Conditions: Advanced Solid Tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 216
Healthy volunteers: no

Brief summary:
This was an open-label, multicenter, non-randomized Phase 1b clinical trial for participants with histologically or cytologically confirmed locally advanced or metastatic tumors including non-squamous or squamous non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), ovarian cancer (OC), or melanoma.

Detailed description:
All participants received sitravatinib 120 mg orally once daily in combination with tislelizumab 200 mg intravenously (IV) once every 3 weeks until occurrence of progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. Participants were enrolled according to their tumor type and prior anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody treatment into the following cohorts:

* Cohort A: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, non-squamous NSCLC
* Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC
* Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic or advanced RCC
* Cohort D: Metastatic or advanced RCC without prior systemic therapy
* Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum resistant epithelial OC
* Cohort F: Anti-PD-1/PD-L1 antibody treated metastatic, squamous NSCLC
* Cohort G: Anti-PD-1/PD-L1 antibody refractory/resistant unresectable or metastatic melanoma
* Cohort H: PD-L1 positive, locally advanced or metastatic, non-squamous NSCLC without prior systemic treatment in the metastatic setting
* Cohort I: PD-L1 positive, locally advanced or metastatic, squamous NSCLC without prior systemic treatment in the metastatic setting

Arms:
arm 1: Sitravatinib 120 mg was administered orally once daily in combination with tislelizumab 200 mg intravenously (IV) once every 3 weeks

Interventions: intervention 1: Sitravatinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: Administered orally as a capsule intervention 2: Administered intravenously

Protocol document:
Prot_000.pdf: 
BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 1
CLINICAL STUDY PROTOCOL
Protocol Title: 
A Phase 1b Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Antitumor Activity of 
Sitravatinib in Combination With Tislelizumab in Patients With 
Advanced Solid Tumors
Protocol Identifier:
BGB-900-103
Phase:
1b
Investigational 
Products:
Sitravatinib (MGCD516) and Tislelizumab (BGB-A317)
Indication:
Advanced Solid Tumors
Sponsor:
BeiGene, Ltd.
c/o BeiGene AUS Pty Ltd.
1C/528 Compton Road Stretton
Queensland 4116, Australia
BeiGene, Ltd.
c/o BeiGene USA, Inc.
2955 Campus Drive, Suite 200 
San Mateo, CA 94403
USA
BeiGene (Beijing) Co., Ltd.
No. 30 Science Park Road
Zhong-Guan-Cun Life Science 
Park
Changping District
Beijing, China 102206
China
Sponsor Medical 
Monitor:
BeiGene, Ltd.
Email: 
Original Protocol:
26 June 2018
Amendment 1.0
Amendment 2.0
22 March 2019
12 June 2019
Amendment 3.0
19 November 2019
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.
1&7




BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 3
INVESTIGATOR SIGNATURE PAGE
Protocol Title:
A Phase 1b Study to Assess the Safety, Tolerability, Pharmacokinetics, 
and Preliminary Antitumor Activity of Sitravatinib in Combination With 
Tislelizumab in Patients With Advanced Solid Tumors
Protocol Identifier: BGB-900-103
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. PRINT your name, title, and the 
name and address of the center in which the study will be conducted. Return the signed copy to BeiGene or its 
designee.
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: _______________________________
_______________________________
_______________________________
_______________________________


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 4
PROTOCOL AMENDMENT 3.0 (19 NOVEMBER 2019)
The main purpose of this amendment is to increase sample size to 60 subjects in Cohort E and 
update the background information of tislelizumab and sitravatinib.
Applicable Section
Description of Revision
Change:
Non-content related changes made throughout the document.
Reason:
Consistency with other sitravatinib/tislelizumab protocols and correction of errors.
All Sections
x
Administrative updates, editorial changes, and/or style and formatting 
revisions have been made to improve clarity and consistency 
throughout the document.
Change:
Update the background information based on current sitravatinib Development 
Safety Update Report (DSUR).
Reason:
Consistency with current sitravatinib DSUR.
Section 1.2.4.1: Study 
516-001
Section 1.2.4.2: Study
MRTX-500
x
Update safety data of Study 516-001.
x
Update safety data of Study MRTX-500.
Change:
Update the background information based on current tislelizumab IB.
Reason:
Consistency with current tislelizumab IB.
Section 1.3.1:
Pharmacology
Section 1.3.3: Clinical 
Pharmacology
Section 1.3.4: Clinical 
Experience With 
Tislelizumab
x
Update section Pharmacology.
x
Update section Clinical pharmacology.
x
Update section Clinical experience with tislelizumab.
Change:
Change the number of subjects and criteria in Cohort E as well as the study sample 
size.
Reason:
To increase the number of subjects with ovarian cancer.
Synopsis: Study Design
Synopsis: Sample Size 
Consideration
Synopsis: Study Schema
Section 3.1: Summary of 
Study Design
Section 3.1: Figure 1
Section 9.7: Sample Size 
Consideration
x
Approximately 220 to 240 patients (approximately 60 patients for 
Cohort E, and 20 patients for each of the rest of the cohorts) are 
expected to be enrolled to analyze safety and preliminary efficacy for 
sitravatinib plus tislelizumab. Of the approximately 60 patients 
enrolled into Cohort E, at least 20 patients who failed the prior 
bevacizumab treatment and at least 20 patients will be Caucasian.
x
Delete Table 8 Estimates of 95% CI of ORR With 20 Patients.


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 5
Applicable Section
Description of Revision
Change:Clarify the enrollment plan of Cohort E.
Reason:
To update enrollment plan of Cohort E.
Synopsis: Study Design
Section 3.1: Summary of 
Study Design
x
Approximately 60 patients will be enrolled into Cohort E, including at
least 20 patients who failed the prior bevacizumab treatment and at 
least 20 patients will be Caucasian. The additional 40 patients of 
Cohort E will not be enrolled in China after the amendment is 
effective.
Change:
Revised the subject type of Cohort F.
Reason:
To refine the subject type of Cohort F. 
Synopsis: Study Design
Synopsis: Study Schema
Section 3.1: Summary of 
Study Design
Section 3.1: Figure 1
Section 4.1: Inclusion 
Criteria
x
Revise the definition of Cohort F:
Cohort F: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, 
squamous NSCLC.
x
Add the notes to clarify “anti-PD-1/PD-L1 antibody refractory/resistant 
metastatic, squamous NSCLC” in Cohort F: 
Note: Radiographic progression per RECIST v1.1 on or after anti-PD-
1/PD-L1-containing therapy as the most recent treatment for metastatic 
NSCLC with best response defined as follows:
o
Resistant (ie, RECIST v1.1-defined partial, complete 
response, or stable disease for at least 12 weeks after 
initiation of treatment followed by radiographic 
progression of disease).
o
Refractory (ie, radiographic progression of disease < 12 
weeks after initiation of treatment).
Change:
Combine the End-of-Treatment and Safety Follow-up visits. 
Reason:
To simplify the study procedures.
Section 3.4: End-of-
Treatment and Safety 
Follow-up Phone calls
Section 3.5: Survival 
Follow-up
Section 3.7: End of 
Study
Section 7.3.4: Laboratory 
Safety Test
Section 7.7: Biomarkers
Appendix 1
Appendix 2
Appendix 3
x
Delete Section 3.3.2 and 3.4.1.
x
Revise the text in Section 3.4, 3.5, 3.7, 7.3.4, 7.7; Appendix 1 EOT 
Visit and footnotes 5, 6, 12, 13 and 20; Appendix 2 EOT Visit and 
footnotes c, d, e; Appendix 3 footnotes.


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 6
Applicable Section
Description of Revision
Change:
Revise the criteria of biomarker test and tumor sample collection for NSCLC cohorts.
Reason:
To specify the criteria of biomarker test and tumor sample collection for NSCLC 
cohorts.
Section 4.1: Inclusion 
Criteria
x
Specify the criteria of biomarker test and tumor sample collection in 
NSCLC cohorts (A, B, F, H, I).
o
ALK/ROS1: No documented rearrangement.
o
BRAF: No documented mutation.
Change:
Revise the requirements to perform Pulmonary Function Tests (PFT) at Screening 
Visit.
Reason:
To specify the requirements to perform PFT at Screening Visit.
Section 4.1: Inclusion 
Criteria
Section 7.1: Screening
Section 7.1.5: Pulmonary 
Function Tests
Appendix 1
x
Delete inclusion criterion 10.
x
Revise the text in Section 7.1, 7.1.5, and Appendix 1 footnote 16 
regarding PFT.
Change:
Revise the dose resume criteria.
Reason:
To correct the dose resume criteria.
Section 5.5.2: Dose 
Delay
x
Revise text as shown below.
Patients should resume study drugs as soon as possible after the AEs 
recover to baseline or Grade 1 (whichever is more severe) within 
4 weeks for sitravatinib or 12 weeks for tislelizumab after last 
dose of the respective study drug.
Change:
Add safety monitoring for eye-related adverse events.
Reason:
To monitor eye-related adverse events.
Section 7.3.2: Physical 
Examinations
x
Add text as below.
In addition, investigators should solicit patients regarding changes in 
vision, visual disturbance, or ocular inflammation at each scheduled 
study visit during study treatment. For any change in vision, referral to 
an appropriate specialist will be made for further management 
guidance.
Change:
Revise the management of Non-Hematological Toxicities of Sitravatinib.
Reason:
Consistency with the current management guideline of Non-Hematological Toxicities 
of Sitravatinib.


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 7
Applicable Section
Description of Revision
Section 8.9.1:
Management of Non-
Hematological Toxicities 
of Sitravatinib
Section 8.9.1: Table 10
x
Update the management of Non-Hematological Toxicities of 
Sitravatinib. 
Change:
Revise sampling volume and time of pharmacodynamic biomarker and ctDNA.
Reason:
Avoid unnecessary blood sampling or testing.
Appendix 2
x
Revise sampling time of pharmacodynamic biomarker and footnote e.


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 8
TABLE OF CONTENTS
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE.........................................................................................3 
PROTOCOL AMENDMENT 3.0 (19 NOVEMBER 2019) ...........................................................4 
TABLE OF CONTENTS.................................................................................................................8 
LIST OF TABLES.........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
SYNOPSIS ...................................................................................................................................15 
LIST OF ABBREVIATIONS AND TERMS................................................................................21 
1. 
INTRODUCTION AND RATIONALES ..................................................................23 
1.1. 
Background Information on Advanced Solid Tumors................................................23 
1.1.1. 
Non-Small Cell Lung Cancer .....................................................................................23 
1.1.2. 
Renal Cell Carcinoma.................................................................................................24 
1.1.3. 
Ovarian Cancer ...........................................................................................................26 
1.1.4. 
Melanoma ...................................................................................................................27 
1.2. 
Sitravatinib as an RTK Inhibitor.................................................................................29 
1.2.1. 
Pharmacology .............................................................................................................29 
1.2.2. 
Toxicology..................................................................................................................30 
1.2.3. 
Clinical Pharmacology................................................................................................30 
1.2.4. 
Clinical Experience With Sitravatinib........................................................................31 
1.2.5. 
Rationale for Selection of Sitravatinib Dose ..............................................................34 
1.3. 
Tislelizumab as a PD-1 Blocker .................................................................................35 
1.3.1. 
Pharmacology .............................................................................................................35 
1.3.2. 
Toxicology..................................................................................................................36 
1.3.3. 
Clinical Pharmacology................................................................................................36 
1.3.4. 
Clinical Experience With Tislelizumab......................................................................37 
1.3.5. 
Rationale for Selection of Tislelizumab Dose............................................................43 
1.4. 
Rationale for Combination of Sitravatinib and Tislelizumab in the Treatment 
of Advanced Solid Tumors.........................................................................................44 
1.5. 
Benefit-Risk Assessment............................................................................................45 
2. 
STUDY OBJECTIVES AND ENDPOINTS..............................................................46 
2.1. 
Study Objectives.........................................................................................................46 
2.1.1. 
Primary Objective.......................................................................................................46 


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2.1.2. 
Secondary Objectives .................................................................................................46 
2.1.3. 
Exploratory Objectives ...............................................................................................46 
2.2. 
Study Endpoints..........................................................................................................46 
2.2.1. 
Primary Endpoints ......................................................................................................46 
2.2.2. 
Secondary Endpoints ..................................................................................................46 
2.2.3. 
Exploratory Endpoints................................................................................................47 
3. 
STUDY DESIGN .......................................................................................................48 
3.1. 
Summary of Study Design..........................................................................................48 
3.2. 
Screening Period.........................................................................................................50 
3.3. 
Treatment Period ........................................................................................................50 
3.3.1. 
Unscheduled Visit.......................................................................................................50 
3.4. 
End-of-Treatment and Safety Follow-up Phone Calls................................................50 
3.5. 
Survival Follow-up .....................................................................................................51 
3.6. 
Discontinuation From Study Treatment or From the Study.......................................51 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................51 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)..........51 
3.7. 
End of Study ...............................................................................................................52 
4. 
STUDY POPULATION.............................................................................................53 
4.1. 
Inclusion Criteria ........................................................................................................53 
4.2. 
Exclusion Criteria.......................................................................................................58 
5. 
STUDY TREATMENT..............................................................................................62 
5.1. 
Formulation, Packaging, and Handling ......................................................................62 
5.1.1. 
Sitravatinib..................................................................................................................62 
5.1.2. 
Tislelizumab ...............................................................................................................62 
5.2. 
Dosage and Administration ........................................................................................62 
5.2.1. 
Sitravatinib..................................................................................................................62 
5.2.2. 
Tislelizumab ...............................................................................................................63 
5.3. 
Compliance and Accountability .................................................................................63 
5.4. 
Overdose.....................................................................................................................64 
5.4.1. 
Sitravatinib..................................................................................................................64 
5.4.2. 
Tislelizumab ...............................................................................................................64 
5.5. 
Dose Modification and Delay.....................................................................................64 


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5.5.1. 
Dose Modification ......................................................................................................65 
5.5.2. 
Dose Delay..................................................................................................................65 
6. 
PRIOR AND CONCOMITANT THERAPY.............................................................66 
6.1. 
Concomitant Therapy .................................................................................................66 
6.1.1. 
Permitted Concomitant Medications and Therapy .....................................................66 
6.1.2. 
Prohibited Concomitant Medications and Therapy ....................................................66 
6.1.3. 
Restricted Concomitant Medications and Therapy.....................................................67 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications.................................................................................................................67 
7. 
STUDY ASSESSMENTS AND PROCEDURES......................................................69 
7.1. 
Screening ....................................................................................................................69 
7.1.1. 
Demographics.............................................................................................................69 
7.1.2. 
Medical History ..........................................................................................................69 
7.1.3. 
Other Baseline Characteristics....................................................................................70 
7.1.4. 
Informed Consent and Screening Log ........................................................................70 
7.1.5. 
Pulmonary Function Tests..........................................................................................70 
7.2. 
Enrollment ..................................................................................................................71 
7.3. 
Safety Assessments.....................................................................................................71 
7.3.1. 
Vital Signs ..................................................................................................................71 
7.3.2. 
Physical Examinations................................................................................................71 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status........................................71 
7.3.4. 
Laboratory Safety Test ...............................................................................................71 
7.3.5. 
Hepatitis B and Hepatitis C Testing ...........................................................................72 
7.3.6. 
Electrocardiograms.....................................................................................................72 
7.3.7. 
Multigated Acquisition (MUGA) Scans or Echocardiograms....................................73 
7.3.8. 
Adverse Events ...........................................................................................................73 
7.4. 
Tumor and Response Evaluations ..............................................................................73 
7.5. 
Pharmacokinetic Assessment......................................................................................74 
7.6. 
Antidrug Antibody Testing.........................................................................................75 
7.7. 
Biomarkers..................................................................................................................75 
8. 
SAFETY MONITORING AND REPORTING .........................................................77 
8.1. 
Risks Associated With Sitravatinib and Tislelizumab................................................77 
8.2. 
General Plan to Manage Safety Concerns ..................................................................77 


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8.2.1. 
Eligibility Criteria.......................................................................................................77 
8.2.2. 
Safety Monitoring Plan...............................................................................................77 
8.3. 
Adverse Events ...........................................................................................................78 
8.3.1. 
Definitions and Reporting...........................................................................................78 
8.3.2. 
Assessment of Severity...............................................................................................79 
8.3.3. 
Assessment of Causality.............................................................................................79 
8.3.4. 
Following Adverse Events..........................................................................................80 
8.3.5. 
Laboratory Test Abnormalities...................................................................................80 
8.4. 
Definition of a Serious Adverse Event .......................................................................81 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................82 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................82 
8.6.1. 
Adverse Event Reporting Period ................................................................................82 
8.6.2. 
Reporting Serious Adverse Events .............................................................................82 
8.6.3. 
Eliciting Adverse Events ............................................................................................83 
8.6.4. 
Progressive Disease ....................................................................................................83 
8.6.5. 
Deaths .........................................................................................................................84 
8.6.6. 
Pregnancies.................................................................................................................84 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees................................................84 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events......................................84 
8.7. 
Management of Adverse Events Potentially Associated with Either or Both 
of Sitravatinib and Tislelizumab.................................................................................84 
8.7.1. 
Timing of Adverse Event Onset .................................................................................85 
8.7.2. 
Severity of Adverse Event..........................................................................................85 
8.8. 
Management of AEs of Special Interest of Tislelizumab...........................................85 
8.8.1. 
Infusion-Related Reactions.........................................................................................85 
8.8.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms.......................................87 
8.8.3. 
Immune-Related Adverse Events ...............................................................................87 
8.9. 
Management of Sitravatinib-Specific Adverse Events...............................................88 
8.9.1. 
Management of Non-Hematological Toxicities of Sitravatinib .................................88 
8.9.2. 
Management of Hematological Toxicities of Sitravatinib..........................................89 
8.9.3. 
Dose Modification Guidelines for Sitravatinib-Specific AEs ....................................89 


