s). For dose escalation decisions, only DLTs occurring within 
21 days will be evaluated. 
Dose escalation in sitravatinib monotherapy or sitravatinib in combination with tislelizumab will 
occur in accordance with the following modified 3 + 3 dose escalation rules. 
A minimum of 3 DLT evaluable patients will be initially enrolled per cohort. 
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x If none of the first 3 evaluable patients enrolled in a given cohort experience a DLT, 
dose escalation may proceed. 
x If one of the first 3 evaluable patients enrolled in a given cohort experiences a DLT, 
additional patients (for a minimum of 6 evaluable patients) will be enrolled in that 
cohort.  
 If less than one third of evaluable patients in a given cohort experiences a DLT 
(eg, DLTs in fewer than two of 6 evaluable patients), escalation will proceed to 
the next higher dose level. 
If a DLT is observed in at least one-third or more of evaluable patients (eg, two or more of up to 
6 evaluable patients), the dose escalation will be stopped. A lower dose level or an intermediate 
dose level may be evaluated if recommended by the SMC. 
The SMC will confirm RP2D of the monotherapy and combination treatment based on all available 
safety, efficacy, PK and exploratory data. Additional dose levels may be evaluated if needed. For 
the sitravatinib combination therapy, RP2Ds for each tumor type will be recommended by SMC 
based on 6 to 12 DLT evaluable patients respectively. 
2.1.2. 
Phase 2 (Dose Expansion for Sitravatinib as Monotherapy and in Combination 
With Tislelizumab) 
There will be a total of 4 cohorts in the study Approximately 20 patients will be enrolled in each 
cohort. 
Sitravatinib monotherapy 
x Cohort A: Anti-PD-1/PD-L1 antibody naïve or refractory/resistant HCC  
Sitravatinib in combination with tislelizumab 
x Cohort B: Anti-PD-1/PD-L1 antibody naïve HCC 
x Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant HCC 
x Cohort D: Anti-PD-1/PD-L1 antibody naïve G/GEJ cancer 
The study schema is in Figure 1. 
Study SchemaFigure 1. 
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Figure 1. 
Study Schema 
 
Abbreviations: Ab, antibody; G/GEJ, gastric/gastroesophageal junction, HCC, hepatocellular carcinoma; PD-1, 
programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; PK, pharmacokinetic; QD, once a 
day; Q3W, once every 3 weeks; RP2D, recommended Phase 2 dose; R/R, refractory or resistant, Sitra, sitravatinib; 
SMC, Safety Monitoring Committee; Tisle, tislelizumab. 
ote: The combination dose escalation may start simultaneously with the monotherapy cohort. The SMC will 
confirm RP2D of the monotherapy and combination treatment based on all available safety, efficacy, PK and 
exploratory data. Additional dose levels may be evaluated if needed. For the sitravatinib combination therapy, 
RP2Ds for each tumor type will be recommended by SMC based on 6 to 12 DLT evaluable patients respectively. 
2.2. 
Study Assessments 
Tumor Assessment: 
Tumor assessments will be performed by investigator using Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v) 1.1 criteria (Eisenhauer et al. 2009). Tumor imaging will be 
performed at baseline (within 28 days prior to the first dose of study drugs). During the study, 
tumor imaging will be performed approximately every 6 weeks (± 7 days) in the first 12 months 
and thereafter approximately every 9 weeks (± 7 days). If a patient discontinues study treatment 
due to any reasons other than disease progression, tumor assessments will continue to be performed 
as scheduled until initiation of a new anticancer therapy, disease progression, loss to follow up, 
withdrawal of consent, death, or until the study terminates, whichever occurs first. 
Safety Assessment: 
Patients will be evaluated for any adverse events (AEs) and serious adverse events (SAEs) 
occurring up to 30 days after the last dose of study drugs (all severity grades, per National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0) or initiation of 
a new anticancer therapy, whichever occurs first, and immune-mediated AEs (imAEs) occurring 
up to 90 days after the last dose of tislelizumab regardless of initiation of a subsequent anticancer 
therapy. At the end of treatment, ongoing AEs considered related to study treatment will be 
followed until the event has resolved to baseline or ≤ Grade 1, the event is assessed by the 
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investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the AE. All drug-related SAEs 
will be recorded by investigator after treatment discontinuation until patient death, withdrawal of 
consent, or loss to follow up, whichever occurs first. 
3. 
STUDY OBJECTIVES 
3.1. 
Study Objective for Phase 1 (Dose Escalation) 
3.1.1. 
Primary Objectives 
x To characterize safety and tolerability of sitravatinib as monotherapy and in 
combination with tislelizumab 
x To confirm the RP2D for sitravatinib as monotherapy and in combination with 
tislelizumab 
3.1.2. 
Secondary Objectives 
x To characterize the Pharmacokinetic (PK) profiles of sitravatinib after single dose and 
at steady state when given in combination with tislelizumab 
x To assess the preliminary antitumor activity of sitravatinib as monotherapy and in 
combination with tislelizumab in HCC or gastric/gastroesophageal junction (G/GEJ) 
cancer patients   
3.1.3. 
Exploratory Objective 
x To assess PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib 
3.2. 
Study Objective for Phase 2 (Dose Expansion) 
3.2.1. 
Primary Objective 
x To assess the preliminary antitumor activity as indicated by ORR per Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of sitravatinib as 
monotherapy and in combination with tislelizumab 
3.2.2. 
Secondary Objectives 
x To assess the preliminary antitumor activity as indicated by duration of response 
(DOR), DCR and PFS per RECIST v1.1 as monotherapy and in combination with 
tislelizumab 
x To characterize the safety and tolerability of sitravatinib as monotherapy and in 
combination with tislelizumab 
x To characterize the PK profile of sitravatinib 
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3.2.3. 
Exploratory Objectives 
x To assess PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib 
x To assess overall survival (OS) 
 
