Clinical trial NCT03379259
Conditions: Advanced Solid Tumors
Sponsor: BeiGene
Start date: 2017-11-27; Completion date: 2020-09-08
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
BGB-A333 is a humanized IgG1-variant monoclonal antibody against programmed cell death 1-ligand 1 (PD-L1), the ligand of an immune check point- receptor, programmed cell death-1 (PD-1). BGB-A317 is a humanized, IgG4-variant monoclonal antibody against PD-1. This study tested the safety and anti-tumor effect of BGB-A333 alone and in combination with BGB-A317 in participants with advanced solid tumors.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: BGB-A333 intervention 2: BGB-A317
Intervention descriptions: intervention 1: Anti-PD-L1 antibody intervention 2: Anti-PD-1 antibodies

Protocol documents:
Prot_000.pdf: 
BeiGene, Ltd. 
CONFIDENTIAL
BGB-900-101 
Protocol Amendment 1.0 
12 June 2018
Page 1 of 139 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Anti-PD-L1 Monoclonal Antibody 
BGB-A333 Alone and in Combination with Anti-PD-1 Monoclonal 
Antibody Tislelizumab in Patients with Advanced Solid Tumors 
Protocol Identifier: 
BGB-900-101 
Phase: 
1-2
Investigational Products: 
BGB-A333 and tislelizumab (BGB-A317) 
EudraCT Number 
2018-000265-37 
Indication: 
Advanced Solid Tumors 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1900 Powell Street, 5th Fl., Suite 500 
Emeryville, CA 94608 
USA 
Sponsor Medical Monitor: 
Original Protocol: 
2 August 2017
Amendment 1.0 
12 June 2018
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 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. 


BeiGene, Ltd. 
CONFIDENTIAL
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12 June 2018
Protocol Amendment 1.0 
Page 2 of 139 
FINAL PROTOCOL APPROVAL SHEET 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of 
Anti-PD-L1 Monoclonal Antibody BGB-A333 Alone and in Combination with Anti-PD-1 Monoclonal 
Antibody Tislelizumab in Patients with Advanced Solid Tumors 
BeiGene, Ltd. Approval: 
________________________
_____________________ 
DocuSign Envelope ID: 12A7537A-2810-457B-B089-8319362EEC88


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CONFIDENTIAL
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12 June 2018
Protocol Amendment 1.0 
 
 
 
Page 3 of 139 
 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Anti-PD-L1 Monoclonal Antibody 
BGB-A333 Alone and in Combination with Anti-PD-1 Monoclonal Antibody 
Tislelizumab in Patients with Advanced Solid Tumors 
 
Protocol Identifier: 
 
BGB-900-101 
 
This protocol is a confidential communication of BeiGene, Ltd. I confirm that I have read this protocol, I 
understand it, and I will work according to this protocol. 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 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: 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................12 
PROTOCOL AMENDMENT, VERSION 1: RATIONALE AND SUMMARY OF 
CHANGES .................................................................................................................13 
SYNOPSIS ....................................................................................................................................16 
LIST OF ABBREVIATIONS AND TERMS ................................................................................25 
1. 
INTRODUCTION AND RATIONALES ..................................................................28 
1.1. 
Introduction.................................................................................................................28 
1.2. 
BGB-A333 as a PD-L1 Blocker .................................................................................28 
1.2.1. 
Pharmacology .............................................................................................................28 
1.2.2. 
Toxicology ..................................................................................................................29 
1.2.3. 
Comparison Between BGB-A333 and OtherAnti-PD-L1 Agents ..............................30 
1.3. 
Tislelizumab as a PD-1 Blocker .................................................................................30 
1.3.1. 
Pharmacology .............................................................................................................31 
1.3.2. 
Toxicology ..................................................................................................................31 
1.3.3. 
Clinical Pharmacology................................................................................................32 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................32 
1.3.4.1. 
BGB-A317_Study_001 (Data cut off 28August 2017) ..............................................32 
1.3.4.2. 
Study BGB-A317-102 (Data cut off 28 August 2017) ...............................................33 
1.3.4.3. 
Immune-related Reactions ..........................................................................................34 
1.4. 
Study Rationales .........................................................................................................34 
1.4.1. 
Rationale for BGB-A333 as a Monotherapy ..............................................................34 
1.4.2. 
Rationale for Combination of BGB-A333 and Tislelizumab in the Treatment of 
Advanced Solid Tumors .............................................................................................34 
1.4.3. 
Rationale for Selection of BGB-A333 Starting Dose .................................................36 
1.4.3.1. 
Compartmental Pharmacokinetic Model ....................................................................36 
1.4.3.2. 
Pharmacologically Active Dose of BGB-A333 ..........................................................37 