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8.9.4. 
Hypertension...............................................................................................................90 
8.9.5. 
Palmar-Plantar Erythrodysesthesia.............................................................................91 
8.9.6. 
Diarrhea ......................................................................................................................91 
8.9.7. 
Hemorrhagic Events ...................................................................................................91 
8.9.8. 
Thrombotic Events......................................................................................................91 
8.9.9. 
Thyroid Dysfunction Other Than Immune-Mediated.................................................92 
8.9.10. 
Decreased Left Ventricular Ejection Fraction ............................................................92 
8.9.11. 
Proteinuria...................................................................................................................92 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.................93 
9.1. 
Statistical Analysis......................................................................................................93 
9.1.1. 
Analysis Sets...............................................................................................................93 
9.1.2. 
Patient Disposition......................................................................................................93 
9.1.3. 
Demographic and Other Baseline Characteristics ......................................................93 
9.1.4. 
Prior and Concomitant Medications ...........................................................................93 
9.2. 
Efficacy Analyses .......................................................................................................94 
9.3. 
Safety Analyses ..........................................................................................................95 
9.3.1. 
Extent of Exposure .....................................................................................................95 
9.3.2. 
Adverse Events ...........................................................................................................95 
9.3.3. 
Laboratory Analyses...................................................................................................96 
9.3.4. 
Vital Signs ..................................................................................................................96 
9.4. 
Pharmacokinetic Analysis ..........................................................................................96 
9.5. 
Immunogenicity Analyses ..........................................................................................97 
9.6. 
Other Exploratory Analyses .......................................................................................97 
9.7. 
Sample Size Consideration.........................................................................................98 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................99 
10.1. 
Safety Monitoring Committee....................................................................................99 
10.2. 
Communication...........................................................................................................99 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................100 
11.1. 
Access to Information for Monitoring......................................................................100 
11.2. 
Access to Information for Auditing or Inspections ..................................................100 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................101 
12.1. 
Regulatory Authority Approval................................................................................101 


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12.2. 
Quality Assurance.....................................................................................................101 
12.3. 
Study Site Inspections...............................................................................................101 
12.4. 
Drug Accountability .................................................................................................101 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................103 
13.1. 
Ethical Standard........................................................................................................103 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................103 
13.2.1. 
Protocol Amendments ..............................................................................................103 
13.3. 
Informed Consent .....................................................................................................103 
13.4. 
Patient and Data Confidentiality...............................................................................104 
13.5. 
Financial Disclosure .................................................................................................105 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................106 
14.1. 
Data Collection and Management Responsibilities..................................................106 
14.1.1. 
Data Collection .........................................................................................................106 
14.1.2. 
Data Management/Coding........................................................................................106 
14.2. 
Study Records Retention ..........................................................................................106 
14.3. 
Protocol Deviations ..................................................................................................107 
14.4. 
Publication and Data Sharing Policy........................................................................108 
14.5. 
Study and Study Center Closure...............................................................................108 
14.6. 
Information Disclosure and Inventions ....................................................................109 
15. 
REFERENCES .........................................................................................................110 
16. 
APPENDICES ..........................................................................................................116 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................117 
APPENDIX 2. SCHEDULE OF PK, ADA, PGX, AND BIOMARKER 
ASSESSMENTS.......................................................................................................122 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................124 
APPENDIX 4. ECOG PERFORMANCE STATUS.................................................................125 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES................................................................................................................126 
APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL”...........................................................................................................127 
APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION..................................................................................................129 


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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................130 
APPENDIX 9. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND
MANAGEMENT .....................................................................................................131 
APPENDIX 10. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1................................................................141 
APPENDIX 11. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH SITRAVATINIB...................150 
APPENDIX 12. CA-125 RESPONSE CRITERIA...................................................................152 
LIST OF TABLES
Table 1. 
Summary of Treatment-Emergent, Treatment-Related Adverse Events (Ӌ
10%) by Preferred Term for Study 516-001...............................................................32 
Table 2. 
Summary of Treatment-Emergent, Treatment-Related Adverse Events (Ӌ
10%) by Preferred Term for Study MRTX-500 .........................................................34 
Table 3. 
Demographics, Baseline Characteristics, Treatment Exposure Duration, and 
Study Follow-up Duration in Pooled Monotherapy Studies.......................................38 
Table 4. 
Immune-Related Adverse Events of Any Grade Occurring in ≥1% in Pooled 
Monotherapy Studies..................................................................................................40 
Table 5. 
Treatment-Emergent Fatal Adverse Events Regardless of Causality in 
Pooled Monotherapy Studies......................................................................................42 
Table 6. 
Sitravatinib Dose Reductions .....................................................................................65 
Table 7. 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................82 
Table 8. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab ...............................................................................................................86 
Table 9. 
Immune-Related Adverse Events ...............................................................................88 
Table 10. 
Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities ....................................................................................................................89 
Table 11. 
Sitravatinib Dose Modification for Increased Blood Pressure ...................................90 
Table 12. 
Sitravatinib Dose Modification for Increased Hepatic Transaminase........................90 
LIST OF FIGURES
Figure 1. 
Study Schema .............................................................................................................49 


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SYNOPSIS
Name of Sponsor:
BeiGene, Ltd.
Investigational Products:
Sitravatinib (MGCD516) and Tislelizumab (BGB-A317)
Title of Study:
A Phase 1b Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Antitumor Activity of 
Sitravatinib in Combination With Tislelizumab in Patients 
With Advanced Solid Tumors
Protocol Identifier:
BGB-900-103
Phase of Development:
1b
Study Centers:
Approximately 20 to 30 centers in Asia Pacific including 
Australia and China
Duration of Patient Participation:
Patients will receive treatment of sitravatinib daily and 
tislelizumab once every 3 weeks during the study until 
occurrence of progressive disease (PD), unacceptable toxicity, 
death, withdrawal of consent, or study termination by sponsor.
Study Objectives
Primary:
x
To characterize the safety and tolerability of sitravatinib in combination with tislelizumab
Secondary:
x
To assess the preliminary antitumor activity of sitravatinib in combination with tislelizumab
x
To characterize the pharmacokinetics (PK) profiles of sitravatinib after single dose and at 
steady state when given in combination with tislelizumab
Exploratory:
x
To assess the PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib
x
To explore potential pharmacodynamic biomarkers for sitravatinib in combination with 
tislelizumab   
x
To explore potential biomarkers of efficacy, resistance, or PD in tumor tissue and in peripheral 
whole blood
x
To assess overall survival (OS)
x
To explore the effect of pharmacogenetic (PGx) polymorphisms on the PK of sitravatinib
x
To assess the preliminary antitumor activity of sitravatinib in combination with tislelizumab
for ovarian cancer patients based on the Gynecologic Cancer Intergroup (GCIG) working 
group criteria.


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Study Endpoints
Primary:
x
Safety and tolerability will be assessed throughout the study by monitoring adverse events 
(AEs) and serious adverse events (SAEs) per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, relevant physical 
examinations, electrocardiograms (ECGs), and laboratory assessments as needed
Secondary:
x
Efficacy evaluations: objective response rate (ORR), duration of response (DOR), disease 
control rate (DCR), and progression-free survival (PFS) based on Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1. 
x
Plasma concentrations and the derived PK parameters of sitravatinib:
o
Single dose: maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax), area under the plasma concentration-time curve from time zero to 
the last measurable time point (AUC(0-t)), clearance after oral administration (CL/F)
o
Repeated dose: Cmax, trough concentration at steady state (Cτ), Tmax, area under the 
plasma concentration-time curve from time zero to 24 hours postdose at steady state 
(AUC(0-τ)), CL/F, accumulation ratio (Ro)
Exploratory:
x
Serum concentrations of tislelizumab and anti-tislelizumab-antibodies
x
Changes of potential pharmacodynamic biomarkers in response to sitravatinib in combination 
with tislelizumab, such as soluble vascular endothelial growth factor receptor 2 (sVEGFR-2), 
and immune cell subpopulations in peripheral blood
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, and the association with disease status and/or the response to sitravatinib in 
combination with tislelizumab
x
OS 
x
The effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, 
including but not limited to CYP1A2, 2D6, and 2C8 on the PK of sitravatinib
x
Efficacy evaluations for ovarian cancer patients: PFS per CA-125 (GCIG working group 
criteria)
Study Population
Patients with histologically or cytologically confirmed locally advanced or metastatic, non-squamous 
or squamous non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), ovarian cancer (OC), 
and melanoma.
Key Eligibility Criteria
Adult patients (≥ 18 years of age or acceptable age according to local regulations, whichever is older at 
the time of voluntarily signing of informed consent) with histologically or cytologically confirmed 
advanced or metastatic solid tumors. All patients are also required to have an Eastern Cooperative 
Oncology Group (ECOG) Performance Status score of ≤ 1 and adequate end-organ function.


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Test Product, Dose, and Mode of Administration
Sitravatinib: 120 mg will be administered orally once daily. 
Tislelizumab: 200 mg will be administered intravenously (IV) once every 3 weeks. 
Study Design
This is an open-label, multicenter, non-randomized Phase 1b clinical trial for patients with 
histologically or cytologically confirmed locally advanced or metastatic tumors including non-
squamous or squamous NSCLC, RCC, OC, or melanoma. 
All patients will receive sitravatinib 120 mg orally once daily in combination with tislelizumab 200 mg 
IV once every 3 weeks until occurrence of PD, unacceptable toxicity, death, withdrawal of consent, or 
study termination by sponsor.
There will be 9 cohorts in the study. Approximately 60 patients will be enrolled into Cohort E, 
including at least 20 patients who failed the prior bevacizumab treatment and at least 20 patients will 
be Caucasian. The additional 40 patients of Cohort E will not be enrolled in China after the amendment 
is effective. In addition, approximately 20 patients will be enrolled into each of the rest of the cohorts.
The patients will be enrolled according to their tumor type and prior anti-programmed cell death 
protein-1 (PD-1)/PD-L1 antibody treatment.
x
Cohort A: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, non-squamous NSCLC
x
Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC
x
Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic or advanced RCC
x
Cohort D (China-only): Metastatic or advanced RCC without prior systemic therapy
x
Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum resistant epithelial OC
x
Cohort F: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, squamous NSCLC
x
Cohort G: Anti-PD-1/PD-L1 antibody refractory/resistant unresectable or metastatic melanoma
x
Cohort H: PD-L1 positive, locally advanced or metastatic, non-squamous NSCLC without 
prior systemic treatment in metastatic setting
x
Cohort I: PD-L1 positive, locally advanced or metastatic, squamous NSCLC without prior 
systemic treatment in metastatic setting
Cohort F will only enroll prior anti-PD-1/PD-L1 antibody refractory/resistant squamous NSCLC until 
the total number of prior anti-PD-1/PD-L1 antibody treated squamous NSCLC reaches 20 patients. The 
prior anti-PD-1/PD-L1 naïve patients who enrolled before the amendment is effective can continue 
their treatment per the protocol. It is to further explore the safety and efficacy for patients with 
anti-PD-1/PD-L1 antibody treated squamous NSCLC. The anti-PD-1/PD-L1 antibody naïve patient 
will be no longer enrolled in this cohort after this amendment is effective.
A Safety Monitoring Committee (SMC) will review the safety, tolerability, and pharmacology data 
from the initial 6 patients (regardless of assigned cohort) that complete the first treatment cycle in 
Australia. Recruitment will be on hold in Australia until these data have been reviewed. For 
participating China sites only, the initial 6 patients enrolled in China regardless of assigned cohort will 
have their safety, tolerability, and pharmacology data reviewed by the SMC. Recruitment in China 
only will be on hold until the data have been reviewed. 
The SMC may assess the combination regimen as safe, but may also decide to evaluate a dosing 
regimen that was not predefined or not previously studied, if evaluation of toxicity at such a dose is 
desired.


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Study Schema
Abbreviations: IHC, immunohistochemistry; mNSCLC, metastatic non-small cell lung cancer; mRCC, metastatic renal cell 
carcinoma; NSCLC, non-small cell lung cancer; OC, ovarian cancer; PD, progressive disease; PD-1, programmed cell death 
protein-1; PD-L1, programmed cell death protein ligand-1; RCC. renal cell carcinoma; SMC, Safety Monitoring Committee; 
VEGF, Vascular endothelial growth factor; VEGFR TKI, vascular endothelial growth factor receptor tyrosine kinase 
inhibitors. 
Note: The SMC will review the safety, tolerability, and pharmacology data from the initial 6 patients regardless of assigned 
cohort that complete the first cycle of treatment in Australia. Recruitment will be on hold in Australia until the data have been 
reviewed. For participating China sites only, the SMC will also review the safety, tolerability, and pharmacology data of the 
initial 6 patients enrolled in China regardless of assigned cohort. Recruitment in China only will be on hold until the data have 
been reviewed. 
Study Assessments
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely monitored 
for safety and tolerability throughout the study.
Tumor Assessments
Radiological assessment of tumor-response status will be performed approximately every 6 weeks 
± 7 days during the first year, and every 9 weeks ± 7 days thereafter. 
Tumor response will be assessed by investigators using RECIST v1.1. For ovarian cancer patients, 
response will be assessed using RECIST v1.1 and the GCIG working group criteria. 


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The decision to continue study drug(s) beyond investigator-assessed progression must be agreed by the 
medical monitor and documented in the study records. In such cases, patients are also required to be re-
consented.
Statistical Methods
This trial is designed to establish the safety and tolerability of sitravatinib in combination with 
tislelizumab and to assess the preliminary antitumor activity of the combination therapy 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, PFS, DOR, DCR and OS) 
data will be presented by cohort.
Analysis Sets
x
The Safety analysis set includes all patients who received ≥1 dose of any study drug (any 
component of the combination therapy). 
x
The Efficacy Evaluable analysis set includes all dosed patients who had measurable disease at 
baseline per RECIST v1.1 and who had at least 1 evaluable postbaseline tumor assessment 
unless treatment was discontinued due to disease progression or death before tumor 
assessment.
x
The PK analysis set includes patients who contributed at least 1 quantifiable PK sample.
x
The antidrug antibody (ADA) Analysis Set includes all patients who received at least 1 dose of 
tislelizumab and for whom both baseline ADA and at least 1 postbaseline ADA results are 
available.
Safety Analysis
Safety will be determined by the collection 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 
NCI-CTCAE v5.0. The incidence of treatment-emergent AEs (TEAEs) will be reported as the number 
(percentage) of patients with TEAEs by system organ class (SOC) and preferred term. Descriptive 
summary statistics (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.
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 in 
combination with tislelizumab. 
x
ORR is defined as the proportion of patients who have confirmed or unconfirmed complete 
response (CR) or partial response (PR) as assessed by the investigator using RECIST v1.1. The 
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 
stable disease (SD). 


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x
PFS is defined as the time from the date of the first dose of study drugs to the date of the first 
documentation of PD as assessed by the investigator using RECIST v1.1 or death, whichever 
occurs first. 
x
OS is defined as the time from the date of the first dose of study drugs to the date of death due 
to any cause. 
x
PFS assessed per CA-125 criteria will be summarized descriptively.
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 including PFS, DOR, and OS will be estimated using the Kaplan-Meier 
method and will be plotted over time. Median PFS, DOR and OS, if possible to estimate, will be 
presented for each cohort, with 2-sided 95% CIs. 
Waterfall plots of maximum tumor shrinkage per patient will be presented.
Efficacy analyses will be provided based on both the Efficacy Evaluable analysis set and the Safety 
analysis set. The Efficacy Evaluable analysis set will be the primary analysis set for response analyses; 
and the Safety analysis set will be the primary analysis set for time-to-event analyses. Details of 
statistical analyses will be described in the Statistical Analysis Plan.
Sample Size Considerations
Approximately 220 to 240 patients (approximately 60 patients for Cohort E, and 20 patients for each of 
the rest of the cohorts) are expected to be enrolled to analyze safety and preliminary efficacy for 
sitravatinib plus tislelizumab. Of the approximately 60 patients enrolled into Cohort E, at least 20 
patients who failed the prior bevacizumab treatment and at least 20 patients will be Caucasian.
Enrollment into these cohorts will occur simultaneously, independently 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
AUC
area under the plasma or serum concentration-time curve
BOR
best overall response
CI
confidence interval
CL
clearance
CR
complete response
CT
computed tomography
DCR
disease control rate
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End-of-Treatment
FFPE
formalin-fixed paraffin-embedded
GCIG
Gynecologic Cancer Intergroup
HBV
hepatitis B virus
HCV
hepatitis C virus
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
irAE
immune-related adverse event
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NSCLC
non-small cell lung carcinoma
OC
ovarian cancer
ORR
objective response rate


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Abbreviation
Definition
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein-1
PD-L1
programmed cell death protein ligand-1
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
RCC
renal cell carcinoma
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
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
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.
Non-Small Cell Lung Cancer
Worldwide, lung cancer has been the most common malignancy in the past few decades and the 
leading cause of cancer death by far. In 2012, it was estimated that a total of 1.8 million new 
cases were diagnosed, accounting for 12.9% of all new cancer diagnoses (Wong et al 2017).
Likewise, lung cancer is also the most common cancer and the leading cause of cancer death in 
China; about 782,000 new cases of lung cancer were diagnosed in 2014 (Chen et al 2015).
According to statistics from the National Office on Tumor Cure and Prevention, about 
626,000 people die of lung cancer each year in China (Chen et al 2018). Meanwhile, lung cancer 
was the fifth most commonly diagnosed cancer in Australia in 2013. In 2018, it is estimated that 
this will increase to 9,198 deaths from lung cancer in Australia (Australian Government 2018).
Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers 
(PDQ Adult Treatment Editorial Board 2017). It includes 2 major pathological types: 
1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, and other 
subtypes); 2) squamous cell (epidermoid) carcinoma (NCCN Guideline Version 4, 2019).
For decades, the conventional anticancer strategies have been surgery, chemotherapy, and 
radiotherapy. The success in immune checkpoint therapy in recent years has revolutionized 
traditional cancer treatment. PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint 
inhibitors being developed for the treatment of cancer. The FDA has approved six different 
monoclonal antibodies targeting the PD-1/PD-L1 pathway: pembrolizumab (PD-1 inhibitor) 
(KEYTRUDA® prescribing information), nivolumab (PD-1 inhibitor) (OPDIVO® prescribing 
information), atezolizumab (PD-L1 inhibitor) (TECENTRIQ® prescribing information),
durvalumab (PD-L1 inhibitor) (IMFINZI™prescribing information), avelumab (PD-L1 inhibitor) 
(BAVENCIO® prescribing information) and cemiplimab-rwlc (PD-1 inhibitor) 
(LIBTAYO® prescribing information).
In the first-line setting, KEYNOTE-042 (Lopes et al 2018) demonstrated that single-agent 
pembrolizumab significantly improved overall survival (OS) compared with platinum-based 
chemotherapy with advanced NSCLC, PD-L1 expression of 1% or more, but without EGFR 
mutation or ALK rearrangement. Treatment -related adverse events of Grade 3 or worse occurred 
in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the 
chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively 
(Mok et al, 2019).
Based on these results, the FDA approved pembrolizumab as a single agent for the first-line 
treatment of patients with stage III NSCLC, who are not candidates for surgical resection or 
definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor 
proportion score ≥1%) with no EGFR or ALK genomic tumor aberrations
(KEYTRUDA® prescribing information).
Furthermore, pembrolizumab in combination with chemotherapy for patients with metastatic 
non-squamous or squamous NSCLC was also approved by FDA in 2018.