4. 
STUDY EDPOITS 
4.1. 
Primary Endpoints for Phase 1 (Dose Escalation) 
4.1.1. 
Primary Endpoints 
x Safety and tolerability will be assessed throughout the study by monitoring AEs and 
SAEs per National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0, relevant physical examination, electrocardiograms (ECGs), and 
laboratory assessments as needed  
4.1.2. 
Secondary Endpoints 
x Plasma concentrations and the derived PK parameters of sitravatinib if data permit: 
 Single dose: Cmax, time to maximum plasma concentration (Tmax), AUC0-t, 
clearance after oral administration (CL/F) 
 Repeating dose: Cmax, Cτ, Tmax, AUC0-tau, CL/F, accumulation ratio (Ro) 
x Efficacy evaluations by investigators: ORR, DOR, DCR, and PFS based on RECIST 
v1.1. 
4.1.3. 
Exploratory Endpoints 
x Serum concentrations of tislelizumab and anti-tislelizumab antibodies 
4.2. 
Primary Endpoints for Phase 2 (Dose Expansion) 
4.2.1. 
Primary Endpoint 
x 
Objective response rate (ORR), defined as the percentage of patients whose best overall 
response (BOR) is CR or PR assessed by investigators per RECIST v1.1  
4.2.2. 
Secondary Endpoints 
x Duration of response (DOR), defined as the time from the first determination of an 
objective response until the first documentation of PD as assessed by investigator per 
RECIST v1.1, or death, whichever comes first 
x Disease control rate (DCR), defined as the proportion of patients with BOR as CR, PR, 
or SD assessed by investigator per RECIST v1.1 
x Progression-free survival (PFS), defined as the time from the date of first dose to the 
date of first documentation of PD assessed by the investigator per RECIST v1.1 or 
death, whichever occurs first. 
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x Safety and tolerability will be assessed throughout the study by monitoring AEs and 
SAEs per NCI-CTCAE v5.0, relevant physical examination, ECGs, and laboratory 
assessments as needed  
x Plasma concentrations of sitravatinib predose and postdose at steady state  
4.2.3. 
Exploratory Endpoints 
x Serum concentrations of tislelizumab and anti-tislelizumab antibodies 
x OS is defined as the time from date of first dose of study drug(s) to date of death due 
to any cause 
5. 
SAMPLE SIZE COSIDERATIOS 
The study plans to enroll approximately 98 to 116 patients.  
x Phase 1 (sitravatinib as monotherapy and in combination with tislelizumab dose 
escalation): Approximately 18 to 36 DLT evaluable patients with unresectable locally 
advanced or metastatic HCC or G/GEJ cancer will be enrolled.  
x Phase 2 (sitravatinib as monotherapy and in combination with tislelizumab 
combination dose expansion): Approximately 80 patients will be enrolled in Phase 2 
(approximately 20 patients per cohort). Enrollment into these cohorts will occur 
simultaneously and independent of each other. Each cohort will be evaluated 
separately.  
Estimates of the exact 95% CI of the observed ORR for several potential outcomes using the 
sample size of 20 patients are provided in Table 1. 
Table 1: Estimates of 95% CI of ORR With 20 Patients 
umber of Observed Response 
ORR 
95% Exact CI 
4 
20% 
5.7%, 43.7% 
6 
30% 
11.9%, 54.3% 
8 
40% 
19.1%, 63.9% 
10 
50% 
27.2%, 72.8% 
12 
60% 
36.1%, 80.9% 
 
6. 
STATISTICAL METHODS 
In general, data from phase 1 and phase 2 studies will be summarized together by indication for 
efficacy analysis, and by dosage, and indication separately for patient characteristic and safety 
analysis, unless otherwise specified. Four patients who are in phase 1 with GC/GEJC were either 
anti-PD-(L)1 R/R (086022-008) or took Sitravatinib monotherapy (086022-001, 086022-004, 
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086025-004). These four patients are not included in summary statistics by indication because of 
small sample size. The layout for tables by indication or by dosage is presented in Table 2 and 
Table 3. 
 
Table 2: Layout for tables by indication 
 
Sitra  
HCC  
anti-PD-(L)1 
Naïve or R/R 
Sitra + Tisle 
HCC  
anti-PD-(L)1 
Naïve 
Sitra + Tisle  
HCC  
anti-PD-(L)1 
R/R 
Sitra + Tisle  
HCC 
Subtotal 
Sitra + Tisle 
GC/GEJC 
anti-PD-(L)1 
Naïve 
Row 1  
 
 
 
 
Table 3: Layout for tables by dosage 
 
Sitra 
80 
mg 
Sitra 120 
mg 
Sitra 
Monotherapy 
Sitra 80 mg 
+ Tisle 
Sitra 120 mg  
+ Tisle 
Sitra + Tisle 
Combination Therapy 
Row 1 
 
 
 
 
 
 
 