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1.4.3.3. 
Recommendation of the First-in-Human Dose of BGB-A333 ...................................38 
1.4.4. 
Rationale for Selection of Tislelizumab Dose ............................................................39 
1.5. 
Benefit-Risk Assessment ............................................................................................40 
2. 
STUDY OBJECTIVES AND ENDPOINTS..............................................................41 
2.1. 
Study Objectives for Phase 1A (Dose Escalation for BGB-A333 Monotherapy) 
and Phase 1B (Dose Confirmation for BGB-A333 and Tislelizumab 
Combination) ..............................................................................................................41 
2.1.1. 
Primary Objectives .....................................................................................................41 
2.1.2. 
Secondary Objectives .................................................................................................41 
2.1.3. 
Exploratory Objectives ...............................................................................................41 
2.2. 
Study Objectives for Phase 2A (BGB-A333 Monotherapy Dose Expansion) and 
Phase 2B (BGB-A333 and Tislelizumab Combination Dose Expansion)..................41 
2.2.1. 
Primary Objectives .....................................................................................................41 
2.2.2. 
Secondary Objectives .................................................................................................41 
2.2.3. 
Exploratory Objectives ...............................................................................................41 
2.3. 
Study Endpoints for Phase 1 .......................................................................................42 
2.3.1. 
Primary Endpoints ......................................................................................................42 
2.3.2. 
Secondary Endpoints ..................................................................................................42 
2.3.3. 
Exploratory Endpoints ................................................................................................42 
2.4. 
Study Endpoints for Phase 2 .......................................................................................43 
2.4.1. 
Primary Endpoint ........................................................................................................43 
2.4.2. 
Secondary Endpoints ..................................................................................................43 
2.4.3. 
Exploratory Endpoints ................................................................................................43 
3. 
STUDY DESIGN .......................................................................................................44 
3.1. 
Summary of Study Design ..........................................................................................44 
3.1.1. 
Phase 1A (BGB-A333 Dose Escalation) ....................................................................45 
3.1.2. 
Phase 1B (BGB-A333 and Tislelizumab Combination Dose Confirmation) .............46 
3.1.3. 
Phase 2A (BGB-A333 Dose Expansion) ....................................................................46 
3.1.4. 
Phase 2B (BGB-A333 and Tislelizumab Dose Expansion) .......................................46 
3.2. 
Enrollment Priority .....................................................................................................46 
3.3. 
Study Periods ..............................................................................................................47 
3.3.1. 
Screening Period .........................................................................................................47 
3.3.2. 
Treatment Period ........................................................................................................47 


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3.3.3. 
Safety Follow-Up Period ............................................................................................47 
3.4. 
Patient Discontinuation and Study Completion ..........................................................48 
3.4.1. 
Patient Discontinuation from Study Treatment ..........................................................48 
3.4.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) ...........48 
3.4.3. 
Study Completion or Termination ..............................................................................48 
3.5. 
DLT Definition ...........................................................................................................49 
4. 
STUDY POPULATION .............................................................................................51 
4.1. 
Inclusion Criteria ........................................................................................................51 
4.2. 
Exclusion Criteria .......................................................................................................52 
5. 
STUDY TREATMENT ..............................................................................................54 
5.1. 
Formulation, Packaging, and Handling ......................................................................54 
5.1.1. 
BGB-A333 ..................................................................................................................54 
5.1.2. 
Tislelizumab ...............................................................................................................54 
5.2. 
Dosage, Administration, and Compliance ..................................................................54 
5.3. 
Overdose of Tislelizumab and Incorrect Administration of BGB-A333....................56 
5.4. 
Dose Delay and Modification .....................................................................................57 
5.4.1. 
Dose Modification ......................................................................................................57 
5.4.2. 
Dose Delay..................................................................................................................57 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................58 
6.1. 
Concomitant Therapy .................................................................................................58 
6.1.1. 
Permitted Concomitant Medications and Therapy .....................................................58 
6.2. 
Prohibited or Restricted Concomitant Medications and Therapy ...............................59 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant Medications .......59 
7. 
STUDY ASSESSMENTS AND PROCEDURES......................................................60 
7.1. 
Screening ....................................................................................................................60 
7.1.1. 
Demographic Data and Medical History ....................................................................60 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................61 
7.1.3. 
Informed Consent and Screening Log ........................................................................61 
7.1.4. 
Pulmonary Function Tests ..........................................................................................61 
7.2. 
Enrollment ..................................................................................................................61 
7.2.1. 
Confirmation of Eligibility .........................................................................................61 
7.3. 
Safety Assessments .....................................................................................................61 