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In the KEYNOTE-189 study, for patients with metastatic non-squamous NSCLC without 
sensitizing EGFR or ALK mutations, the addition of pembrolizumab to chemotherapy resulted in 
significantly longer OS (estimated rate of OS at 12 months was 69.2% versus 49.4%, hazard 
ration of 0.49) and PFS (median 8.8 months versus 4.9 months, hazard ration of 0.52) and a 
higher response rate (47.6% versus 18.9%) than chemotherapy alone (Gandhi et al 2018).
Equally in the KEYNOTE-407 study, the addition of pembrolizumab to standard chemotherapy 
in patients with previously untreated metastatic squamous NSCLC resulted in significantly 
longer OS (median 15.9 months versus 11.3 months, hazard ration of 0.64) and PFS (median 
6.4 months versus 4.8 months, hazard ration of 0.56) and a higher response rate (57.9% versus 
38.4%) than chemotherapy alone, regardless of the level of PD-L1 expression 
(Paz-Ares et al 2018).
The addition of pembrolizumab did not appear to increase the frequency of adverse events that 
are commonly associated with chemotherapy regimens involving pemetrexed and a 
platinum-based drugs. Adverse events of grade 3 or higher in the pembrolizumab-combination
group versus placebo-combination group were 67.2% versus 65.8% in KEYNOTE-189 and 
69.8% versus 68.2% in KEYNOTE-407.
Identically, three studies evaluated the efficacy and safety of atezolizumab plus chemotherapy 
(IMpower130 [Cappuzzo et al 2018], 131 [Jotte et al 2018] and 132 [Papadimitrakopoulou et al 
2018]) as first line of treatment for advanced NSCLC. The use of the PD-L1 inhibitor 
atezolizumab in combination with chemotherapy demonstrated improved PFS in patients with 
stage IV non-squamous or squamous NSCLC.
In addition, adding atezolizumab to bevacizumab plus chemotherapy significantly improved PFS 
and OS among patients with metastatic non-squamous NSCLC, regardless of PD-L1 expression 
and EGFR or ALK genetic alteration status (Socinski et al 2018) (Reck et al, 2019).
Treatment-related adverse events of grade 3 or higher in 
atezolizumab/bevacizumab/chemotherapy group versus bevacizumab/chemotherapy group were
58.5% versus 50.0%. 
While in second-line therapy, two immune checkpoint inhibitors targeting PD-1, nivolumab and 
pembrolizumab, were approved in 2015. Among these, nivolumab demonstrated a survival 
benefit versus docetaxel in advanced non-squamous NSCLC, reporting 27% lower risk of death 
at a minimum follow-up of 13.2 months (median OS: 12.2 versus 9.4 months; ORR: 19% versus 
12%), and better safety profile than standard-of-care chemotherapy (Grade 3 and Grade 4 AEs: 
10% versus 54%) (Borghaei et al 2015). In 2016, another checkpoint inhibitor targeting PD-L1, 
atezolizumab, was approved for the same indication.
Despite the recent advances with anti-PD-L1 therapy, most patients with advanced NSCLC have 
incurable disease; more effective treatment options with better tolerability profile are needed, as 
first-line treatment and as treatment after failure of a platinum-based chemotherapy regimen and 
resistance to anti- PD-L1 therapy. Alternative treatment approaches to eliminate the resistant 
tumor cells are warranted.
1.1.2.
Renal Cell Carcinoma
Each year, an estimated 338,000 new cases of renal-cell carcinoma (RCC) are diagnosed 
worldwide, and approximately 30% of patients present with metastatic disease at the time of 


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diagnosis. According to the National Cancer Registry under the National Cancer Center of 
China, there were 68,000 new RCC cases in 2014. The incidence of RCC was 6.09/100,000 and 
3.84/100,000 in males and females (Chen et al 2018). The mortality of RCC is 1.87/100,000 
nationwide at about 26,000 cases in 2014. In 2018, it is estimated that 3,617 new cases of kidney 
cancer will be diagnosed in Australia and it is estimated that this will increase to 1,069 deaths. 
Between 1984-1988 and 2009-2013, 5-year relative survival from kidney cancer improved from 
49% to 75% (Australia Institute of Health and Welfare 2017).
RCC is exquisitely resistant to chemotherapy. Targeted therapy utilizing tyrosine kinase 
inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies is widely used in first-
and second-line treatments. To date, 9 such agents have been approved by the FDA for the 
treatment of advanced RCC in the first or subsequent line of therapy. These agents have provided 
significant clinical benefit for many patients with metastatic RCC (mRCC), but infrequently lead 
to durable responses (Motzer et al 2013).
In 2015, the FDA approved the first checkpoint inhibitor, nivolumab, for patients with advanced 
RCC following treatment with antiangiogenic therapy based on improved OS compared with the
standard of care. A strong biological rationale supports the strategy of combining 
immunotherapy with anti-VEGFR agents as the latter agents can promote T-cells infiltration into 
tumors and boost synergism with PD-1 or PD-L1 blockade. The treatment combination of 
pembrolizumab plus lenvatinib has shown promising antitumor activity with manageable AEs in 
patients with mRCC who had ≤ 2 prior systemic therapies (Lee et al 2018). The ORR per 
immune-related RECIST by investigator review was 70.0% (n = 21; 95% CI, 50.6% to 85.3%). 
Median duration of response for patients with complete response (CR) or partial response (PR) 
was 18.4 months (95% CI, 10.3 months to not evaluable). The combination of pembrolizumab 
and lenvatinib recently received a breakthrough therapy designation from the FDA for the 
treatment of patients with advanced and/or mRCC who had progressed after treatment with 
approved therapies or for which there are no standard effective therapies available (Merck 2018).
Several anti-PD-1/PD-L1 based combination regimens are being evaluated as first line RCC 
therapy. The treatment combination with pembrolizumab plus axitinib has demonstrated 
promising antitumor activity in 52 patients with treatment-naïve advanced RCC 
(Atkins et al 2018). The ORR was 73% (95% CI, 59.0% to 84.4%) with 4 patients achieving CR 
and 34 patients achieving PR. Median PFS was 22.1 months (95% CI, 15.2 months to not 
evaluable) and 20.7 months (95% CI, 8.2 months to not evaluable) for patients with PD-L1 
negative and PD-L1-positive tumors, respectively. The most common ≥ Grade 3 treatment-
emergent AEs (TEAEs) included hypertension (n = 12 [23%]), diarrhoea (n = 5 [10%]), fatigue 
(n = 5 [10%]), and increased alanine aminotransferase (ALT) concentration (n = 4 [8%]). 
Another study evaluating axitinib with avelumab as first-line therapy reported encouraging 
antitumor activity in patients with advanced RCC. The proportion of patients with confirmed 
objective responses was 58% in 55 patients treated (Choueiri et al 2018). Based on these 
promising data in early phase studies, two Phase 3 pivotal trials with anti-PD-L1 blocking agent 
plus axitinb as first-line treatment for patients with advanced RCC was initiated later 
(KeyNote-426 [Rini et al 2019] and JAVELIN Renal 101 [Motzer et al 2019]). With significant 
improvements in overall survival (OS), progression-free survival (PFS) and objective response 
rate (ORR) versus sunitinib, FDA had approved pembrolizumab-axitinib combination 
[U.S. Food & Drug Administration 2019 a] and avelumab-axitinin combination 


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[U.S. Food & Drug Administration 2019 b] in the second quarter of 2019 for the frontline 
treatment of patients with advanced RCC. A Phase 3 study of lenvatinib plus everolimus or 
pembrolizumab versus sunitinib as first-line treatment for advanced RCC is also in progress 
(NCT02811861).
Despite the recent approval of new therapies for advanced RCC, many patients who do not 
respond to the existing treatments have a poor prognosis. The majority of patients who initially 
achieved regression inevitably develop recurrence with PD. For patients who have failed initial 
therapies, new treatment options are urgently needed. For treatment naïve patients, the new 
strategies of combining a more selective VEGF inhibitor with a PD-1 inhibitor to improve 
tolerability while offering synergistic antitumor activity may provide new treatment options.
1.1.3.
Ovarian Cancer
Ovarian cancer (OC) is the eighth most common cancer among women, and it comprises about 
4% of all women’s cancers. According to global estimates 225,000 new cases were detected each 
year, and 140,000 people annually die from the disease (Ferlay et al 2010). According to the 
National Cancer Registry under the National Cancer Center of China, there were 51,000 new OC 
cases in 2014 (Chen et al 2018). The mortality of OC is 1.64/100,000 nationwide at about 
23,000 cases in 2014. In 2018, it is estimated that 1,613 new cases of ovarian cancer will be 
diagnosed in Australia. In 2018, it is estimated that this will increase to 1,069 deaths. Between 
1984-1988 and 2009-2013, 5-year relative survival from ovarian cancer improved from 34.1% to 
44.4% (Australian Institute of Health and Welfare 2017).
Standard front-line systemic treatment for epithelial OC consists of platinum-based 
chemotherapy, with the option to add the antiangiogenic agent bevacizumab (anti-VEGF 
antibody) according to local approval and availability. Although response rates are high, disease 
recurrence is frequent and almost all patients eventually become refractory (PD < 1 month of last 
dose of platinum-based chemotherapy) or resistant (relapse 1 to 6 months after last dose of 
platinum-based treatment) to platinum-based therapy (Asano et al 2015). In either case, the 
prognosis for patients with platinum-resistant/refractory disease is poor.
The standard of care for patients with platinum-resistant/refractory disease includes single 
nonplatinum agents with or without bevacizumab. Pegylated liposomal doxorubicin 
monotherapy is a commonly used treatment option in this setting and has been associated with 
ORRs of 10% to 20%, a median PFS of 2.1 to 3.7 months, and median OS of 8.4 to 16.8 months 
in platinum-resistant ovarian cancer (Davis et al 2014).
In ovarian cancer, there are few published studies utilizing immunotherapies. Nevertheless, there 
is a strong rationale to investigate checkpoint inhibition in patients with ovarian cancer for whom 
high expression of PD-L1 in ovarian cancer is associated with lower 5-year survival rate. 
Furthermore, nonclinical experiments in syngeneic ovarian cancer murine models show tumor 
regression with PD-1/PD-L1 blockade. A Phase 2 study of nivolumab in 20 patients in Japan 
with platinum-resistant epithelial OC demonstrated a response rate of 15% (3/20) and a disease 
control rate of 45%. Two patients experienced a complete response, one with serous and one 
with clear cell histology (Hamanishi et al 2015). Although small, the presence of complete 
responses in a heavily pretreated group of patients with an overall poor prognosis is promising.


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1.1.4.
Melanoma
In 2018, it’s estimated that 287,723 new cases of malignant melanoma were diagnosed 
worldwide. The age-standardized incidence rate and mortality rate worldwide were 3.1/100,000 
and 0.63/100,000, respectively (Globocan 2018). Melanoma was the 4th most common cancer in 
Australia, with estimated 15,229 new cases and 1,725 deaths in 2019. From 1986 to 1990 and 
2011 to 2015, 5-year relative survival from melanoma improved from 87.7% to 91.0% 
(Australia Institute of Health and Welfare 2017). According to the National Cancer Registry
under the National Cancer Center of China, there were 7,000 new melanoma cases in 2014, with 
incidence rates of 0.36/100,000 in males and 0.33/100,000 in females (Chen et al 2018).
Melanoma is generally classified into 4 main subtypes based on the anatomical location and the 
degree of sun exposure: melanoma on skin without chronic sun-induced damage, melanoma on 
skin with chronic sun-induced damage, mucosal melanoma, and acral melanoma. Cutaneous 
subtype is the predominantly subtype among Caucasian melanoma patients. Acral and mucosal 
melanomas are biologically and clinically distinctive subtypes more frequently seen among 
Chinese melanoma patients, accounting for 41.8% and 22.6%, respectively (Chi et al 2011). 
Immune-checkpoint inhibitors are expected to be less effective against acral and mucosal 
melanomas because their somatic mutation burden is lower than those in non-acral cutaneous 
melanomas.
Since 2011, immune checkpoint inhibitors have revolutionized the treatment landscape of 
melanoma with remarkable PFS and OS improvement and a favorable safety profile. 
Consequently, they are now established standard of care options for patients with unresectable 
and metastatic melanoma.
Ipilimumab was the first immunotherapy to demonstrate a survival improvement in metastatic 
melanoma and was approved by FDA in 2011. In MDX010-20 study, 676 unresectable stage III 
or IV melanoma patients were randomly assigned in a 3:1:1 ratio to receive ipilimumab plus 
glycoprotein 100 (gp100) vaccine (n = 403), ipilimumab (n = 137), or gp100 (n = 136). The 
median OS was 10.0 months in ipilimumab arm, compared with 6.4 months in gp100 arm [HR 
0.66 (95% CI: 0.55 to 0.85), p = 0.0004] (Hodi et al 2010). A pooled analysis demonstrated a 
median OS of 11.4 months (95% CI, 10.7 to 12.1 months) among 1,861 melanoma patients 
receiving ipilimumab monotherapy (Schadendorf et al 2015).
Anti-PD-1 antibodies have demonstrated a high response rate and durable responses in 
melanoma patients pretreated with ipilimumab in KEYNOTE 002 (Ribas et al 2015) and 
CheckMate 037 (Weber et al 2015) studies, which led to FDA accelerated approval of 
pembrolizumab and nivolumab in 2014. Soon after, both pembrolizumab and nivolumab showed 
superiority over ipilimumab, and both were approved in the first line setting
(KEYTRUDA® prescribing information; OPDIVO® prescribing information).
KEYNOTE-006 was the first head-to-head comparison of pembrolizumab versus ipilimumab for
advanced melanoma. In this open-label, randomized phase 3 study, ipilimumab-naïve melanoma 
patients were assigned by 1:1:1 to pembrolizumab in two dosing schedules (10 mg/kg every 2 or 
3 weeks) versus ipilimumab 3 mg/kg (every 3 weeks for 4 doses) (Robert et al 2015). In 
treatment-naive population, ORR was 39.4% (95% CI, 34.4% to 44.6%) with pembrolizumab, 
almost triple of the ORR of 13.3% (95% CI, 8.7% to 19.1%) with ipilimumab, median PFS was 
6.6 months (95% CI, 4.4 to 9.8 months) for pembrolizumab and 2.8 months (95% CI, 2.8 to 3.0 