6.1. 
Analysis Sets 
The Safety Analysis Set includes all patients who received at least 1 dose of any study drug (any 
component for the combination therapy). Patients from either Phase 1 or 2 are eligible for inclusion 
in the Safety Analysis Set.  
The Efficacy Evaluable Analysis Set includes all patients who received at least 1 dose of any 
study drug with measurable disease at baseline per RECIST v1.1 and who had at least 1 evaluable 
postbaseline tumor assessment unless treatment was discontinued due to clinical disease 
progression or early death (within 13 weeks of the first dose date). Patients from Phase 1 or 2 are 
eligible for inclusion in the Efficacy Evaluable Analysis Set.  
DLT Evaluable Analysis Set for sitravatinib monotherapy includes patients who received at 
least 75% of the assigned total dose of sitravatinib for the DLT assessment window. Additionally, 
patients who had a DLT event will also be considered evaluable. Only patients from Phase 1 are 
eligible for inclusion in the DLT Evaluable Analysis Set of sitravatinib monotherapy.  
DLT Evaluable Analysis Set for sitravatinib and tislelizumab combination includes patients 
who received at least 75% of the assigned total dose of sitravatinib and ≥ 67% (approximately two-
thirds) of the assigned total dose of tislelizumab for the DLT assessment window. Additionally, 
patients who had a DLT event will also be considered evaluable. Only patients from Phase 1 are 
eligible for inclusion in the DLT evaluable analysis set of sitravatinib and tislelizumab 
combination therapy.  
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The Sitravatinib Pharmacokinetic Analysis Set includes all patients who contributed at least 1 
quantifiable PK sample for sitravatinib. The sitravatinib pharmacokinetic analysis set will be used for 
PK analysis for sitravatinib. 
The Tislelizumab Pharmacokinetic Analysis Set includes all patients who contributed at least 1 
quantifiable PK sample for tislelizumab. The Tislelizumab Pharmacokinetic Analysis Set will be used 
for PK analysis for tislelizumab. 
The ADA Evaluable Analysis Set includes all patients who received at least 1 dose of 
tislelizumab and for whom both baseline ADA and at least 1 post-baseline ADA results are 
available. Patients from either Phase 1 or 2 are eligible for inclusion in the ADA Evaluable 
Analysis Set.  
6.2. 
Multiplicity Adjustment 
Since no formal hypothesis is tested in this study, multiplicity adjustment is not needed. 
6.3. 
Data Analysis General Considerations 
6.3.1. 
Definitions and Computations 
Study drugs 
Study drugs include tislelizumab and sitravatinib. Tislelizumab (200 mg) will be administered on 
Day 1 of each 21-day cycle (every 3 weeks). Sitravatinib capsules will be administered orally, 
once daily continuously for a total daily dose of 120 mg. 
Study day 
Study day will be calculated in reference to the date of the first dose of study drug for both safety 
analysis and efficacy analysis. For assessments conducted on or after the date of first dose of study 
drug, the study day will be calculated as (assessment date – date of first dose of study drug + 1). 
For assessments conducted before the date of first dose of study drug, study day is calculated as 
(assessment date – date of first dose of study drug). 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. 
Baseline value 
Unless otherwise specified, a baseline value is defined as the last non-missing value collected 
before the first dose of study drug. 
Study Follow-up Duration  
Study follow-up duration (SFD) is defined as the duration from the first dose date to the study 
discontinuation date (e.g., death, consent withdrawal, lost to follow-up) or to cutoff date if a patient 
is still ongoing. 
All calculations and analyses will be conducted using SAS® Version 9.4 or higher. 
6.3.2. 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
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x 
1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 decimal 
place. 
x 
1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up to 1 
decimal place. 
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 laboratory results collected in numerical range, if lab results ≥ x then set as x; if < x, then 
x/2. 
x 
For by-visit observed data analysis, percentages will be calculated based on the number of 
patients with non-missing data as the denominator, unless otherwise specified. 
x 
For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). For PK concentration and parameters, 
geometric mean, and geometric coefficient of variance (CV%) will also be included in the 
summary while Q1 and Q3 may not be calculated.  
x 
For discrete endpoints, summary statistics will include frequencies and percentages. 
6.3.3. 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in this SAP. 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 and prior/concomitant medications/procedures are provided in Appendix 1. By-
visit endpoints will be analyzed using observed data unless otherwise specified. For observed data 
analysis, missing data will not be imputed, and only the observed records will be included. 
6.4. 
Patient Characteristics 
6.4.1. 
Patient Disposition 
The number (percentage) of patients who signed informed consent, enrolled in the study, screen 
failures, screened previously, and reason for screen failure will be summarized by phase in all 
patients.  
The number (percentage) of patients treated, discontinued from the study, discontinued from the 
treatment (all treatments), reasons for discontinued from the study, reasons for discontinued from 
the treatment, and the duration of study follow-up will be summarized by phase, indication and 
dosage in the safety analysis set. 
The reasons for patients discontinued from tislelizumab or sitravatinib will be summarized 
separately by phase in safety analysis set.  
Patient data listings of patient disposition will be provided. 
6.4.2. 
Protocol Deviations 
Protocol deviation criteria will be established together with its category/term of important and not 
important. Patients with important protocol deviations will be identified and documented before 
the database lock. Important protocol deviations will be summarized by phase for all patients in 
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the safety analysis set. They will also be listed by each category. Deviation categories are not 
mutually exclusive. Multiple deviations within the same category are counted once per patient. 
6.4.3. 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using descriptive statistics in 
the safety analysis set by indication and by dosage, respectively, including the following variables: 
x Age (continuously and by categories [< 65 or ≥ 65 years]) 
x Sex 
x Race 
x Ethnicity 
x Country 
x Weight (kg) 
x BMI (kg/m2) 
x ECOG performance status 
x PD-L1 score status (TC ≥ 1%, TC < 1%, unknown) 
x Smoking status 
x Alcohol consumption 
6.4.4. 
Disease History 
The number (percentage) of patients reporting a history of disease and characteristics, as recorded 
on the eCRF, will be summarized by indication and dosage in the safety analysis set.  
Disease history of HCC includes the following characteristics. 
x BCLC stage at initial diagnosis 
x HCC method of first diagnosis 
x Histology grade at initial diagnosis 
x Time from initial diagnosis to time of diagnosis of metastatic disease/locally advanced 
disease 
x Disease status at study entry 
x Time from diagnosis of metastatic disease/locally advanced disease to first dose date 
x BCLC staging at study entry 
x Child-Pugh classification at study entry 
x Known metastatic site at study entry 
x Number of metastatic sites at study entry 
x Alpha-fetoprotein at baseline 
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x Macrovascular invasion 
x Extrahepatic spread 
x HCC etiology 
Disease history of Epithelial GC/GEJC includes the following characteristics. 
x Primary location 
x Disease status at study entry 
x Time from initial diagnosis to time of diagnosis of metastatic disease/ locally advanced 
disease 
x Time from diagnosis of metastatic disease/locally advanced disease to first dose date  
x Known metastatic site at study entry 
x Number of metastatic sites at study entry 
x Histology grade at initial diagnosis 
x Histology type 
x TNM staging at initial diagnosis 
x Disease stage at initial diagnosis 
The listings of disease history and characteristic with different indications will be provided. 
6.4.5. 
Prior Anticancer Drug Therapies and Surgeries 
Prior anticancer drug therapies, prior anticancer surgeries/ procedures with therapeutic intent, and 
prior radiotherapies will be summarized by indication and by dosage in the safety analysis set. The 