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7.3.1. 
Vital Signs ..................................................................................................................61 
7.3.2. 
Physical Examinations ................................................................................................61 
7.3.2.1. 
Ophthalmologic Examination .....................................................................................62 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status ........................................62 
7.3.4. 
Laboratory Safety Test ...............................................................................................62 
7.3.5. 
Electrocardiograms .....................................................................................................63 
7.3.6. 
Adverse Events ...........................................................................................................63 
7.3.7. 
Hepatitis B and C Testing ...........................................................................................63 
7.4. 
Tumor and Response Evaluations ..............................................................................63 
7.5. 
Pharmacokinetic Assessment and Antidrug Antibody Testing ..................................65 
7.6. 
Biomarkers ..................................................................................................................66 
7.7. 
Safety Follow-Up Visit ...............................................................................................66 
7.8. 
Visit Windows ............................................................................................................67 
7.9. 
Unscheduled Visits .....................................................................................................67 
7.10. 
Site Closure .................................................................................................................67 
8. 
SAFETY MONITORING AND REPORTING .........................................................68 
8.1. 
Risks Associated with BGB-A333 and Tislalizumab .................................................68 
8.2. 
General Plan to Manage Safety Concerns ..................................................................68 
8.2.1. 
Eligibility Criteria .......................................................................................................68 
8.2.2. 
Safety Monitoring Plan ...............................................................................................68 
8.3. 
Adverse Events ...........................................................................................................69 
8.3.1. 
Definitions and Reporting...........................................................................................69 
8.3.2. 
Assessment of Severity ...............................................................................................70 
8.3.3. 
Assessment of Causality .............................................................................................70 
8.3.4. 
Following Adverse Events ..........................................................................................71 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................71 
8.4. 
Definition of a Serious Adverse Event .......................................................................72 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................73 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................73 
8.6.1. 
Adverse Event Reporting Period ................................................................................73 
8.6.2. 
Reporting Serious Adverse Events .............................................................................73 


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8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................73 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................73 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................74 
8.6.3. 
Eliciting Adverse Events ............................................................................................74 
8.6.4. 
Recording Disease Progression ..................................................................................74 
8.6.5. 
Recording Deaths........................................................................................................75 
8.6.6. 
Recording Pregnancies ...............................................................................................75 
8.6.7. 
Recording Post-Study Adverse Events .......................................................................75 
8.6.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees .............................................................75 
8.6.9. 
Assessing and Recording Immune-Related Adverse Events ......................................75 
8.7. 
Management of AE of Special Interest .......................................................................76 
8.7.1. 
Infusion-Related Reactions .........................................................................................76 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................77 
8.7.3. 
Immune-Related Adverse Events ...............................................................................78 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................80 
9.1. 
Statistical Analysis......................................................................................................80 
9.1.1. 
Randomization Methods .............................................................................................80 
9.1.2. 
Analysis Populations ..................................................................................................80 
9.1.3. 
Patient Disposition ......................................................................................................80 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................80 
9.1.5. 
Prior and Concomitant Medications ...........................................................................81 
9.2. 
Efficacy Analyses .......................................................................................................81 
9.2.1. 
Primary Efficacy Analysis in Phase 2 ........................................................................81 
9.2.2. 
Secondary Efficacy Analysis in Phase 2 ....................................................................81 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................82 
9.3. 
Safety Analyses ..........................................................................................................82 
9.3.1. 
Extent of Exposure .....................................................................................................82 
9.3.2. 
Adverse Events ...........................................................................................................82 
9.3.3. 
Laboratory Analyses ...................................................................................................83 
9.3.4. 
Vital Signs ..................................................................................................................83 
9.3.5. 
Ophthalmologic Examination .....................................................................................83 


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9.4. 
Pharmacokinetic Analysis ..........................................................................................83 
9.5. 
Immunogenicity Analyses ..........................................................................................84 
9.6. 
Other Exploratory Analyses .......................................................................................84 
9.7. 
Sample Size Consideration .........................................................................................84 
9.8. 
Interim Analyses .........................................................................................................85 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................86 
10.1. 
Safety Monitoring Committee ....................................................................................86 
10.2. 
Communication...........................................................................................................86 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................87 
11.1. 
Access to Information for Monitoring ........................................................................87 
11.2. 
Access to Information for Auditing or Inspections ....................................................87 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................88 
12.1. 
Regulatory Authority Approval ..................................................................................88 
12.2. 
Quality Assurance .......................................................................................................88 
12.3. 
Study Site Inspections.................................................................................................88 
12.4. 
Drug Accountability ...................................................................................................88 
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................89 
13.1. 
Ethical Standard ..........................................................................................................89 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................89 
13.2.1. 
Protocol Amendments ................................................................................................89 
13.3. 
Informed Consent .......................................................................................................89 
13.4. 
Patient and Data Confidentiality .................................................................................90 
13.5. 
Financial Disclosure ...................................................................................................91 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................92 
14.1. 
Data Collection and Management Responsibilities ....................................................92 
14.1.1. 
Data Collection ...........................................................................................................92 
14.1.2. 
Data Management/Coding ..........................................................................................92 
14.2. 
Data Integrity ..............................................................................................................92 
14.3. 
Study Records Retention ............................................................................................93 
14.4. 
Protocol Deviations ....................................................................................................94 
14.5. 
Publication and Data Sharing Policy ..........................................................................94 