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months) for ipilimumab (Carlino et al 2018). And the median OS was 38.7 months with 
pembrolizumab arm and 17.1 months with ipilimumab [HR=0.73(0.75-0.93)] (Long et al 2018).
CheckMate 067 was a phase 3 trial to evaluate safety and efficacy of nivolumab monotherapy or 
nivolumab and ipilimumab combination therapy, compared to ipilimumab monotherapy. In this 
study, 945 treatment-naïve melanoma patients with known BRAF mutation status were randomly 
assigned by 1:1:1 to receive nivolumab in combination with ipilimumab, or nivolumab plus 
placebo, or ipilimumab plus placebo. The confirmed ORR was 14% (95% CI, 10% to 18%) for 
ipilimumab, 40% (95% CI, 34% to 46%) for nivolumab, and 50% (95% CI, 44% to 55%) for 
nivolumab and ipilimumab combination, the median PFS was 2.9 months (95% CI, 2.8 to 3.4 
months) , 6.9 months (95% CI, 4.3 to 9.5 months), and 11.5 months (95% CI, 8.9 to 16.7 
months), respectively (Larkin et al 2015). After 4 years follow-up, the median OS was 19.9 
months (95% CI, 16.9 to 24.6 months) for ipilimumab group, 36.9 months (95% CI, 28.3 months 
to not reached) for nivolumab group and was not reached (95% CI, 38.2 months to not reached)
for the combination group. However, the downside to the nivolumab and ipilimumab 
combination therapy is significantly increased toxicity. The treatment-related grade 3-4 adverse 
events occurred in 28% of the patients treated with ipilimumab monotherapy, 22% of nivolumab 
monotherapy, and 59% of nivolumab plus ipilimumab combination (Hodi et al 2018).
Recently, FDA has approved nivolumab adjuvant treatment of melanoma patients with lymph 
node involvement on 20 December 2017 based on the recurrence-free survival improvement in 
CheckMate 238. Earlier this year, pembrolizumab adjuvant treatment has also been granted FDA 
approval based on KEYNOTE-054.
CheckMate 238 compared outcomes for nivolumab versus ipilimumab given for up to 1 year, in 
906 surgically resected melanoma patients with stages IIIB, IIIC, and IV melanoma. In this
phase 3, double-blind trial, patients were randomly allocated (1:1) to receive nivolumab 
(n = 453) or ipilimumab (n = 453). BRAF mutation was positive for 42% of the patients. Patients 
in nivolumab arm experienced fewer recurrences/deaths, 34% (n = 154), compared with 45.5% 
(n = 206) in ipilimumab arm (HR 0.65; 95% CI, 0.53 to 0.80; p<0.0001). Median recurrence-free 
survival was not reached on either arm (Weber et al 2017).
KEYNOTE-054 enrolled patients with completely resected stage IIIA, IIIB or IIIC melanoma to 
receive pembrolizumab (n = 514) or placebo (n = 505) for up to 1 year or until disease 
recurrence or unacceptable toxicity. BRAF mutation was positive for 50% of the patients. At a 
median follow-up of 15 months, pembrolizumab group achieved significantly longer 
recurrence-free survival than placebo group: 1-year rate of recurrence-free survival was 75.4% 
(95% CI, 71.3% to 78.9%) versus 61.0% (95% CI, 56.5% to 65.1%); (HR 0.57; 95% CI, 0.46 to 
0.7) (Eggermont et al 2018).
In China, anti-PD-1 antibodies, including pembrolizumab and toripalimab (also known as 
JS001), have also been approved for patients with unresectable or metastatic melanoma in 2018. 
KEYNOTE-151 was a phase 1b study investigating second line pembrolizumab for Chinese 
patients with advanced or metastatic melanoma that progressed after first-line therapy. In this 
study, 103 patients were enrolled, the ORR per RECIST v1.1 was 16.7% (95% CI, 10.0% to 
25.3%), median PFS was 2.8 months (95% CI, 2.7 to 3.5 months) and median OS was 12.1 
months (95% CI, 9.6 months to not reached). In this study, the ORR was 19.5% for nonacral 
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However, only approximately 20%-40% patients initially respond to anti-PD-1 checkpoint 
inhibitors, and increasing clinical evidence indicates that a substantial proportion of initial 
responders ultimately relapse with lethal, drug-resistant disease months or years later. Currently, 
the management for melanoma patients progressed on 1st line immune checkpoint inhibitor 
treatment remains challenging, representing a huge unmet medical need. Clinical trials 
investigating combination immunotherapy are ongoing in this field.
1.2.
Sitravatinib as an RTK Inhibitor
Receptor tyrosine kinases (RTK) 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, 
VEGFR2, VEGFR3, PDGFRα, DDR2, TRKA, and TRKB. Sitravatinib targets are genetically 
altered in a variety of cancers and act as oncogenic drivers, promoting cancer development and 
progression. In addition to targeting genetically altered oncogenic drivers, sitravatinib targets are 
expressed in a number of immune cell types and promote an immunosuppressive tumor 
microenvironment (TME) 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 anti-angiogenic 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 results from the hERG assay demonstrate an IC50 of 0.6 μM (0.38 μg/mL) on the 
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 


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290-fold lower than the hERG IC50 concentration. There were no adverse effects on the 
cardiovascular system, including no effect on the QTc interval, when sitravatinib was 
administered to dogs at doses up to 4 mg/kg (mean 6 hr concentration of 0.072 μg/mL). 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 (IB) for 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 one 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, 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 animals given 
≥10 mg/kg/day, the NOAEL is 2.5 mg/kg/day.
Sitravatinib was evaluated in a standard battery of Good Laboratory Practice genotoxicity studies 
(Ames, chromosome aberrations and in vivo rat micronucleus assays) and was considered 
negative for mutagenicity and clastogenicity.
Refer to the sitravatinib IB 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, 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 curve [AUC]) are approximately dose proportional with single doses up to 200 mg. Median 
elimination half-life varies between approximately 42 and 58 hours after oral administration. The 


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steady state PK is reached in a mean time of 11 to 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 was determined to be the maximum tolerated dose 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 VEGF-R2 and soluble MET 
ectodomain (sMET) levels in patients’ plasma samples. The mean prediction (95% CI) percent 
change from baseline in biomarker modulation with exposure, approached: VEGFA (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 IB 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 IB 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 an ongoing multi-center 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 maximum tolerated dose 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 
solid tumors. As of 26 June 2019, among the 186 patients with available safety data, 183 patients 
(98%) had experienced at least one treatment-emergent AE, and 167 patients (90%) had 
experienced treatment-related AEs. Treatment-related AEs reported in ≥ 10% of patients are 
provided in Table 1.
Treatment-related Grade 3-5 AEs reported in ≥ 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%).


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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%)
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 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 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 


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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 2018b) and data from 
MRTX-500, Mirati decided to evaluate only the 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 reported 
in ≥10% of patients provided in Table 2.
Treatment-related Grade ≥ 3 AEs reported in ≥ 5% of patients were hypertension (17%), diarrhea 
(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%).


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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%)
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, 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.


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Study MRTX-500, an ongoing Phase 2 combination therapy study in patients with NSCLC, 
began with a lead-in evaluation of 120 mg once daily of sitravatinib in combination with 
nivolumab. No protocol defined DLTs were reported in the first 6 evaluable patients treated at 
120 mg which was selected as the RP2D for combination therapy. As recently reported 
(Mirati 2018a), 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 VEGF and TAM receptors necessary to 
achieve antitumor efficacy in the combination setting. 
Sitravatinib 120 mg once daily is the recommended initial dose for combination with 
tislelizumab.
1.3.
Tislelizumab as a PD-1 Blocker
Immune checkpoint-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-γ and IFN-α in the tumor microenvironment. Furthermore, the 
increased PD-1 expression in tumor-infiltrating lymphocytes and/or PD-L1 expression in tumor 
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, RCC, 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). 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 pre-activated, primary peripheral blood mononuclear cells (PBMCs). In addition, 
tislelizumab has demonstrated antitumor activity in several allogeneic xenograft models, in 
which PBMCs were co-injected with human cancer cells (A431 [epidermoid carcinoma]) or 
tumor fragments (BCCO-028 [colon cancer]) into immunocompromised mice. 
In addition, tislelizumab is an IgG4-variant antibody to gamma fragment crystallizable (Fc)
region receptors (FcγR) such as FcγRI and FcγRIIIA, and it has very low binding affinity to 
complement 1q (C1q), a subunit of complement 1. In vitro assays with tislelizumab suggest 


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either low or no antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular 
phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC) effects in humans
(Labrijn et al 2009; Zhang et al 2018). Tislelizumab was specifically engineered to abrogate 
these potential mechanisms of T-cell clearance and potential resistance to anti-PD-1 therapy.
Please refer to the tislelizumab IB 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 Good Laboratory Practice regulations. 
The single dosing regimens spanned from the intended human doses to 10-fold higher than the 
maximum of the intended human doses, and the repeat dosing regimens spanned to 3-fold higher 
than the maximum of the intended human doses. Cynomolgus monkey was the only relevant 
species based on the target sequence homology and binding activity. 
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in 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 
considered to be 30 mg/kg. The safety profile of tislelizumab is considered adequate to support 
the current study of BGB-900-103.
Please refer to the tislelizumab IB for more detailed information on the toxicology of 
tislelizumab.
1.3.3.
Clinical Pharmacology
Population PK analysis was conducted on data from 798 patients who received doses of 0.5, 2.0, 
5.0, and 10 mg/kg once every 2 weeks, 2.0 and 5.0 mg/kg once every 3 weeks, and 200 mg once 
every 3 weeks. The PK of tislelizumab was best characterized using a 3-compartmental linear 
population PK model with linear clearance mechanisms. No time-varying clearance was 
observed in tislelizumab PK. The typical estimates of clearance (CL), central volume (Vc), and 
peripheral volumes (V2, V3), were 0.164 L/day, 2.92 L, 0.928 L, and 1.39 L, respectively, with 
moderate inter-individual variability in CL (32.2%), Vc (16.7%), V2 (56.6%), and V3 (94.2%). 
The volume of distribution at steady state (Vss) was 5.238 L, which is typical of monoclonal 
antibodies with limited distribution, which is consistent with a standard immunoglobulin G (IgG)
monoclonal antibody (Deng et al 2012; Dirksand Meibohm 2010; Keizer et al 2010;
Ryman and Meibohm 2017). Based on the population PK analysis, tislelizumab PK was 
characterized by a terminal half-life of approximately 25.5 days, which is consistent with other 
therapeutic IgG monoclonal antibodies.


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Population PK analysis demonstrated that baseline age, race, alanine aminotransferase, aspartate 
aminotransferase, bilirubin, lactate dehydrogenase, estimated glomerular filtration rate, ECOG
Performance Status, immunogenicity, and sum of products of perpendicular diameters in 
classical Hodgkin lymphoma patients did not show statistically significant impact on the PK of 
tislelizumab. Although tumor size, albumin, and tumor type were significant covariates on CL, 
while body weight, sex, and tumor type were significant covariates on Vc, these covariates are 
not expected to have a clinically relevant impact on tislelizumab exposure. Exposure-response 
analysis indicated that there was a lack of clinically significant exposure-response relationships 
for ORR and safety endpoints across a variety of advanced solid tumors and classical Hodgkin 
lymphoma for tislelizumab. Population PK analysis 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 Investigator’s Brochure (IB):
7 monotherapy studies, 2 chemotherapy combination therapy studies; and 4 investigational agent 
combination therapy studies.
Please refer to the tislelizumab IB for more detailed information on tislelizumab safety and 
efficacy data when given as monotherapy or in combination with chemotherapy.
1.3.4.1.
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; and 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
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 regimensa
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)
≥3
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.
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.


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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 
least one ≥Grade 3 TEAE assessed as related to tislelizumab. The only ≥Grade 3 TEAEs that
occurred in ≥1% (≥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 adverse events (irAEs) 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 occur in ≥1% in the total Pooled Monotherapy studies are shown in Table 4.


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Table 4.
Immune-Related Adverse Events of Any Grade Occurring in ≥1% in Pooled 
Monotherapy Studies
Categories
Preferred Term
Total
(N = 1273)
Any Grade
n (%)a
Grade ≥3
n (%)a
Patients with at least one potential immune-related AEa
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.
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.


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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 total patients with at least one irAE that also was ≥Grade 3
in severity showed that 121 patients (9.5%) experienced such events. The most commonly 
occurring irAEs ≥Grade 3 in severity were 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%), and lung 
infection (8 patients, 0.6%).
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 patients, 0.9%). There were 6 patients who reported a total of 7 ≥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.


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Table 5.
Treatment-Emergent Fatal Adverse Events Regardless of Causality in Pooled 
Monotherapy Studies
Category
Overall
(N = 1273)
n (%)
All deaths at data cutoff
641 (50.4)
Death ≤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
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 shows a total of 105 patients (8.2% of the total population) died ≤30 days after the last 
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, and Phase 1b investigates efficacy and safety in select tumor types.


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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 SD. A total of 199 patients (45.1%) 
had a best response of PD in this study.
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 maximum tolerated dose 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 


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evaluable patients treated (n = 13), 3 patients (23%) had a BOR of partial response (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.
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 tyrosine kinase inhibitors to treat cancer is well established based on 
robust clinical efficacy achieved with well tolerated inhibitors directed toward oncogenic 
tyrosine kinases. In addition, selected tyrosine kinase inhibitors 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 non-responders 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 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 IL-12, IL-6, and TNF. These downstream effects 


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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 receptor tyrosine kinases inhibit key molecular and cellular pathways strongly 
implicated in 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
Immunotherapy with checkpoint inhibitors has demonstrated responses in patients with NSCLC 
or RCC. 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 1.1.2 and Section 1.2.4.2). For patients with OC, combination 
therapy may improve the clinical efficacy of single-agent immunotherapies. 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 IB.
More than 1000 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥2 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 IB.
A Safety Monitoring Committee (SMC) will be established and will monitor the preliminary 
safety and activity data for sitravatinib in combination with tislelizumab. 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
2.1.1.
Primary Objective
x
To characterize safety and tolerability of sitravatinib in combination with tislelizumab
2.1.2.
Secondary Objectives
x
To assess the preliminary antitumor activity of sitravatinib in combination with 
tislelizumab
x
To characterize the PK profiles of sitravatinib after single dose and at steady state 
when given in combination with tislelizumab 
2.1.3.
Exploratory Objectives
x
To assess PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib
x
To explore potential pharmacodynamic biomarkers for sitravatinib in combination 
with tislelizumab
x
To explore potential biomarkers of efficacy, resistance, or progressive disease (PD) in 
tumor tissue and in peripheral whole blood
x
To assess overall survival (OS)
x
To explore effect of pharmacogenetic (PGx) polymorphisms on PK of sitravatinib
x
To assess the preliminary antitumor activity of sitravatinib in combination with 
tislelizumab for ovarian cancer patients based on the Gynecologic Cancer Intergroup 
(GCIG) working group criteria 
2.2.
Study Endpoints 
2.2.1.
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) Version 5.0, relevant physical examination, 
electrocardiograms, and laboratory assessments as needed
2.2.2.
Secondary Endpoints
x
Efficacy evaluations: ORR, duration of response (DOR), disease control rate (DCR), 
and PFS based on RECIST version 1.1 
x
Plasma concentrations and the derived PK parameters of sitravatinib:
-
Single dose: Cmax, time to maximum plasma concentration (Tmax), AUC(0-t),
clearance after oral administration (CL/F)


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-
Repeat dose: Cmax, Cτ, Tmax, AUC(0-τ), CL/F, accumulation ratio (Ro)
2.2.3.
Exploratory Endpoints
x
Serum concentrations of tislelizumab and anti-tislelizumab antibodies
x
Changes of potential pharmacodynamic biomarkers in response to sitravatinib 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
Potential biomarkers, including but not limited to PD-L1 expression, immune cell 
profiling, tumor mutation load and gene expression profiling; and the association with 
disease status and or the response to sitravatinib in combination with tislelizumab
x
OS
x
Effect of genetic polymorphisms of hepatic metabolizing enzymes and transporters, 
including but not limited to CYP1A2, 2D6, 2C8 on the PK of sitravatinib
x
Efficacy evaluations for ovarian cancer patients: PFS per CA-125 (GCIG working 
group criteria, Appendix 12)


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3.
STUDY DESIGN
3.1.
Summary of Study Design 
This is an open-label, multicenter, non-randomized Phase 1b clinical trial for patients with 
histologically or cytologically confirmed locally advanced or metastatic tumors including 
non-squamous or squamous non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), 
epithelial ovarian cancer (OC), or melanoma. 
All patients will receive sitravatinib 120 mg orally, once daily in combination with tislelizumab 
200 mg intravenously once every 3 weeks until occurrence of PD, unacceptable toxicity, death, 
withdrawal of consent, or study termination by sponsor.
There will be a total of 9 cohorts in the study. Approximately 60 patients will be enrolled into 
Cohort E, including at least 20 patients who failed the prior bevacizumab treatment and at least 20 
patients will be Caucasian. The additional 40 patients of Cohort E will not be enrolled in China 
after the amendment is effective. In addition, approximately 20 patients will be enrolled into 
each of the rest of the cohorts. The patients will be enrolled according to their tumor type and 
prior anti-PD-1/PD-L1 antibody treatment.
x
Cohort A: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, non-squamous 
NSCLC
x
Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC
x
Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic or advanced 
RCC
x
Cohort D (China-only): Metastatic or advanced RCC without prior systemic therapy 
x
Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum-resistant 
epithelial OC
x
Cohort F: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, squamous 
NSCLC
x
Cohort G: Anti-PD-1/PD-L1 antibody refractory/resistant unresectable or metastatic 
melanoma
x
Cohort H: PD-L1 positive, locally advanced or metastatic, non-squamous NSCLC 
without prior systemic treatment in metastatic setting
x
Cohort I: PD-L1 positive, locally advanced or metastatic, squamous NSCLC without 
prior systemic treatment in metastatic setting
Cohort F will only enroll prior anti-PD-1/PD-L1 antibody refractory/resistant squamous NSCLC
until the total number of prior anti-PD-1/PD-L1 antibody treated squamous NSCLC reaches 20
patients. The prior anti-PD-1/PD-L1 naïve patients who enrolled before the amendment is 
effective can continue their treatment per the protocol. It is to further investigate the safety and 
efficacy for patients with anti-PD-1/PD-L1 antibody treated squamous NSCLC. The anti-PD-
1/PD-L1 antibody naïve patient will be no longer enrolled in this cohort after this amendment is 
effective.


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The SMC will review the safety, tolerability, and pharmacology data from the initial 6 patients 
regardless of assigned cohort that complete the first cycle of treatment (21 days per cycle) in 
Australia. Recruitment will be on hold in Australia until these data have been reviewed by the 
SMC. For participating China sites only, the initial 6 patients enrolled in China regardless of 
assigned cohort will have their safety, tolerability, and pharmacology data reviewed by the SMC 
after the first cycle of treatment. Recruitment in China only will be on hold until the data have 
been reviewed. 
The SMC may assess the combination regimen as safe, but may also decide to evaluate a dosing 
regimen that was not predefined or not previously studied, if evaluation of toxicity at such a dose 
is desired.
Figure 1.
Study Schema
Abbreviations: IHC, immunohistochemistry; mNSCLC, metastatic non-small cell lung cancer; mRCC, metastatic 
renal cell carcinoma; NSCLC, non-small cell lung cancer; OC, ovarian cancer; PD, progressive disease; PD-1, 
programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; RCC. renal cell carcinoma; 
RECIST, Response Evaluation Criteria in Solid Tumors; SMC, Safety Monitoring Committee; VEGF, Vascular 
endothelial growth factor; VEGFR TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitors.