therapies and surgeries with the same sequence/regimen number are counted as one prior 
therapy/surgery. 
Patient data listings of prior anticancer systemic therapies and prior radiotherapies will be provided 
in the safety analysis set. 
6.4.5.1 Prior Anticancer Drug Therapies 
The number (percentage) of patients with any prior anticancer therapy, number of prior lines, type 
of prior anticancer drug received, duration of last prior anticancer systemic therapy, reasons for 
discontinuation of last anticancer drug therapy, best overall response to the last anticancer drug 
therapy, time from end of last anticancer drug therapy to first dose date, time from last disease 
progression to first dose date, and treatment setting will be summarized in the safety analysis set. 
6.4.5.2 Prior Anticancer Surgeries/ Procedures with Therapeutic Intent 
The number (percentage) of patients with any prior anticancer surgery, treatment intent of 
surgeries, time from last anticancer surgery to first dose, patients with any prior anticancer 
procedures, prior anticancer procedure name, number of prior anticancer procedures name, number 
of TACE therapy, treatment intent of procedures, and time from last anticancer procedure to first 
dose will be summarized in the safety analysis set.  
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6.4.5.3 Prior Radiotherapies 
The number (percentage) of patients with any prior radiotherapy, treatment intent, treatment 
setting, time from end of last radiotherapy to first dose date, and site irradiated will be summarized 
in the safety analysis set. 
6.4.6. 
Prior and Concomitant Medications 
Prior medications are defined as medications that stopped before the first dose of study drugs. 
Concomitant medications will be defined as medications that 1) started before the first dose of 
study drugs and were continuing at the time of the first dose of study drugs, or 2) started on or 
after the date of the first dose of study drugs up to 30 days after the patient’s last dose.   
Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes Version B3 March 12022. They will be further classified 
to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name in the safety analysis set.  
6.4.7. 
Medical History 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0. 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 for the 
Safety Analysis Set.  
Patient data listings of medical history will be provided. 
6.5. 
Efficacy Analysis 
No formal hypothesis testing is planned for efficacy analysis. Efficacy analyses, except overall 
survival, will be performed descriptively by indication. Overall survival will be performed 
descriptively by cohort, i.e., cohort A, B, C, B + C, D. 
6.5.1. 
Primary Efficacy Endpoints 
ORR by Investigators 
The BOR is the best overall response observed from the date of first dose until disease progression, 
death, cut-off date, or initiation of post-treatment anticancer therapy, whichever occurs first. 
The ORR is defined as the percentage of patients whose BOR is confirmed CR or confirmed PR  
assessed by investigators per RECIST v1.1. Patients with no post-baseline response assessment (for 
any reason) will be considered as non-responders. The ORR will be summarized with descriptive 
statistics by indication and the corresponding two-sided 95% CIs calculated from Clopper-Pearson 
exact method will be also presented. The primary analysis of ORR is based on Efficacy Evaluable 
Analysis Set and the sensitivity analysis of ORR is based on the Safety Analysis Set. 
ORR based on unconfirmed PR or CR will also be calculated in this study. 
6.5.2. 
Secondary Efficacy Endpoints 
Disease Control Rate and Clinical Benefit Rate by Investigators 
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DCR is defined as the proportion of patients with BOR of CR, PR, and SD in accordance with 
RECIST v1.1 criteria.  
CBR is defined as the proportion of patients with BOR as CR, PR, or SD lasting ≥ 24 weeks 
assessed by investigator per RECIST v1.1. 
DCR assessed and CBR by investigators will be analyzed similarly to ORR. 
Progression Free Survival by Investigators 
PFS is defined as the time from the date of first dose of study drugs to the date of first 
documentation of disease progression assessed by investigator per RECIST v1.1 or death, 
whichever occurs first. The primary analysis of PFS is based on Safety Analysis Set. The censoring 
rules for the analysis of PFS are presented in Table 4. Kaplan Meier methodology will be used to 
estimate median, Q1, and Q3 of PFS, and the event-free rates at 3, 6, 9, and 12 months. 95% CIs 
for median and other quantiles of PFS will be estimated using the method of Brookmeyer and 
Crowley (Brookmeyer and Crowley 1982). And 95% CIs for event-free rates will be estimated 
using Greenwood's formula (Greenwood M. 1926). Kaplan-Meier curves will be constructed to 
provide a visual description of the PFS change with time.  
Table 4: 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 
prior to disease progression or 
death  
Last adequate radiological assessment 
before the new anticancer therapy 
(hypothetical strategy) 
Censored 
No baseline or post-baseline 
tumor assessments without death 
within 13 weeks after first dose  
Date of first dose 
Censored 
No baseline or post-baseline 
tumor assessments with death 
within 13 weeks after first dose  
Date of death 
Event 
Death or progression after more 
than one missed visit  
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
Duration of Response by Investigators 
DOR is defined as the time from the first determination of an objective response until the first 
documentation of PD as assessed by the investigator per RECIST v1.1, or death, whichever comes 
first. All the censoring rules for PFS will be applied to DOR. DOR will be analyzed in the 
responders only. The distribution of DOR, including median, Q1 and Q3, and event-free rates at 
every 3 months, will be estimated using the Kaplan-Meier method by indication. The 95% CIs for 
median, Q1, and Q3 of DOR will be estimated using the method of Brookmeyer and Crowley 
(Brookmeyer and Crowley 1982). And 95% CIs for event-free rates will be estimated using 
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Greenwood's formula (Greenwood M. 1926). The analysis of DOR is based on Efficacy Evaluable 
Analysis Set.  
DOR without confirmation by investigator will also be calculated in this study. 
Time to Response by Investigators 
Time to response (TTR) will be summarized using descriptive statistics, such as mean, median, 
and standard deviation. Only patients who have achieved objective response by investigators per 
RECIST v1.1 will be included in the analysis of TTR. 
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesion. The 
maximum tumor shrinkage based on target lesion used in the plots will be listed. The postbaseline 
nadir will be summarized using descriptive statistics. These analyses will be performed based on 
RECIST v1.1. 
Subgroup Analysis 
To assess if the treatment effect is consistent across various subgroups, ORR and DCR by the 
investigator’s review and their 95% CIs will be estimated and plotted within each category of the 
following subgroups by indication in the Efficacy Evaluable Analysis Set. 
For HCC indication, subgroup variables may include, but not limited to,  
x Age (< 65 versus ≥ 65) 
x Sex (Male versus Female) 
x Baseline ECOG (0 versus 1) 
x Macrovascular invasion (Yes/No) 
x Extrahepatic spread (Yes/No)  
x Treatment setting (2L/3L+) 
x Disease status (Locally advanced/Metastatic) 
x BCLC staging at study entry (B/C) 
x Initial dose of Sitravatinib (80mg/120mg) 
x Baseline alpha fetoprotein (≤400/>400) 
For GC/GEJC indication, subgroup variables may include, but not limited to,  
x Age (< 65 versus ≥ 65) 
x Sex (Male versus Female) 
x Baseline ECOG (0 versus 1) 
x Primary tumor location (Stomach/Gastro-esophageal junction)  
x Treatment setting (2L/3L+) 
x Disease status (Locally advanced/Metastatic) 
x Initial dose of Sitravatinib (80mg/120mg) 
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6.5.3. 
Exploratory Efficacy Endpoints 
Overall Survival  
OS is defined as the time from first dose date to the documented death date for patients who died 
prior to or on the clinical cutoff date. For patients who are alive by the clinical cutoff date, OS will 
be censored at the last known alive date. 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 month of death date). The patient with imputed death date will be considered as an event 
for OS analysis. 
OS will be analyzed by cohort for patients enrolled in Phase 2 only. The primary analysis of OS is 
based on Safety Analysis Set.  
The distribution of OS, including median, Q1, and Q3, and event-free rates at 3, 6, 9, and 12 
months, will be estimated using the Kaplan-Meier method. 95% CIs for median, Q1, and Q3 of 
OS will be estimated using the method of Brookmeyer and Crowley (Brookmeyer and Crowley, 
1982). The 95% CIs for event-free rates will be estimated using Greenwood's formula 
(Greenwood, 1926). Kaplan-Meier survival probabilities over time for each cohort will be plotted.  
6.6. 
Safety Analysis 
All safety analyses will be performed by indication and by dosage in Safety Analysis Set. Safety 
and tolerability will be assessed, where applicable, by incidence, severity, and change from 
baseline values for all relevant parameters including AEs, laboratory values, vital signs, and ECG 
findings.  
6.6.1. 
Extent of Exposure 
The following measures of the extent of exposure will be summarized: 
x Duration of exposure (months) for tislelizumab is 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 tislelizumab and discontinued from 
treatment, 'last date of exposure' is defined as the earliest date of cutoff date, death date 
and last dose date + 20. 
x Duration of exposure (months) for sitravatinib is 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 (mg) is defined as the cumulative dose of the study drug 
during the treatment period of the study. 
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x Actual dose intensity (ADI) (mg/cycle) for tislelizumab is defined as the 21 * total 
cumulative dose (mg) received by a patient / (last dose date prior to cut off date + 21 – 
first dose date).  
x Actual dose intensity (ADI) (mg/day) for sitravatinib is defined as the cumulative dose 
(mg) received by a patient divided by duration of exposure (days). 
x Relative dose intensity (RDI) is defined as the actual dose intensity divided by the 
planned dose intensity * 100. The planned dose intensity is 200 (mg/cycle) for 
tislelizumab and 120 (mg/day) or 80 (mg/day) planned dose for sitravatinib. 
x Number (%) of patients with dose modifications 
x Number (%) of patients with dose reductions and number of dose reductions per patient 
(sitravatinib only) 
x Number (%) of patients with dose interruptions  
x Number (%) of patients with dose delay (tislelizumab only) 
x Duration of dose interruption (sitravatinib only)  
Patient data listings will be provided for all dosing records, and for the above calculated summary 
statistics. 
6.6.2. 
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. AEs 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). 
6.6.2.1 Treatment Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that had onset or increase in 
severity level date on or after the date of the first dose of study drug up to 30 days after the last 
dose (any component of combination treatment whichever is last) or the initiation of subsequent 
anticancer therapy, whichever comes first. Treatment-related TEAEs include those events 
considered by the investigator to be related to study drug or with a missing assessment of the causal 
relationship. Summary tables will generally focus on those TEAEs and treatment-related TEAEs. 
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, treatment-related version of any of the above categories will be provided by 
indication and by dosage.  
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC, PT, and the worst grade. A patient will be counted only once by the highest severity grade 
within an SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC 
and PT. Summaries of the number (%) of patients with the below types of TEAE will be generated 
by dosage: 
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x All TEAEs  
 TEAEs by SOC and PT 
 TEAEs by PT 
 Treatment-related TEAEs by SOC and PT 
 Treatment-related TEAEs by PT 
 TEAEs related to sitravatinib by SOC and PT 
 TEAEs related to tislelizumab by SOC and PT 
x Serious TEAEs  
 Serious TEAEs by SOC and PT 
 Serious TEAEs by PT 
 Serious Treatment-related TEAEs by SOC and PT 
 Serious TEAEs related to sitravatinib by SOC and PT 
 Serious TEAEs related to tislelizumab by SOC and PT 
x TEAEs with NCI-CTCAE grade ≥3  
 TEAEs with grade ≥3 by SOC and PT 
 TEAEs with grade ≥3 by PT 
 Treatment-related TEAEs with grade ≥ 3 by SOC and PT 
 Treatment-related TEAEs with grade ≥ 3 by PT 
 TEAEs related to sitravatinib with grade ≥ 3 by SOC and PT 
 TEAEs related to tislelizumab with grade ≥ 3 by SOC and PT 
x TEAEs leading to death  
 TEAEs leading to death by SOC and PT 
 Treatment-related TEAEs leading to death by SOC and PT 
x TEAEs leading to treatment discontinuation by SOC and PT 
 TEAEs leading to treatment discontinuation by SOC and PT 
 Treatment-related TEAEs leading to treatment discontinuation by SOC and PT 
 TEAEs leading to treatment discontinuation of sitravatinib by SOC and PT 
 TEAEs leading to treatment discontinuation of tislelizumab by SOC and PT 
x TEAEs leading to treatment modification by SOC and PT 
 TEAEs leading to treatment modification by SOC and PT 
 Treatment-related TEAEs leading to treatment modification by SOC and PT 
 TEAEs leading to treatment modification of sitravatinib by SOC and PT 
 TEAEs leading to treatment modification of tislelizumab by SOC and PT 
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Summaries of the number (%) of patients with the below types of TEAE will also be generated by 
indication: 
x All TEAEs  
 TEAEs by SOC and PT 
 Treatment-related TEAEs by SOC and PT 
x Serious TEAEs  
 Serious TEAEs by SOC and PT 
x TEAEs with NCI-CTCAE grade ≥3  
 TEAEs with grade ≥3 by SOC and PT 
 Treatment-related TEAEs with grade ≥ 3 by SOC and PT 
x TEAEs leading to death  
 TEAEs leading to death by SOC and PT 
 Treatment-related TEAEs leading to death by SOC and PT 
x TEAEs leading to treatment discontinuation by SOC and PT 
 TEAEs leading to treatment discontinuation by SOC and PT 
 Treatment-related TEAEs leading to treatment discontinuation by SOC and PT 
x TEAEs leading to treatment modification by SOC and PT 
 TEAEs leading to treatment modification by SOC and PT 
 Treatment-related TEAEs leading to treatment modification by SOC and PT 
In addition, Dose-Limiting Toxicity Treatment-Emergent Adverse Events will be summarized by 
dosage in DLT Evaluable Analysis Set. 
Patient data listings of all AEs, treatment-emergent or otherwise will be provided. 
6.6.2.2 Immune- Mediated Adverse Event 
Immune-mediated adverse events 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. All imAE up to 90 days from the last dose of study drug, regardless 
of whether the patient starts a new anticancer therapy, will be summarized.  
An overall summary table and separate summaries of the following incidence of immune-mediated 
adverse events will be provided by indication and by dosage: 
x imAEs by category and PT 
x imAEs by PT 
x imAEs ≥ Grade 3 by category and PT 
x Serious imAEs by category and PT 
x imAEs leading to treatment discontinuation by category and PT   
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x imAEs leading to tislelizumab discontinuation by category and PT   
x imAEs leading to dose modification by category and PT   
x imAEs leading to dose modification of tislelizumab by category and PT   
x imAEs leading to death by category and PT 
Patient data listings of imAEs will be provided. 
6.6.2.3 Infusion-related Adverse Event 
All AE terms with the wording "Infusion-Related Reactions" (IRRs) or "Infusion Reaction" will 
be considered as infusion-related AE. Summaries of IRRs incidence by SOC and PT, summaries 
of IRRs of grade ≥3 or higher by SOC and PT will be provided by indication and by dosage 
separately 
6.6.2.4 Death 
All deaths and causes of death will be summarized by dosage, including those occurred during the 
study treatment period and those reported during the survival follow-up period after treatment 
completion/discontinuation. 
Patient data listings of deaths will be provided. 
6.6.3. 
Laboratory Values 
All the below analysis of laboratory values, vital signs and other safety data will be performed by 
dosage only. 
Laboratory safety tests will be evaluated for selected parameters described in Table 5. 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables) for laboratory parameters and their changes 
from baseline will be summarized by visit. 
Laboratories parameters (e.g., hematology, chemistry, and coagulation) are graded in NCI-CTCAE 
Version 5.0 will be summarized by shifts from baseline NCI-CTCAE grades to maximum post-
baseline grades. In the summary of laboratory abnormalities worsened by ≥ 2 Grades (eg, 
hematology and chemistry), parameters with NCI-CTCAE grading in both high and low directions 
will be summarized separately. The summary tables will report laboratory assessments up to 30 
days of the last dose date.  
Laboratory parameters for potential Hy’s Law for liver injury and abnormal thyroid function will 
also be summarized.  
 