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Note: The SMC will review the safety, tolerability, and pharmacology data from the initial 6 patients and, 
additionally, 6 patients from China sites regardless of assigned cohort that complete the first cycle of treatment. 
Refer to Section 3.1 for additional details.
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. 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 will be 
treated with sitravatinib in combination with tislelizumab. All patients will receive study drug 
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.
On days with PK assessments, study drug should be administered in the clinic in accordance with 
the schedule for the PK samples. Assessments should be obtained before study drug 
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 by the investigator or subinvestigator and doses should be adjusted, if necessary, before 
study drug administration.
3.3.1.
Unscheduled Visit
Unscheduled visits may be performed at any time at the patient’s or investigator’s request for 
reasons such as assessment or follow-up of AEs. Study activities of an unscheduled visit should 
be performed based on the reason for the unscheduled visit and are outlined in Appendix 1. The 
date and reason for the unscheduled visit must be recorded in the unscheduled visit electronic 
case report form (eCRF).
3.4.
End-of-Treatment and Safety Follow-up Phone Calls
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
End-of-Treatment (EOT) Visit within 30 days after the last dose of study drug, or before the 
initiation of a new anticancer treatment, whichever occurs first. If routine laboratory tests (eg, 
hematology, clinical chemistry) were completed ≤ 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.


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In addition, telephone contacts with patients should be conducted to assess immune-related AEs 
and concomitant medications (if appropriate, ie, associated with an immune-related AE or is a 
new anticancer therapy) at 60 days (± 14 days) and 90 days (± 14 days) after the last dose of 
study drug, regardless of whether or not the patient starts a new anticancer therapy. If patients 
report a suspected immune-related AE at a telephone follow-up contact, the investigator should 
arrange an unscheduled visit if further assessment is indicated.
All AEs, including SAEs, will be collected as described in Section 8.6.
Patients who discontinue study treatment prior to PD will have their tumors assessed as outlined 
in Section 7.4.
See Appendix 1 for assessments to be performed at the EOT Visit.
3.5.
Survival Follow-up
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. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients 
who discontinue study treatment for reasons other than 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 eCRF. Patients may discontinue study treatment for reasons that include, but are not 
limited to, the following: 
x
Patient withdrawal of consent
x
Pregnancy
x
Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if the patient 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 or other 
country herbal medicine and Chinese or other country 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 that include, but are not limited to, the following: 


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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 time point when the final data for a clinical study were 
collected after the last study patient has made the final visit to the study location. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following: 
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 
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) 


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4.
STUDY POPULATION
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers.
4.1.
Inclusion Criteria
Each patient eligible to participate in this study must meet all of the following criteria:
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the Schedule of Assessments
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of 
consent in the jurisdiction in which the study is taking place)
3. At least 1 measurable lesion as defined by RECIST v1.1
Note: Selected target lesion(s) must meet one of these criteria: 1) not previously treated 
with local therapy or 2) within the field of prior local therapy but with subsequent 
progression as per RECIST v1.1.
4. Biomarker tests and tumor sample collections meet the following criteria for respective 
cohorts:
PD-L1
EGFR
ALK/ROS1
BRAF
NSCLC
nsq
Cohort A/B
N/A
Documented 
wild-type
No 
documented
rearrangement
No documented 
mutation
Cohort H
Central testing 
required 
sq
Cohort F
N/A
No documented 
mutation
Cohort I
Central testing 
required  
RCC
Cohort C/D
N/A
N/A
Melanoma
Cohort G
N/A
N/A
N/A
Documented 
status
Abbreviations: NSCLC, non-small cell lung carcinoma; nsq, non-squamous; RCC, renal cell carcinoma; sq, 
squamous
Documented tests results: identified by local or central tissue-based testing.
For Cohorts A and B patients with unknown EGFR mutation status, Cohort G patients with unknown BRAF 
mutation status as well as Cohorts H and I patients, archival/fresh biopsy tumor tissues (formalin-fixed 
paraffin-embedded [FFPE] blocks with tumor tissues or unstained FFPE slides) will be required during 
screening period. If no archival tumor tissue(s) can be provided, a fresh biopsy is mandatory.
Notes: Written informed consent is required prior to obtaining fresh tumor biopsies. Biopsy tumor tissue needs 
to originate from core or punch biopsy. Tumor tissue from fine-needle aspiration is not acceptable.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (Appendix 4)


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6. Adequate hematologic and end-organ function, as defined by the following laboratory 
values (obtained ≤7 days before first dose):
a.
Patients must not have required a blood or platelet transfusion or growth factor 
support ≤14 days before sample collection 
i.
Absolute neutrophil count ≥ 1.5 x 109/L
ii.
Platelets ≥ 75 x 109/L
iii.
Hemoglobin ≥90 g/L
b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or estimated glomerular 
filtration rate ≥60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration equation (Appendix 8)
c.
AST and ALT ≤3.0 x ULN, or AST and ALT ≤ 5.0 x ULN for patients with 
documented liver metastases
d. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome) 
e.
International normalized ratio (INR) ≤ 1.5 or prothrombin time ≤ 1.5 x ULN
f.
Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
7. Patients with inactive/asymptomatic carrier, chronic, or active hepatitis B virus (HBV) 
must have HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at 
Screening 
Note: Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV 
DNA should be managed per treatment guidelines. Patients receiving antivirals at 
Screening should have been treated for > 2 weeks prior to enrollment.
8. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and ≥ 120 days after the last dose of study 
drugs and have a negative serum pregnancy test ≤ 7 days of first dose of study drugs  
9. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of study drugs
10. Criteria removed.
Cohort-Specific Inclusion Criteria
Cohort A: Anti-PD-1/PD-L1 antibody refractory or resistant metastatic, non-squamous NSCLC
11. Histologically or cytologically confirmed, Stage IV NSCLC
12. Disease progression on or after ≥1 line of systemic therapy; and ≤ 3 lines of systemic 
therapy
Note: Patients who have progressed or have disease recurrence during or after neo-
adjuvant or adjuvant therapy with platinum-containing regimen (counted as one line of 
therapy) within 6 months after last dose are eligible provided the target lesion(s) have not 
been previously treated with local therapy (radiation) or the target lesion(s) within the 
field of local therapy have subsequently progressed as defined per RECIST v1.1


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13. Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1-containing 
therapy as the most recent treatment for metastatic NSCLC with best response defined as 
follows:
a.
Resistant (ie, RECIST v1.1-defined partial, complete response, or stable disease for at 
least 12 weeks after initiation of treatment followed by radiographic progression of 
disease)
b. Refractory (ie, radiographic progression of disease < 12 weeks after initiation of 
treatment) 
14. Wild-type EGFR status is required and patients with documented ALK rearrangement,
ROS1 rearrangement, or BRAF mutations are not eligible for the study.
15. No other prior immunotherapies, including, but not limited to, anti-CTLA-4, anti-OX40 
and anti-CD137  
Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC
16. Histologically or cytologically confirmed, Stage IV NSCLC
17. Disease progression on or after ≥1 line of systemic therapy; and ≤ 2 lines of systemic 
therapy
18. Wild-type EGFR status is required and patients with documented ALK rearrangement,
ROS1 rearrangement, or BRAF mutations are not eligible for the study.
Note: Patients who have progressed or have disease recurrence during or after neo-
adjuvant or adjuvant therapy with platinum-containing regimen (counted as one line of 
therapy) within 6 months after last dose are eligible provided the target lesion(s) have not 
been previously treated with local therapy (radiation) or the target lesion(s) within the 
field of local therapy have subsequently progressed as defined per RECIST v1.1
19. Radiographic progression per RECIST v1.1 on or after systemic treatment for metastatic 
NSCLC without prior exposure to anti-PD-1/PD-L1 agent 
Cohort C, Cohort D: Metastatic or advanced Renal Cell Carcinoma (RCC) 
20. Histologically or cytologically confirmed metastatic or advanced clear cell RCC, or RCC 
with a primary clear cell component
Cohort C: Anti-PD-1/PD-L1 antibody refractory or resistant metastatic or advanced RCC
21. Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1 therapy as the 
most recent treatment for mRCC with best response defined as follows:
a.
Resistant (ie, RECIST-defined partial, complete response, or stable disease for at least 
12 weeks followed by radiographic progression of disease)
b. Refractory (ie, radiographic progression of disease < 12 weeks after initiation of 
treatment)
22. ≤ 2 lines of systemic therapy including anti-PD-1/PD-L1 antibody treatment
23. No other prior immunotherapies, including, but not limited to, anti-CTLA-4, anti-OX40 
and anti-CD137


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Cohort D: Metastatic or advanced RCC without prior systemic therapy
Note: Cohort D will only enroll in China.
24. Systemic therapy is not available, is considered not suitable, or has been refused by the 
patient 
25. Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed > 12 months prior 
to enrollment.
Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum-resistant Epithelial Ovarian 
Cancer (OC) 
Note: Resistant to platinum-based therapy is defined as relapse about 1 to 6 months after 
last dose of platinum-based treatment.
26. Histologically confirmed advanced ovarian cancer
27. No platinum-refractory disease (PD < 1 month of last dose of platinum-based 
chemotherapy)
28. No prior exposure to anti-PD-1/PD-L1 agent
Cohort F: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, squamous NSCLC
Note: Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1-
containing therapy as the most recent treatment for metastatic NSCLC with best response 
defined as follows:
a.
Resistant (ie, RECIST v1.1-defined partial, complete response, or stable disease for at 
least 12 weeks after initiation of treatment followed by radiographic progression of 
disease).
b. Refractory (ie, radiographic progression of disease < 12 weeks after initiation of 
treatment).
29. Histologically or cytologically confirmed, Stage IV NSCLC
30. Disease progression on or after ≥1 line of systemic therapy; and ≤ 3 lines of systemic 
therapy
Note: Patients who have progressed or have disease recurrence during or after neo-
adjuvant or adjuvant therapy with platinum-containing regimen (counted as one line of 
therapy) within 6 months after last dose are eligible provided the target lesion(s) have not 
been previously treated with local therapy (radiation) or the target lesion(s) within the 
field of local therapy have subsequently progressed as defined per RECIST v1.1
31. Patients with documented EGFR mutation, BRAF mutation, ALK rearrangement, or
ROS1 rearrangement are not eligible for the study.
Cohort G: Anti-PD-1/PD-L1 antibody refractory or resistant unresectable or metastatic 
melanoma
Note: Patients with ocular melanoma are not allowed.


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32. Radiographic disease progression per RECIST v1.1 on or after the immediate prior first 
line anti-PD-1/PD-L1 monotherapy. If adjuvant, disease progression within 6 months of 
last dose of anti-PD-1 therapy
a.
Resistant (ie, RECIST v1.1 defined partial, complete response or stable disease for at 
least 12 weeks after initiation of treatment followed by radiographic progression of 
disease. If treated with anti-PD-1/PD-L1 adjuvant therapy, patient relapses while on 
treatment or within 6 months after last dose of anti-PD-1/PD-L1 therapy is also 
considered resistant
b. Refractory (ie, radiographic progression of disease < 12 weeks after initiation of 
treatment
33. No other prior immunotherapies, including, but not limited to, anti-CTLA-4, anti-OX40 
and anti-CD137
34. No prior exposure to anti-VEGF or VEGFR TKI agents
35. Patients with BRAF wild-type, or BRAF mutation but are not suitable for or refuse 
BRAF inhibitor and/or MEK inhibitor targeted therapy. 
Note: Patients with a BRAF mutation and received prior BRAF inhibitor and/or MEK 
inhibitor targeted therapy in metastatic setting will be excluded.
36. Documentation of BRAF status is required.
Cohorts H, Cohort I: Locally advanced or metastatic (Stage IIIB-IV) NSCLC 
37. Histologically or cytologically confirmed, locally advanced (Stage IIIB-IIIC) not 
amenable to curative surgery or radiotherapy, or metastatic (Stage IV) non-squamous or 
squamous NSCLC
38. Has not received prior systemic therapy in metastatic setting
Note: Patients who have received prior neoadjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for nonmetastatic disease must 
have experienced a disease-free interval of ≥6 months from the last dose of 
chemotherapy and/or chemoradiotherapy prior to the first dose of study drugs.
39. Positive membrane staining of PD-L1 on ≥ 1% of tumor cells as determined by PD-L1 
immunohistochemistry assay (SP263) at a central laboratory during screening 
40. No prior exposure to any anti-PD-1/PD-L1 agent or other immunotherapies, including, 
but not limited to, anti-CTLA-4, anti-OX40 and anti-CD137 
Cohort H: PD-L1 positive, locally advanced or metastatic, non-squamous NSCLC without prior 
systemic treatment in metastatic setting
41. Wild-type EGFR status required and patients with documented ALK rearrangement,
ROS1 rearrangement, or BRAF mutations are not eligible for the study.
Cohort I: PD-L1 positive, locally advanced or metastatic, squamous NSCLC without prior 
systemic treatment in metastatic setting
42. Patients with documented EGFR mutation, BRAF mutation, ALK rearrangement, or
ROS1 rearrangement are not eligible for the study 


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4.2.
Exclusion Criteria
Patients who meet any of the following criteria are not eligible to enroll:
1. Unacceptable toxicity on prior anti-PD-1/PD-L1 treatment, defined as follows:
a.
≥Grade 3 AE related to anti-PD-1/PD-L1 treatment that did not respond to standard 
therapy and warranted treatment discontinuation. 
b. ≥Grade 2 irAE associated with anti-PD-1/PD-L1 unless the AE resolved or was well 
controlled by withholding the 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.
c.
Central nervous system or ocular AE of any grade related to anti-PD-1/PD-L1
Note: Patients with a prior endocrine AE are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic.
2. Active leptomeningeal disease or uncontrolled, untreated brain metastasis
x
Patients with a history of treated and, at the time of screening, asymptomatic CNS 
metastases are eligible, provided they meet all the following:
a.
Brain imaging at screening shows no evidence of interim progression
b. All brain metastases with supratentorial location
c.
No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsants at a stable dose allowed
d. No stereotactic radiation or whole-brain radiation within 14 days prior to first dose of 
study drug(s) 
x
Patients with new asymptomatic central nervous system metastases detected at the 
screening scan must receive radiation therapy and/or surgery for central nervous 
system metastases.
e.
Following treatment, these patients may then be eligible, provided all other criteria, 
including those for patients with a history of brain metastases, are met.
3. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 5)
Note: Patients with the following diseases are not excluded and may proceed to further 
screening:
a.
Controlled Type I diabetes
b. Hypothyroidism (provided it is managed with hormone replacement therapy only)
c.
Controlled celiac disease
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia)
e.
Any other disease that is not expected to recur in the absence of external triggering 
factors


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4. Any active malignancy ≤2 years before first dose of study drugs except for the specific 
cancer under investigation in this study and any locally recurring cancer that has been 
treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder 
cancer, carcinoma in situ of the cervix or breast) 
5. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
first dose of study drugs
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded:
a.
Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption
c.
Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen)
6. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥Grade 3 hypoalbuminemia 
≤14 days before first dose of study drugs
7. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases, 
including pulmonary fibrosis, acute lung diseases, etc.
8. 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 drugs
9. Known history of HIV infection 
10. Active hepatitis C infection (defined by a detectable HCV RNA). 
11. Any major surgical procedure requiring general anesthesia ≤ 28 days before first dose of 
study drugs
12. Prior allogeneic stem cell transplantation or organ transplantation
13. Any of the following cardiovascular risk criteria:
a.
Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤28 days before first dose of study drugs
b. Symptomatic pulmonary embolism ≤ 28 days before first dose of study drugs
c.
Any history of acute myocardial infarction ≤ 6 months before first dose of study 
drugs
d. Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 7) ≤ 6 months before first dose of study drugs
e.
Any event of ventricular arrhythmia ≥Grade 2 in severity ≤ 6 months before first 
dose of study drugs
f.
Any history of cerebrovascular accident ≤ 6 months before first dose of study drugs


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g. QTc interval (corrected by Fridericia’s method) > 450 msec 
Note: If QTc interval is > 450 msec on initial electrocardiogram (ECG), a follow up 
ECG will be performed to confirm result
h. Cardiac left ventricular ejection fraction ≤40% or lower limit of normal as assessed 
by echocardiography. The same modality used at baseline must be applied for 
subsequent evaluations. 
i.
Any episode of syncope or seizure ≤28 days before first dose of study drugs
14. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg)
15. Hypersensitivity to tislelizumab or sitravatinib, to any ingredient in the formulation, or to 
any component of the container
16. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar 
agents requiring therapeutic INR monitoring within 6 months before first dose of study 
drugs 
17. Any systemic chemotherapy within 28 days of the first dose of study drugs 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 
18. Any herbal medicine used to control cancer within 14 days of first dose of study drugs 
19. Toxicities (as a result of prior anticancer therapy) that have not improved to baseline or 
stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, 
and specific laboratory abnormalities)
20. Administration of live vaccine ≤ 4 weeks prior to first dose of study drugs 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed.
21. Underlying medical conditions or alcohol or drug abuse or dependence that will be 
unfavorable for the administration of study drugs or affect the explanation of drug 
toxicity or AEs; or expected insufficient compliance during the study according to 
investigator’s judgement
22. Participation in another clinical study, unless it is an observational (non-interventional) 
clinical study or during the follow-up period of an interventional study
23. Inability to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, bariatric 
surgery procedures, symptomatic inflammatory bowel disease, or partial or complete 
bowel obstruction
24. Spinal cord compression in one or more of the following criteria
a.
Not definitively treated with surgery and/or radiation  
b. Treated but without evidence that disease has been clinically stable for > 2 weeks 
prior to first dose of study drugs 
25. Pregnant or breastfeeding woman


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26. Regardless of the severity, patients with any signs or medical history of bleeding; within 
4 weeks prior to allocation, patients with any bleeding events ≥ CTCAE level 3, unhealed 
wounds, ulcers or fractures
27. Patients with artery/venous thrombotic occurred within 6 months before allocation, such 
as cerebrovascular accident (including temporary ischemic attack), deep vein thrombosis 
and pulmonary embolism
28. For NSCLC, patients with hemoptysis of > 50 mL/day
29. For squamous NSCLC, patients with central cavitation or tumor(s) shown to be invading 
or abutting major blood vessels by imaging or the investigator determines the tumor(s) is 
likely to invade major blood vessels and cause fatal bleeding 


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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 study drug must be stored in a labeled carton at refrigerated conditions (2-8oC) in 
the study site Pharmacy. Once dispensed to patients, the bottles will be removed from the carton 
and should be stored at room temperature as specified on the bottle label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
Please also refer to the sitravatinib IB for other details regarding sitravatinib. 
5.1.2.
Tislelizumab
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial (20R 
glass, USP type I), containing a total of 100 mg antibody in 10 mL of isotonic solution. 
Tislelizumab has been aseptically filled in single-use vials with a Flurotec-coated butyl rubber 
stopper and an aluminum cap. Each vial is packaged into a single carton box.
The contents of the label will be in accordance with all applicable local regulatory requirements.
The study drug must be kept at the temperature condition as specified on the label.
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal. Please also refer to the tislelizumab IB 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
Sitravatinib capsules will be administered orally, once daily continuously for a total daily dose of 
120 mg. The following guidelines should be followed for sitravatinib administration:
x
Dosing in the morning is preferred.
x
Capsules should be taken on an empty stomach (at least 2-hour fast before each dose 
and no food for a minimum of 1 hour after each dose). 
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.