Table 5: Clinical Laboratory Assessment 
Serum 
Chemistry 
Hematology 
Coagulation a 
Thyroid 
Function 
Alkaline 
phosphatase 
Hematocrit 
Prothrombin time 
or INR 
TSH 
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Alanine 
aminotransferase 
Hemoglobin 
aPTT  
T3 
Aspartate 
aminotransferase 
Platelet counts 
 
T4 
Albumin 
WBC count  
 
 
Total bilirubin 
Lymphocyte 
count 
 
 
Direct bilirubin 
Neutrophil count 
 
 
Blood 
urea 
nitrogen or urea 
 
 
 
Potassium 
 
 
 
Sodium  
 
 
 
Corrected 
calcium c 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate 
dehydrogenase 
 
 
 
Total protein 
 
 
 
Creatine Kinase 
(CK) d  
 
 
 
CK-MB d,e 
 
 
 
Abbreviations: aPTT, activated partial thromboplastin time; CK, creatine kinase; CK-MB, 
creatine kinase cardiac isoenzyme; INR, International Normalized Ratio; WBC, white blood cell. 
a Coagulation tests are required at baseline and subsequently as clinically indicated  
b On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample 
for total protein or a random urine sample for total protein and creatinine to determine a protein 
to creatinine ratio. 
c If testing for corrected calcium is not feasible at the local laboratory, total calcium may be 
performed instead. 
d Patients receiving tislelizumab will receive CK and CK-MB testing. If tislelizumab has been 
permanently discontinued, CK and CK-MB testing is no longer required. Patients with a history 
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of cardiological disease receiving sitravatinib monotherapy, either in Cohort A or after 
discontinuation of tislelizumab, may receive CK and CK-MB testing if clinically indicated.  
e In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin 
T instead.  
 