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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 (every 3 weeks). 
Tislelizumab will be administered by IV infusion through an IV line containing a sterile, non-
pyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on filter. Specific instructions 
for product preparation and administration are provided in the Pharmacy Manual.
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents. 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 8.8 and 
Appendix 9.
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.
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 management.


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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
Any overdose of tislelizumab (defined as ≥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.
Dose Modification and Delay
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided below. Reasons for dose modifications or delays, the supportive
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
eCRF.
Based on the known toxicity profiles of sitravatinib and tislelizumab, it is known that certain 
AEs are likely to be associated with one drug versus the other. For example, treatment-emergent 
hypertension or proteinuria are likely to be associated with sitravatinib rather than tislelizumab; 
similarly, immune-related AEs are likely to be associated with tislelizumab rather than 
sitravatinib. However, some drug-related AEs such as diarrhea and elevation in the liver function 
tests are overlapping. Therefore, it is crucial to fully evaluate each AE to confirm etiology or 
exclude other causes in order to determine proper management of the adverse reaction and action 
regarding study treatment. The management guidelines for AEs of special interest of tislelizumab 
and sitravatinib-specific adverse events are provided in detail in Section 8.8 and Section 8.9,
respectively.
Adverse events (both non-serious and serious) associated with tislelizumab exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. Therefore, early recognition and initiation of treatment is 
critical to reduce complications. Tislelizumab must be withheld for drug related toxicities and 
severe or life-threatening AEs. See Appendix 9 for supportive care guidelines, including use of 
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5.5.1.
Dose Modification
There will be no dose reductions for tislelizumab in this study. Dose reductions for sitravatinib 
are presented in 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 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 8.9.
Table 6.
Sitravatinib Dose Reductions 
Dose Level
Dose
Starting Dose
120 mg once daily
Dose Level -1
80 mg once daily
Dose Level -2
60 mg once daily
Note: Dose reduction below 60 mg once daily may be undertaken after discussion with the sponsor.
5.5.2.
Dose Delay
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) within 
4 weeks for sitravatinib or 12 weeks for tislelizumab after last dose of the respective study drug.
The following dose delays or interruptions will be permitted:
x
Sitravatinib can be interrupted for up to approximately 28 days consecutively. If 
treatment with sitravatinib is delayed for ≥14 days, then resumption at a reduced 
dose should be considered. If drug is planned to be interrupted ≥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 
tislelizumab 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 more than 10 days, the subject 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). 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.
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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6.
PRIOR AND CONCOMITANT THERAPY
6.1.
Concomitant Therapy
6.1.1.
Permitted Concomitant Medications and Therapy
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, 
anti-emetics, antidiarrheals) and in a patient’s interest are allowed. 
Proton pump inhibitors and H2 antagonists should be avoided during treatment 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 9) and be at nonimmunosuppressive doses (≤ 10 mg/Day of prednisone or equivalent) 
before the next administration of study drug(s). The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted. 
Patients with active hepatitis B, defined as either detectable HBsAg or HBV DNA at baseline, 
must initiate treatment 2 weeks prior to first dose of study drugs 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 for pain control or prophylaxis of bone fracture to sites 
of bone disease present at baseline is permitted. 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 and the medical monitor agrees that the conditions required to receive palliative 
radiation are met.
Additionally, palliative radiation or other focally ablative therapy for other non-target sites of the 
disease is permitted if clinically indicated per investigators’ discretion and after consultation with 
the medical monitor. Whenever possible, these patients should have a tumor assessment of the 
lesion(s) before receiving the radiotherapy in order to rule out PD.
6.1.2.
Prohibited Concomitant Medications and Therapy
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 or other 
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x
Live vaccines within 28 days prior to the first dose of study drug(s) and 60 days 
following the last dose of study drug(s)
x
Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with liver or other major organ functions (eg, 
hypericin). Patients must notify the investigator of all herbal remedies used during the 
study.
6.1.3.
Restricted Concomitant Medications and Therapy
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
Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.1.1
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.
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 
less than 0.1 μM potency, Sitravatinib perpetrator risk at projected clinical dose and exposure 
levels is considered to be low.
Per the International Council on Harmonisation (ICH) E14 guidance, it is recommended to avoid 
medications with potential to prolong QT/QTc or cause Torsades. Please refer to Appendix 11
for a list of medications or substances to be avoided or used with caution during treatment with 
sitravatinib.
Potential Interaction With Tislelizumab
Sitravatinib administered in combination with tislelizumab is unlikely to result in clinically 
relevant drug-drug interactions based on absorption, metabolism, elimination, or protein binding. 
Tislelizumab is a monoclonal antibody (mAb) and is administered intravenously, whereas 
sitravatinib is a small molecule therapeutic administered orally. No absorption interactions are 
expected. No studies on the metabolism of tislelizumab have been reported in vitro or in humans. 


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Like most therapeutic proteins, tislelizumab is not expected to be metabolized by liver 
cytochrome P-450 (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 drugs. 
Patients who agree to participate will sign the ICF prior to undergoing any screening procedure. 
The Screening period begins on the first day a screening procedure is conducted. Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess
patient eligibility according to the latest screening assessment results. 
Results of standard of care tests or examinations performed prior to obtaining informed consent 
and ≤28 days prior 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. Patients who 
are suspected or known to have concurrent serious respiratory illness or exhibit significant 
respiratory symptoms unrelated to underlying cancer should take a pulmonary function test (refer 
to Appendix 1 for details) based upon the treatment physician’s judgement. 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 disease progression. Rescreening is allowed only once.
7.1.1.
Demographics
Demographic data will include gender, date of birth (or age), and race/ethnicity.
7.1.2.
Medical History
Clinically significant medical history findings (eg, previous diagnoses, diseases, or surgeries) 
that were present before signing the ICF and considered relevant for the patient’s study eligibility 
will be collected and captured, including baseline severity if the finding is ongoing, in the eCRF. 
Clinically significant is defined as any events, diagnoses, or laboratory values that require 


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treatment or follow-up, or the presence of signs or symptoms that require medical intervention. 
Concurrent medical signs and symptoms must be documented to establish baseline severities.
Cancer history will include an assessment of prior surgery, prior radiotherapy, 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.
7.1.3.
Other Baseline Characteristics
Information will also be collected regarding alcohol and smoking history, prior 
medications/significant nondrug therapies, childbearing potential (refer to Appendix 6), and any 
other assessments that are performed for the purpose of eligibility for inclusion in the study 
(Section 4), such as physical examination, vital signs, hematology, chemistry, pregnancy test, 
and ECG.
7.1.4.
Informed Consent and Screening Log
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. Informed consent forms for enrolled patients and for 
patients who are screened but not enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before first dose of study drugs. 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.
7.1.5.
Pulmonary Function Tests
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed for all patients in Cohort A, B, F, H, and I during the Screening Period to assist the 
determination of suitability on the study. Respective test results need to be submitted to the 
sponsor.
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
(FEV1) < 60% or carbon monoxide diffusing capacity (DLCO) (if performed) < 60% of age and 
sex adjusted predicted performance levels (Pellegrino et al 2005), the medical monitor needs to 
be consulted to confirm eligibility.
Tests may be repeated as clinically indicated while on study.
Patients in Cohort C, D, E, and G who are suspected or known to have serious/severe respiratory 
conditions, or exhibit significant respiratory symptoms unrelated to the underlying cancer, or 
with a history of thoracic radiotherapy will undergo pulmonary function testing which may 
include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
Screening Period to assist the determination of suitability on the study.


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7.2.
Enrollment
The investigator will assess and the sponsor will confirm the eligibility of each patient. All 
screening procedure results and relevant medical history must be available before eligibility can 
be determined. Eligible patients must meet all inclusion criteria and patients who meet any of the 
exclusion criteria are not eligible to enroll. 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 email it to the medical 
monitor or designee to approve the enrollment in writing. Study site personnel should ensure that 
a medical monitor-approved Eligibility Authorization Packet has been received before 
proceeding with study procedures. 
7.3.
Safety Assessments
7.3.1.
Vital Signs 
Vital signs will include measurements of temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic) while the patient is in a seated or supine position after resting for 
10 minutes. 
7.3.2.
Physical Examinations 
During the Screening 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 v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance.
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 AE eCRF. Refer to 
Section 8.3 Adverse Events regarding AE definitions and reporting and follow-up requirements.
7.3.3.
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group Performance Status (refer to Appendix 4) will be assessed 
during the study. 
7.3.4.
Laboratory Safety Test
Local laboratory assessments on hematology, serum chemistry, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Appendix 3.
If laboratory tests at screening are performed within 7 days prior to the administration of study 
drug(s) on Cycle 1 Day 1, these tests (hematology, clinical chemistry, urinalysis, and pregnancy 
test) do not have to be repeated and must be reviewed before study drug(s) administration. For


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the first 6 patients enrolled in both Australia and in China, hematology and serum chemistry 
(including liver function tests [LFTs]) as specified in Appendix 3 should be performed weekly 
for the first 2 cycles and at the beginning of subsequent cycles. For all other patients, hematology 
and serum chemistry should be performed at the beginning of all cycles. After Cycle 1,
laboratory safety results should be reviewed within 48 hours before study drug administration.
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 administration of study drug(s). Urine or serum pregnancy tests will be 
performed once every 3 weeks during treatment before administration of study 
drug(s) at each cycle, at the EOT Visit. A serum pregnancy test must be performed if 
the urine pregnancy test is positive or equivocal. 
x
Thyroid function testing (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 
at the EOT Visit.
x
Creatine kinase (CK) and creatine kinase cardiac isoenzyme (CK-MB) testing will be 
performed at screening, scheduled assessments during the first 2 treatment cycles, all 
predose assessments from Cycle 3 onward, and at the EOT Visit. Troponin I and/or T 
may be performed if the local lab does not provide CK and CK-MB analysis. If 
tislelizumab has been permanently discontinued, CK and CK-MB testing is no longer 
required.
7.3.5.
Hepatitis B and Hepatitis 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). Viral load assessment (HBV DNA and HCV RNA) will be performed if the 
HBsAg and/or HCV antibody test is positive. 
Patients who have detectable HBV DNA or HCV RNA at Screening will perform the respective 
viral load test every 4 cycles.
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 semi-recumbent supine position for at least 10 minutes prior to ECG 
collection. 


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7.3.7.
Multigated Acquisition (MUGA) Scans or Echocardiograms
Evaluations of cardiac function will be performed at screening and every 12 weeks during 
treatment. 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.
7.3.8.
Adverse Events
Adverse events will be graded and recorded throughout the study according to 
NCI-CTCAE v5.0. Characterization of toxicities will include severity, duration, and time to 
onset. 
All AEs, including SAEs, will be collected as described in Section 8.6.
7.4.
Tumor and Response Evaluations
Tumor imaging will be performed within 28 days prior to the first dose of study drugs. 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). 
Tumor assessments must include computed tomography (CT) scans (with oral/intravenous 
contrast, unless contraindicated) or 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
Imaging of the brain (MRI or CT) at baseline (≤ 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 non-contrast 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/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 positron emission tomography 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 positron emission tomography bone scans should be repeated when a CR 
is suspected in target lesion or when progression in bone is suspected.


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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. 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 10). For ovarian cancer 
patients, response will be assessed using RECIST v1.1 and the GCIG working group criteria 
(refer to Appendix 12). 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 (≥ 4 weeks) 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 progressive disease is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment with study drug(s) 
until PD is confirmed by repeated imaging ≥ 4 weeks later but not exceeding 8 weeks from the 
date of initial documentation of PD. The following criteria must be met in order to continue 
study drugs in patients with suspected pseudoprogression:  
x
Absence of clinical symptoms and signs of PD (including clinically significant 
worsening of laboratory values)
x
Stable ECOG performance status ≤ 1
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 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 re-consented.
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 time of each sample collection will be recorded on the 
source document and CRF. 


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In the event of a 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. Please refer to 
the laboratory manual for details of sample handling. 
If archival tissues are available, archival tumor tissues (FFPE blocks with tumor tissues or 
approximately 15 freshly cut unstained FFPE slides from each block) must be sent to central 
laboratory for biomarker analysis, including but not limited to PD-L1 expression, EGFR or 
BRAF mutation status (for selected cohorts), tumor infiltrating lymphocytes, gene expression 
profiling, and tumor mutation burden. Submission of < 15 unstained slides is not a protocol 
deviation.
For patients with non-squamous NSCLC (Cohorts A, B and H) and melanoma (Cohort G), 
documentation of wild type EGFR status (Cohorts A, B and H only) or BRAF status (Cohort G 
only) by tissue-based test is required to enter the study. For undocumented cases in these cohorts, 
an archival or fresh biopsy tumor tissue(s) (a FFPE block(s) or approximately 15 freshly cut 
unstained FFPE slides from each block) will be required for central assessment of EGFR or
BRAF mutation prior to enrollment and retrospective analysis of other biomarkers. For treatment 
naive non-squamous NSCLC (Cohort H) and squamous NSCLC (Cohort I), only patients with 
PD-L1 membrane staining on ≥ 1% of tumor cells as determined by PD-L1 (SP263) 
immunohistochemistry assay at a central laboratory during screening will be eligible for the 
study. An archival or fresh biopsy tumor tissue(s) (a [FFPE] block(s) or approximately 15 freshly 
cut unstained FFPE slides) will be required for central assessment of PD-L1 expression prior to 
enrollment and retrospective analysis of other biomarkers. If no archival sample(s) can be 
provided, a fresh tumor biopsy(ies) at baseline is required. Written informed consent is required 
for fresh tumor biopsies. Submission of < 15 unstained slides is not a protocol deviation.
For patients in all cohorts, in addition to archival tumor tissue, a fresh biopsy(ies) from an 
accessible tumor site(s) at baseline and/or after 2 cycles of treatment (Cycle 3 Day 1) and/or at 
EOT Visit for the patients who have confirmed PD during the study is recommended to evaluate 
pharmacodynamic effects and to explore of potential response or resistance mechanism(s). If 
feasible, any post-treatment biopsy(ies) should be ideally taken from the same tumor lesion(s) as 


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the baseline biopsy. Written patient informed consent is required before obtaining fresh tumor 
biopsies.
For fresh biopsy, acceptable samples include core needle biopsies for non-superficial 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 for the evaluation of pharmacodynamic and exploratory biomarkers, including but 
not limited to cytokines, plasma proteins, immune cell populations, and circulating tumor DNA 
(ctDNA).


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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 8.8.
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 8.9.
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 9.
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 of the first dose of study drugs 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 
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Serum samples will be drawn for determination of antidrug antibodies (ADAs) to tislelizumab in 
patients. 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 end of treatment, ongoing AEs considered related to study treatment will be followed until 
the event has resolved to baseline or ≤Grade 1, the event is assessed by the investigator as 
stable, the patient is lost to follow-up, the patient withdraws consent, or it has been determined 
that study treatment or participation is not the cause of the AE.
Immune-related AEs will be recorded 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 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 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 and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
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, 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 
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x
are associated with clinical signs or symptoms, or 
x
require active medical intervention, or 
x
lead to dose interruption or discontinuation, or
x
require close observation, more frequent follow-up assessments, or 
x
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 LFT testing should be performed according to the schedule 
in Appendix 9.
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 SAEs:
x
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline
x
Hospitalization for social/convenience considerations


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x
Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience
8.5.
Suspected Unexpected Serious Adverse Reaction
A suspected unexpected serious adverse reaction 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 the last dose of study drugs or initiation of new anticancer 
therapy, whichever occurs first. Immune-related AEs (serious or non-serious) should be reported 
until 90 days after the last dose of tislelizumab, regardless of whether or not the patient starts a 
new anticancer therapy.
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
Updated SAE 
form
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 suspected unexpected serious adverse reactions (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 IB) 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 (including fatal PD) which is expected in this study population and measured as an efficacy 
endpoint, should not be reported as an AE term. Instead, the symptoms, signs or clinical sequelae 
that result from disease progression should be reported as the AE term(s).  
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of PD. If a 
patient experienced a fatal multi-organ failure due to PD, the term “multi-organ failure” should 
be reported as the SAE with death as outcome instead of reporting “fatal disease progression” or 
“death due to disease progression.”