6.6.4. 
Vital Signs 
The number and percentage of patients satisfying the following conditions of systolic blood 
pressure at any time post-baseline will be summarized: 
x 140 mmHg to 159 mmHg, 160 mmHg to 179 mmHg, or ≥ 180 mmHg 
x > 0, > 20, > 40, or > 60 mmHg maximum increase from baseline 
The number and percentage of patients satisfying the following conditions of diastolic blood 
pressure at any time post-baseline will be summarized: 
x 90 mmHg to 99 mmHg, 100 mmHg to 109 mmHg, or ≥ 110 mmHg  
x > 0, > 10, > 20, or > 30 mmHg maximum increase from baseline 
6.6.5. 
Electrocardiograms (ECG) 
The number and percentage of patients satisfying the following QTcF conditions at any time post-
baseline will be summarized: 
x > 450, > 480, or > 500 msec   
x > 30 or > 60 msec maximum increase from baseline 
6.6.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
A shift table from baseline to worst post-baseline in ECOG Performance Status will be 
summarized.  
6.7. 
Pharmacokinetic Analysis 
The PK concentrations will be determined using plasma (sitravatinib) or serum (tislelizumab) 
samples collected at specified time points within a reasonable variation window. 
6.7.1. 
Pharmacokinetic Analysis of Sitravatinib 
Serial PK samples will be collected from all patients per cohort after single dose (C1D1) and at 
steady state (C1D21) in Phase 1. For patients enrolled in Phase 2 samples at predose (within 30 
min before administration of sitravatinib) and 6 hours post dose will be collected on Day 1 of 
Cycles 1, 2, and 5. In the following situations additional PK sample may be collected: when a DLT 
event or SAE occurs, when a dose reduction happens, or when hepatic impairment status proceeds 
from mild to moderate in HCC patient cohorts. 
Plasma Concentrations will be summarized with descriptive statistics for both serial and sparse PK 
samples. A value of concentration below the assay quantification limit (BLQ) will be considered 
zero in the summary and not included in the calculations of geometric mean and geometric 
coefficient of variation (CV). Concentration versus time will be plotted for patients with serial 
plasma samples individually and summarized graphically using arithmetic mean (+SD) plots by 
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cohort for patients, respectively in the linear (ie, original) scale and semi-logarithmic scale. 
Arithmetic mean concentrations that are BLQ shall be set to zero for plotting on both linear scale 
but not shown in semi-logarithmic scale. PK parameters will be calculated based on the BeiGene 
Work Instruction. The PK parameters will be summarized with descriptive statistics for the serial 
PK samples. If data allows, the PK parameters will include: 
x AUC0-t, area under the plasma concentration-time curve from time zero to the last 
measurable time point 
x AUC0-tau, area under the plasma concentration-time curve during dose interval 
x AUC0-inf, area under the plasma concentration-time curve from time zero to infinity 
x Cmax, maximum plasma concentration 
x CL/F, clearance after oral administration 
x Tmax, time to maximum plasma concentration 
x t1/2, terminal elimination half-life 
x Vz/F, the terminal volume of distribution after oral administration 
x Ro, observed accumulation ratio determined by the ratios of parameters (AUC0-tau and 
Cmax) at steady state and single dose. 
Accumulation ratios for selected PK parameters (AUC and Cmax) will be estimated by geometric 
mean ratios of the parameters at steady state (ss, [Cycle 1 Day 21]) and single dose (sd, [Cycle 1 
Day 1]) (i.e., AUC0-tau,ss versus AUC0-tau,sd for AUC and Cmax,ss versus Cmax,sd for plasma 
concentration) in linear mixed effect models. The linear mixed effect model for each selected 
parameter will include the natural logarithmic-transformed PK parameter as the dependent 
variable, fixed effect of Day (steady state vs single dose) and random effect of patient as 
independent variables. Each accumulation ratio will be estimated by applying the exponential 
function on the difference of least square (LS) means of log(PKss) and log(PKsd). Similarly the 
95% CI for an accumulation ratio will be obtained by applying the exponential function on the 
95% CI for the mean of log(PKss) - log(PKsd). For each of the selected PK parameters, the 
intrasubject CV will be calculate by √݁ெௌா−1 where MSE is the expected mean square error for 
within patient variability obtained from the linear mixed effect model. Inter-subject CV will be 
calculated as ඥ݁ௌమ−1 where ܵଶ is the estimate of variance for the random effect of patient. For 
each selected parameter, only patients with valid values at single dose and steady state will be 
included for analyses of accumulation, intra-subject CV and inter-subject CV. 
6.7.2. 
Pharmacokinetic Analysis of Tislelizumab 
In Phase 1 and Phase 2, predose (within 30 min before starting tislelizumab infusion) samples 
should be collected on Day 1 of Cycles 1, 2, 5, 9, and 17 (if achieved); two postdose (within 30 
min after the end of tislelizumab infusion) samples should be collected at C1D1 and C5D1; and 
an additional blood PK sample should be collected at the EOT Visit. Should a patient present with 
DLT event or ≥ Grade 3 or above irAE, additional blood PK samples may be taken to determine 
the serum concentration of tislelizumab. Serum Concentrations will be summarized with 
descriptive statistics. 
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6.8. 
Immunogenicity Analysis 
ADA samples for tislelizumab should be collected Day 1 (Predose of tislelizumab, -30 min) of 
Cycles 1, 2, 5, 9 and 17, and at the EOT Visit. All samples should be drawn at the same time as 
the PK blood collection for pre-dose of tislelizumab. 
The scope of ADA calculations used for characterizing clinical immunogenicity depend on the 
incidence and kinetics of detected (ADA). Therefore, not all parameters described below may be 
derived or additional parameters may be added. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of subjects who develop detectable ADAs.  The incidence of positive and neutralizing 
ADAs will be reported for ADA-evaluable subjects according to the following definitions: 
x ADA-evaluable patient: Number of patients with reportable non-missing baseline result 
and at least one reportable sample taken after Tislelizumab administration during the 
treatment or follow-up observation period with reportable result (used for computing 
treatment-induced ADA incidence). 
x Treatment-emergent ADA: The sum of both treatment-boosted and treatment-induced 
ADA-positive patients. Synonymous with “ADA Incidence”. 
x Treatment-induced ADA: ADA-evaluable patients that were ADA-negative at baseline and 
ADA-positive following administration of biologic product. 
x Treatment-boosted ADA: Baseline-positive ADA-evaluable patient with significant 
increases (4-fold or higher) in ADA titer after Tislelizumab administration. Baseline-
positive ADA-evaluable patient is an ADA-evaluable patient with positive ADA result. 
x Persistent ADA: Treatment-induced ADA detected at two or more sampling time points 
during the treatment (including follow-up period if any), where the first and last ADA-
positive samples (irrespective of any negative samples in between) are separated by a 
period of 16 weeks or longer. 
x Transient ADA: Treatment-induced ADA that is not considered as persistent ADA.  
x Neutralizing ADA: patients with positive NAb. 
The individual immunogenicity results will also be listed. 
Additional ADA analyses (such as the effect of immunogenicity on PK, efficacy, and safety) may 
be conducted if deemed necessary and will be described in a separate analysis plan. 
7. 
ITERIM AALYSIS 
No interim analysis is planned. 
8. 
CHAGES I THE PLAED AALYSIS 

	 summarizes the major changes in the planned analyses from the statistical section of the 
study protocol, including the timing, rational and descriptions of the changes. The changes are all 
made before database lock and not based on any comparative data.  

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Table 6: Statistical Analysis Plan Changes
SAP 
version 
Approval 
date 
Change made 
from 
Rationale of the change Description of the change 
1.0 
This version  Protocol V4.0  To clarify the definition 
of the efficacy evaluable 
analysis set.  
 
1) Change the “disease progression” from the 
definition of efficacy evaluable analysis set 
in the protocol into “clinical disease 
progression” in the SAP.
 
2) Change the “death before tumor 
assessment” from the definition of efficacy 
evaluable analysis set in the protocol into 
“early death (within 13 weeks of the first 
dose date)” in the SAP
1.0 
This version  Protocol V4.0  To clarify the 
pharmacokinetic analysis 
set of different study 
drugs.  
Split the Pharmacokinetic Analysis Set in 
protocol into Sitravatinib Pharmacokinetic 
Analysis Set and Tislelizumab 
Pharmacokinetic Analysis Set in the SAP. 
1.0 
This version  Protocol V4.0  To align with BeiGene’s 
current standard 
The definition of TEAE is different between 
protocol and SAP. In the protocol, “TEAE 
classification also applies to irAEs recorded 
up to 90 days after the last dose of 
tislelizumab, regardless of whether the 
patient starts a new anticancer therapy.” In 
this SAP, ĀIf an imAE occurs outside of the 
above-mentioned TEAE window, it will not 
be classified as a TEAEā The update of 
TEAE window streamlines the TEAE 
derivation so all TEAEs can be identified 
programmatically instead of relying on the 
manual medically review of imAE. 
1.0 
This version  Protocol V4.0  To align with BeiGene’s 
current standard
Change the name of immune-related adverse 
events (irAEs) into immune-mediated AEs 
(imAEs).  
 
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9. 
REFERECES 
BeiGene Work Instruction. Best Practice Guidance: Non-Compartmental Pharmacokinetic 
Data_Analysis for Clinical Studies. Version 1.0, December 2020. 
Brookmeyer, Ron, and John Crowley. 1982. ‘A Confidence Interval for the Median Survival 
Time’. Biometrics 38 (1): 29–41. https://doi.org/10.2307/2530286. 
CTCAE V5.0, November 27, 2017. Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0. Washington, DC, USA: Department of Health and Human Services, National 
Institutes of Health, National Cancer Institute. 
Eisenhauer, E.A., P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, et al. 
2009. ‘New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 
1.1)’. European Journal of Cancer 45 (2): 228–47. https://doi.org/10.1016/j.ejca.2008.10.026. 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926; 33:1-26. 
 
 
 
 
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APPEDIX 1. 
IMPUTATIO OF MISSIG OR PARTIALLY MISSIG 
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. 
1.1 Prior/Concomitant Medications/Procedures  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
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 > death date, then set to death date 
If end date of a medication/therapy/procedure 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 > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
1.2 Adverse Events 
The imputation rule for the safety analysis 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. The following rules will be applied to impute 
partial dates for adverse events: 
If year of the start date is missing or start date is completely missing, do not impute.  Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
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 > death date, then set to death date 
  If year of the end date is missing or end date is completely missing, do not impute. 
 
If start date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
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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 > death date, then set to death date 
1.3 Disease history and prior therapy (Drug, surgery/procedure, radiotherapy) 
For prior therapy, impute end date first.  
If end date of a 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 > first dose date, then set to first dose date -1 
If start date of a 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  
The following rules will be applied to impute partial dates such as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
If date of a disease history 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 > first dose date, then set to first dose 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 > first dose date, then set to first dose date – 1 
x If the imputed date < (imputed) date of initial diagnosis date, then set to initial diagnosis 
date. 
If the date of response to prior therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
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x If only day is missing, then set to the first of the month 
x If the imputed date > first dose date, then set to first dose date – 1 
If the imputed date < the start date of prior therapy, then set to the start date of prior therapy 
+1. 
1.4 Subsequent anti-cancer therapy  
If 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, 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) 
x 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. 
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BGB-900-104 
BeiGene 
Statistical Analysis Plan 1.0 
07 April 2023 
CONFIDENTIAL 
Page 36 
APPEDIX 2. 
RULES FOR IDETIFYIG MISSIG TUMOR ASSESSMETS 
 
Identifying two missing tumor assessments 
1) Input scheduled TA visit list  
a. (6wk-12wk-18wk-24wk-30wk-36wk-42wk-48wk) for this study with TA as every 
6 weeks for the first 12 months (52 weeks), then every 9 weeks thereafter 
2) Identify last evaluable TA before PD or death (--LPTADT) and map it to the closest 
scheduled visit (--LPTADT_WK). 
a. In the event of unscheduled TA, choose the closest scheduled visit number (e.g. 
6wk) as –LPTADT_WK. It can be achieved programmatically by following the 
classification rule (e.g. defining thresholds) depicted in Table 7 below.  (The team 
can consider mapping all tumor visits if the scheduled visits are uncleaned or 
questionable)  
b. Otherwise, assign the scheduled visit number (assuming it is coded correctly) to --
LPTADT_WK 
3) Find the 2nd TA visit after LPTADT_WK according to the list in step 1 (- 
LPTADT_WK_2) 
a. If LPTADT_WK_2+1wk (assuming 1 week TA window) < earliest of PD/death 
date, then censor PFS at the –LPTADT 
b. Otherwise, PFS event at the earliest of PD/death date 
Table 7 shows how to assign unscheduled TA to a schedule visit. The threshold column is defined 
as the mid-point between current and next visit (except for baseline); it is the upper limit for 
LPTADT to be mapped to the prior scheduled assessment (step 2a above). For example, if 
LPTADT is Week 44 for an unscheduled visit, it will be mapped to Week 42 TA since it is within 
the threshold for Week 42. Assuming it is SD and the subsequent TA of the patient is PD after 
Week 58, PFS will be censored at LPTADT (Week 44); had the PD occurred prior to Week 58, it 
would be counted as an PFS event. 
Table 7: Example of scheduled tumor assessments with time window  
Weeks 
Scheduled week -1 
Scheduled week 
Scheduled week+1 
Threshold  
Baseline 
  
Baseline 
  
  
Every 6 weeks 
for the first 52 
weeks 
  
  
  
Week 5 
Week6 
Week 7 
Week 9 
Week 11 
Week 12 
Week 13 
Week 15 
Week 17 
Week 18 
Week 19 
Week 21 
Week 23 
Week 24 
Week 25 
Week 27 
Week 29 
Week 30 
Week 31 
Week 33 
Week 35 
Week 36 
Week 37 
Week 39 
Week 41 
Week 42 
Week 43 
Week 45 
Week 47 
Week 48 
Week 49 
Week 52 
 Every 9 weeks 
thereafter 
  
Week 56 
Week 57 
Week 58 
Week 61 
Week 65 
Week 66 
Week 67 
Week 70 
Week 74 
Week 75 
Week 76 
… 
  
  
  
  
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