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8.6.5.
Deaths
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death,”
“death of unknown cause,” or “death unexplained.”
8.6.6.
Pregnancies
If a female patient or the partner of a male patient 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 should be recorded and reported as an SAE.
8.6.7.
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents:
x
Sitravatinib IB and tislelizumab IB
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 8.8.3) should be classified as irAEs and identified 
as such in the eCRF AE page until Day 90 after treatment discontinuation.
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 9.
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 9 .
8.7.
Management of Adverse Events Potentially Associated with Either or 
Both of Sitravatinib and Tislelizumab
Based on the known toxicity profiles of sitravatinib and tislelizumab, certain treatment-related 
AEs are uniquely associated with one drug versus the other. For example, hypertension, arterial 


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thrombotic events, proteinuria, and hemorrhagic events are known risks for sitravatinib 
treatment, while immune-related AEs are risks for tislelizumab treatment. However, certain AEs 
may be initially considered attributed to either study drugs, such as diarrhea, hypothyroidism,
and liver enzyme elevation. Therefore, evaluation of attribution is important for determining the 
study drug most likely related to the AE, or an alternative etiology, and subsequently proper 
clinical management. The following aspects should be considered:
8.7.1.
Timing of Adverse Event Onset
Since sitravatinib is dosed QD continuously due to a short half-life, and tislelizumab is dosed 
Q3W due to a long half-life, sitravatinib can be interrupted to assess whether an AE 
improves/resolves with de-challenge (ie, interruption of treatment) based on the following two 
scenarios.
1. If an AE occurs during a treatment cycle (ie, between 2 tislelizumab doses), only 
sitravatinib dose interruption is needed.
2. If an AE occurs at the beginning of a treatment cycle, sitravatinib can be interrupted and 
dosing of tislelizumab should be held.
If a patient recovers from an AE in response to sitravatinib interruption (ie, positive de-
challenge), the event is more likely to be attributed to sitravatinib. Otherwise, after excluding 
other alternative explanations, an immune-related AE should be considered.
8.7.2.
Severity of Adverse Event
If an AE is suspected to be treatment related and is severe/life threatening at the time of onset or 
is rapidly worsened, action including interrupting or holding both drugs and initiating treatment 
with a corticosteroid (with exception of hypothyroidism, TIDM) and other supportive care 
should be taken promptly.
8.8.
Management of AEs 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 3 onward, a ≥ 30-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents. The management of infusion-related 
reactions, severe hypersensitivity reactions and irAEs according to the NCI-CTCAE criteria are 
outlined below.
8.8.1.
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, IV antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 


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Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 8.
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, IV fluids); 
prophylactic medications indicated for ≤24 h.
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described 
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; IV, intravenous; 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-related reaction (≥Grade 2) on the slower 
infusion rate, infusion should be discontinued and the patient should be withdrawn from 
tislelizumab treatment.
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen. 
In the next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 


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NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen.
8.8.2.
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). 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.
8.8.3.
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 non-
specific, 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 non-specific 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 9. For any AEs not included in Appendix 9 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.
In the event of an immune-related AE during study treatment, administration of sitravatinib and 
tislelizumab should be interrupted until the event stabilizes to ≤Grade 1. If a toxicity does not 
resolve to ≤Grade 1 within 4 weeks for sitravatinib or 12 weeks for tislelizumab, 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 re-challenge should permanently 
discontinue treatment.
8.9.
Management of Sitravatinib-Specific Adverse Events
8.9.1.
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 the 
investigator, per the reduction schedule (Table 10). Dose reductions are expected to improve 
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Non-hematological toxicities ≥Grade 3 and considered to be related to sitravatinib treatment 
should be managed with sitravatinib interruption, until resolution of toxicity to ≤Grade 1 or to 
baseline value. In the case of Grade 3 or 4 electrolyte abnormalities that are not clinically 
complicated and resolve spontaneously or with conventional medical treatment within 72 hours, 
or Grade 3 asymptomatic amylase or lipase 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 for ≥28 days, permanent 
discontinuation from study treatment should be considered.
Table 10.
Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities
Toxicity
Treatment Delay
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 (e.g., 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 the symptoms or the clinical manifestations 
of pancreatitis
8.9.2.
Management of Hematological Toxicities of Sitravatinib
Hematological toxicities are not a frequent cause of treatment interruption or discontinuation of 
sitravatinib treatment. Observed ≥Grade 3 hematological events that are considered to be 
causally related to sitravatinib should initially be managed using treatment interruption. In 
addition, dose reduction 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 ≥8 days 
x
Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding
8.9.3.
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 8.9.4
Grade 3 hypertension with clinically 
significant increases in BP defined as either 
an increase of ≥ 30 mm Hg in systolic BP to 
≥ 180 mm Hg or increase of ≥ 20 mm Hg in 
diastolic BP to ≥ 110 mm Hg, confirmed 
with repeated testing after at least 5 minutes 
Hold until ≤Grade 2 or 
return to baseline 
Investigator discretion 
Grade 4 hypertension 
Discontinue sitravatinib 
Discontinue sitravatinib 
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 to 3.0 x ULN) 
May be implemented based on investigator and patient discretion 
Grade 2 (>3.0 to 5.0 x ULN)
Not required
Decrease by 1 dose level
Grade 3 or 4 (>5.0 x ULN)
Hold until ≤Grade 1 or return 
to baseline
If resolution occurs within 
22 days, decrease by 1 dose 
level.
If no resolution within 22 days, 
discontinue sitravatinib.
Abbreviation: ULN, upper limit of normal.
8.9.3.1.
Management of Hy’s Law Cases
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 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.
8.9.4.
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 


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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).
8.9.5.
Palmar-Plantar Erythrodysesthesia
Palmar-plantar erythrodysesthesia syndrome has been reported as a DLT in the Phase 1 study of 
sitravatinib. Measures that can be taken to manage include avoidance of exposure of hands and 
feet to hot water when washing dishes or bathing, or to other sources of heat, avoidance of 
activities that cause unnecessary force or friction (rubbing) on the hands or feet, avoiding contact 
with harsh chemicals such as cleaning products, 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.
8.9.6.
Diarrhea
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.
8.9.7.
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. 
8.9.8.
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.


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8.9.9.
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 thyroid replacement and may continue 
treatment with sitravatinib at the investigator’s discretion.
8.9.10.
Decreased Left Ventricular Ejection Fraction
Decreased left ventricular ejection fraction has been reported with sitravatinib. In addition, 
decreases of left ventricular ejection fraction 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). 
8.9.11.
Proteinuria
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
inhibitors of the VEGFR pathway. Patients who develop ≥2+ proteinuria should undergo 
24-hour urine collection for assessment of urine protein; treatment with sitravatinib should be 
discontinued in the presence of ≥2 grams of proteinuria/24 hours and may restart when protein 
levels decrease to less than 2 grams/24 hours. Patients who develop nephrotic syndrome should 
be withdrawn from treatment with sitravatinib.


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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. 
9.1.
Statistical Analysis
9.1.1.
Analysis Sets
The Safety analysis set includes all patients who received at least 1 dose of any study drug (any 
component of the combination therapy). 
The Efficacy Evaluable analysis set includes all dosed patients who had measurable disease at 
baseline per RECIST v1.1 and who had at least 1 evaluable postbaseline tumor assessment 
unless treatment was discontinued due to disease progression or death before tumor assessment.
The PK analysis set includes all patients who contributed at least 1 quantifiable PK sample.
The ADA Analysis Set includes all patients who received at least 1 dose of tislelizumab and for 
whom both baseline ADA and at least 1 postbaseline ADA results are available.
9.1.2.
Patient Disposition
The number of patients treated, discontinued from study drug and/or study and those with major 
protocol deviations will be counted. The primary reason for study drug discontinuation will be 
summarized according to the categories in the eCRF. The end of study status (alive, dead, 
withdrew consent or lost to follow-up) at the data cutoff date will be summarized using the data 
from the eCRF. 
Major protocol deviations will be summarized and listed by each category.
9.1.3.
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 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 


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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) assessed by investigators using 
RECIST v1.1 will be summarized to evaluate the antitumor activities of sitravatinib in 
combination with tislelizumab. 
Efficacy analyses will be provided based on both the Efficacy Evaluable analysis set and the 
Safety analysis set. The Efficacy Evaluable analysis set will be the primary analysis set for 
response analyses; and the Safety analysis set will be the primary analysis set for time-to-event 
analyses.
Details of statistical analyses will be described in detail in the Statistical Analysis Plan.
Objective Response Rate (ORR)
The number and proportion of patients who achieve confirmed or unconfirmed objective tumor 
response (CR or PR) according to RECIST v1.1 will be summarized. Patients without 
postbaseline tumor assessment will be considered as non-responders for the summary based on 
the Safety analysis set. The ORR will be estimated along with Clopper-Pearson 2-sided 95% 
confidence interval.
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. Patients without postbaseline tumor assessment will be considered as non-
responders for the summary based on the Safety analysis set. DCR will be reported with the 95% 
confidence interval.
Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose of study drugs to the date of the first 
documentation of PD as assessed by the investigator using RECIST v1.1 or death, whichever 
occurs first. Kaplan-Meier methodology will be used to estimate median PFS and 95% 
confidence interval. Kaplan-Meier curves will be constructed to provide a visual description of 
the PFS change with time.
Duration of Response (DOR)
Duration of response 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). Duration of response 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% confidence interval for 
duration of response. 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).


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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.
OS is defined as the time from the date of first dose of study drugs to the 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.
PFS assessed per CA-125 criteria will be summarized descriptively.
9.3.
Safety Analyses
Safety will be determined by the spontaneous reporting of adverse events 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 adverse events will be graded according to the NCI-CTCAE v5.0. The incidence of 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.
9.3.2.
Adverse Events
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to MedDRA 
(Version 18.1 or higher) lower-level term, preferred term, and primary SOC.
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pre-treatment) on or after the first dose of study drug and up to 30 days following study drug 
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.


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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 v5.0 within an SOC and preferred term, even if the patient experienced more than 
1 TEAE within a specific SOC and preferred term. The number (percentage) of patients with 
TEAEs will also be summarized by relationship to the study drug. TEAEs include those events 
considered by the investigator to be related to study treatment or with missing assessment of the 
causal relationship. SAEs, deaths, TEAE with ≥Grade 3 severity, 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, serum chemistry, urinalysis) values will be evaluated for 
each laboratory parameter as appropriate. Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be included in the CSR for this protocol. Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n[%] for categorical variables) for laboratory parameters and their changes from 
baseline will be calculated. Laboratory values will be summarized by visit and by worst 
postbaseline visit.
Laboratory parameters that are graded in NCI-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. 
9.4.
Pharmacokinetic Analysis 
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 semi-logarithmic 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 non-compartmental 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 (N, arithmetic mean, standard deviation, minimum, median, maximum, geometric 
mean, and coefficient of variation (CV) % associated to the geometric mean). 


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PK parameters will include, but are not limited to, the following as allowed by data:
Cmax (μg/mL) 
Observed maximum plasma concentration during a sample interval. 
Cτ (μg/mL) 
Observed trough concentration at steady state
Tmax (hr) 
Observed time to maximum plasma concentration during a sampling interval. 
λz (hr-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 three data 
points will be used for determination (Cmax excluded). 
t½ (h) 
Terminal elimination half-life, determined from the quotient 0.693/λz. 
AUC(0-t)
(μg.h/mL) 
Area under the plasma concentration-time curve from time zero to the last measurable 
time point calculated by log-linear trapezoidal summation.
AUC(0-τ)
(μg.h/mL)
Area under the plasma concentration-time curve from time zero to 24 hour 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-τ),ss /AUC(0-24), Day 1
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 clinical study report (CSR).
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 PD 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 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. 


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9.7.
Sample Size Consideration
Approximately 220 to 240 patients (approximately 60 patients for Cohort E, and 20 patients for 
each of the rest of the cohorts) are expected to be enrolled to analyze safety and preliminary 
efficacy for sitravatinib plus tislelizumab. Of the approximately 60 patients enrolled into Cohort E, at
least 20 patients who failed the prior bevacizumab treatment and at least 20 patients will be Caucasian.
Enrollment into these cohorts will occur simultaneously, independently of each other. Each 
cohort will be evaluated separately. 


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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
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 Good Clinical Practice 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 the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country.
12.2.
Quality Assurance
To ensure compliance with Good Clinical Practice 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 lot or batch 
number, date dispensed, patient identifier number, patient initials, if allowed and the initials of 
the person dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene’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 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 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 explanations should be 
recorded in the diary. The diary should be returned to the site personnel for review, and will be 
reviewed by the investigator/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 Good Clinical Practice and the principles of the 
Declaration of Helsinki or the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the 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 re-consented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
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 United States FDA, the China National Medical Products Administration, 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 IB, 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 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 
electronic data capture 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 and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.


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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 re-generating 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 2016).
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation. 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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15.
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Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-15.
National Cancer Institute - Common Toxicity Criteria Version 5.0. Cancer Therapy Evaluation 
Program. 27 November 2017.
National Comprehensive Cancer Network (NCCN) Guidelines Version 4. (2019). Non-Small 
Cell Lung Cancer.
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.


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1L atezolizumab+ carboplatin/cisplatin+ pemetrexed in stage IV non-squamous NSCLC. Journal 
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16.
APPENDICES






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Abbreviations: ADA, antidrug antibody; AE, adverse event; CA-125, cancer antigen 125; CR, completed response; ctDNA, circulating tumor DNA; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; EGFR, epidermal growth factor receptor; 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; irAE, immune-related adverse event; MUGA, multigated acquisition; NSCLC, non-small cell lung 
cancer; PD, disease progression; PGx, pharmacogenetic; PK, pharmacokinetic; PR, partial response; 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 prior to obtaining informed consent and within 28 days prior to first dose of study drugs may be used for screening 
assessments rather than repeating such tests. If laboratory tests at screening are performed within 7 days prior to first dose of study drugs, these tests 
(hematology, clinical chemistry, urinalysis, and pregnancy test) do not have to be repeated and must be reviewed before first dose of study drugs.
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, the first 6 patients in both Australia and in China regardless of assigned cohort will return for assessments on Day 8 and Day 
15. Sitravatinib will be given in the clinic.
4.
Unscheduled visits may occur any time as necessary as per investigator decision or patient’s request for reasons such as assessment or follow-up of 
AEs. Study activities, as indicated by ‘X,’ should be performed based on the reason for the unscheduled visit. If PD is suspected, imaging studies 
should be performed. The date and reason for an unscheduled visit should be recorded in the eCRF.
5.
Patients who discontinue treatment for any reason will be asked to return to the clinic for the EOT Visit within 30 days after the last dose of study drug, 
or before the initiation of a new anticancer treatment, whichever occurs first. If routine laboratory tests (eg, hematology, clinical chemistry) were 
completed ≤ 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.
6.
Telephone contacts with patients should be conducted to assess irAEs and concomitant medications (if appropriate, eg, associated with an AE or is a 
new anticancer therapy) at 60 days (±14 days), and 90 days (±14 days) after the last dose of tislelizumab, regardless of whether or not the patient starts 
a new anticancer therapy. If patients report a suspected irAE at a telephone follow-up contact, the investigator should arrange an unscheduled visit if 
further assessment is indicated.
7.
Vital signs collected on study include temperature, pulse, and blood pressure (systolic and diastolic) while the patient is in a seated or supine position 
after resting for 10 minutes. The patient’s vital signs are required to be recorded within 60 minutes before; during; and within 30 minutes after the first 
infusion of tislelizumab. For subsequent infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 
within 30 minutes after the infusion. Vital signs should 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. 
8.
Patients should rest in semi-recumbent supine position for at least 10 minutes prior to each ECG collection. ECG collection may be done at other time 
points as clinically indicated. 
9.
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE v5.0.
10. All concomitant medications received within 30 days before the first dose of study treatment should be recorded. 
11. Hematology and clinical chemistry will be performed weekly in Cycle 1 and Cycle 2 for the first 6 patients enrolled in both Australia and in China and 
then at the beginning of subsequent cycles. For all other patients, assessments will be performed on Day 1 of each cycle. After Cycle 1, laboratory tests 
can be performed up to 2 days prior to Day 1 of subsequent cycles and results are to be reviewed within 48 hours before study drug administration. 
Coagulation tests as specified in Appendix 3 are required at Screening and subsequently as clinically indicated. Refer to Section 8.3.5 for additional 
information regarding clinical assessment and management of clinical laboratory abnormalities. Urinalysis will be performed on Cycle 1 Day 1 and 
subsequently as clinically indicated.


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12. 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 Day 1. Urine or serum pregnancy tests will be performed during treatment and the EOT Visit. A negative pregnancy test 
must be completed and recorded before administration of study drug(s) at each cycle. A serum pregnancy test must be performed if the urine pregnancy 
test is positive or equivocal. 
13. Thyroid function tests will be performed at Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at the EOT Visit.
14. CA-125 test will be performed within 14 days prior to Cycle 1 Day 1 and while on study approximately every 6 weeks ± 7 days in the first 12 months 
and approximately every 9 weeks ± 7 days thereafter. The CA-125 responses must be confirmed and maintained for at least 28 days. Patients can be 
evaluated according to CA-125 only if they have a screening sample that is at least twice the upper limit of reference range.
15. Testing will be performed by the local laboratory at Screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody). 
Viral load assessment (HBV DNA and HCV RNA) will be performed if the HBsAg and/or HCV antibody test is positive.
16. Cohort C, D, E, and G: Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms 
unrelated to the underlying cancer or with a history of thoracic radiotherapy will 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.
Cohort A, B, F, H, and I: Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, pulse oximetry at rest and 
with exercise, or alternatively, assessment of diffusion capacity, are to be performed for all patients during the Screening Period to assist the 
determination of suitability on the study. Respective test results need to be submitted to the sponsor. For test results indicative of significantly impaired 
pulmonary function, eg, resting pulse oximetry < 90% on room air and further desaturation upon exercise, FEV1 < 60% or Dlco (if performed) < 60% 
of age and sex adjusted predicted performance levels (Pellegrino et al 2005), the medical monitor needs to be consulted to confirm eligibility. Tests 
may be repeated as clinically indicated while on study.
17. Tumor imaging will be performed within 28 days prior to Cycle 1 Day 1 and while on study approximately every 6 weeks ± 7 days in the first 12 
months and approximately every 9 weeks ± 7 days thereafter. All measurable and evaluable lesions should be assessed and documented; MRI scan of 
brain should be performed if clinically indicated. Tumor assessments are required to be performed on schedule regardless of whether study treatment 
has been administered or held. The same imaging technique should be used throughout the study for each patient. After the first documentation of 
response (CR or PR), confirmation of tumor response should occur ≥ 4 weeks after the first response or at the next scheduled assessment time point. 
Progressive disease suspected as pseudo-progression needs to be confirmed by repeated imaging ≥ 4 weeks later but not exceeding 8 weeks from the 
date of initial documentation of PD. Patients who stop treatment prior to documentation of PD will undergo repeated imaging for tumor response 
assessments (see Section 7.4 for details).
18. Archival tumor tissues (a FFPE blocks or approximately 15 freshly cut unstained FFPE slides from each block) must be collected, if archival tissues 
are available. Submission of < 15 unstained slides is not a protocol deviation. For Cohorts A (Anti-PD-1/PD-L1 antibody refractory or resistant 
metastatic, non-squamous NSCLC), B (Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC), and G (PD-1/PD-L1 treatment refractory 
or resistant melanoma), an archival or fresh biopsy tumor tissue(s) (a FFPE block(s) or approximately 15 freshly cut unstained FFPE slides from each 
block) will be required for central assessment of EGFR mutation status (Cohorts A, and B only) and BRAF mutation status (Cohort G only) during the 
screening period in undocumented cases. For Cohorts H (treatment naive non-squamous NSCLC) and I (treatment naïve squamous NSCLC), an 
archival or fresh biopsy tumor tissue(s) (a [FFPE] block(s) or approximately 15 freshly cut unstained FFPE slides from each block) will be required for 
central assessment of PD-L1 expression and EGFR mutation status (Cohort H patients with undocumented EGFR status only) during screening.
19. In addition to archival tumor tissue(s), a fresh biopsy(ies) from an accessible tumor site(s) at baseline (within 28 days before Cycle 1 Day 1) and/or 
after 2 cycles of treatment (approximately Cycle 3 Day 1) and/or at End of Study Visit for patients who have confirmed PD during the study is 
recommended to evaluate pharmacodynamic biomarkers and/or to explore response or resistance mechanism(s). If feasible, post treatment biopsy 
should be ideally taken from the same tumor lesion as the baseline biopsy. For Cohorts A and B patients with unknown EGFR mutation status, Cohort 


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G patients with unknown BRAF mutation status as well as Cohorts H and I patients, if no archival tumor tissue(s) can be provided, a fresh biopsy(ies) 
is mandatory during screening. Written informed consent is required prior to obtaining fresh tumor biopsies.
20. Information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 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.
21. Evaluations of cardiac function will be performed at screening and every 12 weeks (±7 days). 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. 
22. See Appendix 2 for schedule of PK sampling for sitravatinib, PK sampling for tislelizumab, ADA sampling for tislelizumab, and blood sampling for 
pharmacogenetic and biomarker analysis. 


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APPENDIX 2.
SCHEDULE OF PK, ADA, PGX, AND BIOMARKER 
ASSESSMENTS
 
 
Collection 
Time
(Allowable 
Window) 
PK 
sitravatinibb
PK
Tislelizumabc
ADA
Tislelizumabd 
Pharmaco-
dynamic 
Biomarkere
ctDNAe
PGx
The first 5 
patients/cohort
Other 
patients
Screening
(D -28
to D -1)
Cycle 1
D1 & D21
Predose
(-30 min)
Pre-sitra–dose
Pre-sitra–
dose
Day 1 only
Pre-tisle–dose
(-30 min)
Day 1 only
Pre-tisle–dose
(-30 min)
Day 1 only
Pre-sitra-dose
(-30 min)
Day 1 only
Pre-sitra-dose
(-30 min)
Day 1 only
Pre-sitra–
dose
0.5 hr
(+10 min)  
X
Day 1 only
Post-tisle–dose 
(+30 min)
 
Confirmed PR 
or CR (± 
14 days)
 
1 hr
(± 10 min)  
X
 
 
 
2 hr
(± 15 min)  
X
 
 
 
4 hr
(± 20 min)  
X
 
 
 
6 hr
(± 20 min)  
X
X
 
 
 
8 hr
(± 30 min)  
X
 
 
 
10 hr
(± 1 hr)  
X
 
 
 
12 hr a
(± 2 hr)   
X
 
 
 
Cycle 1
D2
&
D22
24 hr a
(± 2 hr)
Pre-C2D1 
dose
X
 
 
 
Cycle 2
D1
Predose
(-30 min) 
X
X
Pre-tisle–dose
(-30 min)  
X
Pre-sitra-dose
(-30 min)  
 
6 hr
(± 1 hr) 
X
X
 
 
Cycle 3
D1
Predose
(-30 min)
Pre-sitra-dose
(-30 min) 
Cycle 5 
D1
Predose
(-30 min)
X
X
Pre-tisle–dose
(-30 min) 
X 
6 hr
(± 1 hr)
X
X
Post-tisle–dose 
(+30 min)
Cycle 9, 17
D1
Predose
(-30 min)   
Pre-tisle–dose
(-30 min)  
X
 
End-of-
Treatment 
Visit
Within 30 
days after 
last dose 
of study 
drug(s) 
X
X
X
Abbreviations: ADA, anti-drug antibody; ctDNA, circulating tumor DNA; CR, completed response; D, Day; EC, 
ethics committee; ECG, electrocardiogram; EOT, end-of-treatment; h, hour; IRB, institutional review board; min, 


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minutes; PGx, pharmacogenetics; PK, pharmacokinetic; PR, partial response; SAE, serious adverse event; sitra, 
sitravatinib; SMC, Safety Monitoring Committee; tisle, tislelizumab
Note: Scheduled vital signs and ECGs precede PK sample collection in all cases. Sitravatinib dosing and sampling 
should precede tislelizumab infusion.
a.
Postdose samples for sitravatinib at 12 h and 24 h are optional and depend on site feasibility. 
b.
PK for sitravatinib: the first five (5) patients per cohort and the twelve (12) patients (6 patients from 
Australian sites and 6 patients from China sites, regardless of cohort) for SMC safety review will contribute 
serial PK samples on Cycle 1 Days 1 and 21 and sparse PK samples on Cycle 2 Day 1 and Cycle 5 Day 1. 
All other patients will contribute sparse PK samples on Cycle 1 Days 1 and 21, Cycle 2 Day 1, and 
Cycle 5 Day 1. An additional PK blood sample should be drawn before a daily sitravatinib dose (trough 
sample) in any of the following events: 1) as soon as possible after an SAE, 2) at a clinic visit at least one 
week following a dose modification of sitravatinib, or 3) as soon as possible after renal function declines by 
one stage as defined in Appendix 8 if the patient continues study treatment. These tests are required when it 
is allowed by local regulations/IRBs/ECs.
c.
PK sampling for tislelizumab: samples should be collected predose of tislelizumab (-30 min) on Day 1 of 
Cycles 1, 2, 5, 9 and 17; postdose (within 30 min after the end of tislelizumab infusion) on Day 1 of 
Cycle 1 and Cycle 5; and at the EOT Visit. Should a patient present with any ≥Grade 3 irAE, an additional 
blood PK sample may be taken to determine the serum concentration of tislelizumab. These tests are 
required when it is allowed by local regulations/IRBs/ECs.
d.
ADA sampling 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 predose of tislelizumab. These tests are required when it is allowed by local 
regulations/IRBs/ECs.
e.
Biomarker sampling: approximately 20 mL and 10 mL of peripheral blood samples will be collected on 
Cycle 1 Day 1 (predose sitravatinib and tislelizumab, -30 min before dosing) and Day 1 (predose 
sitravatinib and tislelizumab, -30 min before dosing) of Cycle 2, and 3, respectively. For the patients who 
have confirmed CR, PR or PD (at EOT Visit) as assessed by the investigator, an additional blood samples 
(approximately 10 mL) will be collected one time. 


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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 counts
Blood 
Albumin
WBC count 
Ketones 
Total bilirubin
Direct bilirubin
Lymphocyte count
Neutrophil count
24-hour proteinb
Blood urea nitrogen or urea
Potassium
Sodium
Corrected calciumc
Creatinine
Glucose
Lactate dehydrogenase
Total protein
Creatine Kinase (CK)d
CK-MBd
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
c.
if not feasible at the local laboratory, total calcium may be performed instead of corrected calcium.
d.
In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. If 
tislelizumab has been permanently discontinued, CK and CK-MB testing is no longer required.
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 once every 3 weeks or monthly during 
treatment, at End of Study Visit, and at 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 testing (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 at the EOT Visit (see Section 7.3.4 for 
details).


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APPENDIX 4.
ECOG PERFORMANCE STATUS
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
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.
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) nephropathy
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia syndrome 
Lupus erythematosus 
Lyme disease (chronic)
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis
Neuromyotonia 
Opsoclonus myoclonus syndrome 
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 6.
CONTRACEPTION GUIDELINES AND DEFINITIONS
OF “WOMEN OF CHILDBEARING POTENTIAL”, “NO
CHILDBEARING POTENTIAL”
Contraception Guidelines
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control. 
These methods include the following:
Combined (estrogen- and progestogen-containing) hormonal contraception associated with the 
inhibition of ovulation (oral, intravaginal, or transdermal)
Progestogen-only hormonal contraception associated with the inhibition of ovulation (oral, 
injectable, or implantable)
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomized male partner, provided that the vasectomized partner is the sole sexual partner of 
the woman of childbearing potential study participant and that the vasectomized partner has 
received medical assessment of surgical success.
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of 
exposure associated with the study treatment).
x
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patient’s usual and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception.
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with a highly effective form of birth control, listed above.
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential”
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria:
Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or hysterectomy)


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Postmenopausal, defined as:
x
≥ 55 years of age with no spontaneous menses for ≥ 12 months OR
x
< 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months have 
been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc.
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded.
Adapted from Clinical Trials Facilitation Group (CTFG).


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APPENDIX 7.
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 8.
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION
In adults, the most widely-used equations for estimating glomerular filtration rate 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 /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black]
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1.
The equation does not require weight because the results are reported normalized to 1.73 m2
body surface area, which is an accepted average adult surface area.
The online calculator for CKD-EPI can be found on the National Institute of Diabetes and 
Digestive and Kidney Diseases webpage (https://www.niddk.nih.gov/health-information/health-
communication-programs/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-calculators.aspx)
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 9.
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. 
Neurological Toxicity
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings.


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Recommended Diagnostic Tests in the Management of Possible Immune-related Adverse Events
Immune-Related Toxicity
Diagnostic Evaluation Guideline
Colitis
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, 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 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 Adverse Events
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. 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.
2
Rash covers 10%-30% 
of BSA
Avoid skin irritants and sun 
exposure; topical emollients 
recommended.
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch. Consider a 
short course of oral steroids.
Continue study 
treatment.


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Autoimmune 
Toxicity
Grade
Treatment Guidelines (Subject to 
Clinical Judgement)
Study Drug 
Management
3
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms
Avoid skin irritants and sun 
exposure; topical emollients 
recommended.
Initiate steroids as follows based on 
clinical judgement:
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/Day for 
3 days then taper over 2-4 weeks.
For severe symptoms: intravenous 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks.
Hold study treatment.
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the medical monitor.
4
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment)
Initiate intravenous 
methylprednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.
Admit to a hospital and seek urgent 
dermatology consultation.
Discontinue study 
treatment.
Hepatitis
1
ALT or AST > ULN to 
3X ULN
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening.
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen.
Continue study 
treatment if LFTs are 
unchanged or 
improving.
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen.
2
ALT or AST 3-5X ULN
Recheck LFTs every 48-72 hours:  
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-
1 mg/kg/Day for 3 days then taper 
over 2-4 weeks.
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/Day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement. 
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤10 mg.
3
ALT or AST 5-20X 
ULN
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks.
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
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.


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Autoimmune 
Toxicity
Grade
Treatment Guidelines (Subject to 
Clinical Judgement)
Study Drug 
Management
4
ALT or AST > 20X 
ULN
Initiate intravenous 
methylprednisolone 2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 6 weeks. 
Discontinue study 
treatment.
Worsening LFTs despite steroids:
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 
replacement therapy is available.
Discontinue study 
treatment.
Diabetes/
Hyperglycemia
1
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L
Monitor closely and treat according 
to local guideline. Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended
Continue study 
treatment.


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Autoimmune 
Toxicity
Grade
Treatment Guidelines (Subject to 
Clinical Judgement)
Study Drug 
Management
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
Abdominal pain, nausea, 
and vomiting
Admit to hospital for urgent 
management. Initiate intravenous 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks.
Hold study treatment; 
reintroduce only after 
discussion with the 
medical monitor.


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Autoimmune 
Toxicity
Grade
Treatment Guidelines (Subject to 
Clinical Judgement)
Study Drug 
Management
4
Acute abdominal pain, 
surgical emergency
Admit to hospital for emergency 
management and appropriate referral. 
Discontinue study 
treatment.
Arthritis
1
Mild pain with 
inflammation, swelling
Management per local guideline. 
Continue study 
treatment.
2
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms worsen 
on treatment manage as a Grade 3
event.
Continue treatment or, 
if symptoms continue 
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 
steroids and treat as Grade 2
Continue study 
treatment.
2
Moderate weakness 
with/without pain
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks
Hold study treatment 
until improved 
to Grade 0-1


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Autoimmune 
Toxicity
Grade
Treatment Guidelines (Subject to 
Clinical Judgement)
Study Drug 
Management
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 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 10. 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 (uni-dimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
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 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable.
Bone lesions:
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.
x
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 target lesions must meet the criterion of a short axis of ≥ 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, 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 nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
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.


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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 
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 progressive disease.
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.


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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 
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 


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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 
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:


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Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on 
a new lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at that site (if so, the date of 
PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at 
follow-up corresponds to a 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.


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Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
CR
PR
SD
Not all evaluated
PD
Any
Any
CR
Non-CR/non-PD
Not evaluated
Non-PD or not all 
evaluated
Non-PD or not all 
evaluated
Non-PD
Any
PD
Any
No
No
No
No
No
No
Yes or No
Yes or No
Yes
CR
PR
PR
PR
SD
NE
PD
PD
PD
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease.
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero” on the eCRF.
In 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. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/ sensitivity.


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For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks).
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall 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 PFS are influenced by the 
frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made.


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APPENDIX 11. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
SITRAVATINIB
The text below was obtained from https://crediblemeds.org/ and 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.
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 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.


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 151
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. 


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 152
APPENDIX 12. CA-125 RESPONSE CRITERIA 
The text below was obtained from Rustin et al 2011.
Definition of Response:
A CA-125 response is defined as at least a 50% reduction in CA-125 levels from a pretreatment 
sample. The response must be confirmed and maintained by using the next scheduled CA-125
data (at least 28 days). Patients can be evaluated according to CA-125 only if they have a 
pretreatment sample that is at least twice the upper limit of the reference range and within 
2 weeks before starting the treatment.
To calculate CA-125 responses accurately, the following rules apply:
x
Intervening samples and the 28-Day confirmatory sample must be less than or equal 
to (within an assay variability of 10%) the previous sample.
x
Variations within the reference range of CA-125 levels will not interfere with the 
response definition.
x
For each patient, the same assay method must be used, and the assay must be tested in 
a quality control scheme.
x
Patients are not evaluable by CA-125 if they have received mouse antibodies (unless 
the assay used has been shown not to be influenced by human antimouse antibody4, 
5) or if there has been medical and/or surgical interference with their peritoneum or 
pleura during the previous 28 days (eg, paracentesis). If assessing therapy that 
includes 2 treatment modalities for relapse (eg, surgery and chemotherapy), any CA-
125 response results from both treatment modalities. CA-125 cannot distinguish 
between the effects of the 2 treatments.
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response. To 
calculate response, an intent-to-treat analysis should be used that includes all patients with an 
initial CA-125 level of at least twice the upper limit of the reference range as eligible and 
evaluable. In addition, as a separate analysis, those patients who have a CA-125 response and 
whose CA-125 level falls to within the reference range can be classified as CA-125 complete 
responder (see following table).


BGB-900-103
BeiGene
Protocol Amendment 3.0
19 November 2019
CONFIDENTIAL
Page 153
CA-125 Level
CA-125 Measurement
Baseline CA-125 more than twice upper limit of normal, 
later reduced by 50% to normal and maintaining for at least 
28 days
CR
Baseline CA-125 more than twice upper limit of normal, 
later reduced by 50% but not to normal
PR
CA-125 change out of range of PR and PD
Non-PR, non-PD
CA-125 increased at baseline returning to normal after 
treatment, later twice or higher upper limit of normal 
(2 consecutive measurements at interval of at least 1 week)
PD (date of first evaluation of 
progression)
CA-125 increased at baseline not returning to normal after 
treatment, later twice or higher the lowest value 
(2 consecutive measurements at interval of at least 1 week)
PD (date of first evaluation of 
progression)
CA-125 within reference range at baseline, later twice or 
higher upper limit of normal (2 consecutive measurements 
at interval of at least 1 week)
PD (date of first evaluation of 
progression)
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response.

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09-Feb-2023 | 06:40:42 PST
09-Feb-2023 | 16:59:39 PST
09-Feb-2023 | 17:06:10 PST
09-Feb-2023 | 05:49:22 PST


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DocuSign Envelope ID: 17332AC3-6EEC-4F8E-941B-0A26475ECB49