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14.7. 
Information Disclosure and Inventions ......................................................................95 
15. 
REFERENCES ...........................................................................................................97 
16. 
APPENDICES ..........................................................................................................100 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................101 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................110 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................111 
APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................112 
APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN 
OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING POTENTIAL” ....113 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................114 
APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION ..........................................................................................115 
APPENDIX 8. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................116 
APPENDIX 9. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................126 
APPENDIX 10. IRECIST CRITERIA......................................................................................135 
APPENDIX 11. CHILD-PUGH CLASSIFICATION SCORING SYSTEM ...........................139 


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LIST OF TABLES 
Table 1. 
Comparison Between BGB-A333 and Other Anti-PD-L1 Agents .............................30 
Table 2. 
Predicted Safety Margins ............................................................................................39 
Table 3. 
Planned Dose Levels for BGB-A333 and Tislelizumab .............................................55 
Table 4. 
Administration of BGB-A333 and Tislelizumab and Monitoring Time ....................56 
Table 5. 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................73 
Table 6. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s)..............................................................................................................76 
Table 7. 
Immune-Related Adverse Events ...............................................................................79 
Table 8. 
Time Probabilities of Observing at least One Responder in 20 Patients under 
Various ORR Assumptions.........................................................................................85 
Table 9. 
95% CI (%) when Observing 1 to 6 Responders in 20 Patients .................................85 
 


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LIST OF FIGURES 
Figure 1. 
Combination of PD-1 and PD-L1 in Mouse MCA205 Sarcoma Model (Hamid 
2016) ...........................................................................................................................35 
Figure 2. 
Combination of PD-1 and PD-L1 inPD-1 resistant model (AT3 Tumor) (Ngiow 
2015) ...........................................................................................................................36 
Figure 3. 
Simulated PK Profiles of BGB-A333 .........................................................................38 
Figure 4. 
Study Schema .............................................................................................................45 


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PROTOCOL AMENDMENT, VERSION 1: RATIONALE AND SUMMARY OF 
CHANGES 
The main objectives for this amendment are to update the recommendation for management and 
reporting of irAE, and to align procedures to comply with company standards.  
Throughout the protocol amendment, editorial changes and formatting revisions were made with the 
purpose of improving clarity and consistency. Additionally, the synopsis was updated to match changes 
made in the protocol body. 
Substantial Changes: 
• 
Throughout the protocol, BGB-A317 was replaced by its generic name tislelizumab 
• 
Section 1.3.3 (Clinical Pharmacology), Section 1.3.4 (Prior Clinical Experience of Tislelizumab), 
Section 1.4.2 (Rationale for Combination of BGB-A333 and Tislelizumab in the Treatment of 
Advanced Solid Tumors), Section 1.4.4 (Rationale for Selection of Tislelizumab Dose), 
Section 5.3 (Overdose of Tislelizumab and Incorrect Administration of BGB-A333), and 
Section 5.4 (Dose Delay and Modification) were revised based on recent clinical analyses and to 
align with the latest version of the Tislelizumab IB (Edition 5.0, release date of 26 February 2018) 
• 
Section 2 (Study Objectives and Endpoints) was revised and OS
 was 
removed. This is an open-label study with relatively small sample size per cohort, it is unlikely to 
obtain clinically meaningful data on OS in the current study. As a result of removing OS, survival 
follow up period was removed 
• 
Section 3.1 (Summary of Study Design) was revised and the following changes were made: 
o For Phase 2A and Phase 2B, approximately 20 patients with UC will be enrolled. In 
addition, Sponsor may consider other tumor types including but not limited to NSCLC, 
RCC, SCCHN, GC, MSI-high cancer, etc. Eligibility criteria for these cohorts will be 
defined in future protocol amendments based on emerging clinical data. Sample size for 
Phase 2A and Phase 2B was adjusted throughout the protocol 
• 
Section 3.1.1 (Phase 1A) was revised to fix a typographical error 
o The original protocol stated that “The MTD dose level is defined as the highest dose at 
which ≤ 33% of the patients experience a DLT.”  It should be “The MTD dose level is 
defined as the highest dose at which < 33% of the patients experience a DLT.” 
• 
Section 3.3.3 (Safety Follow-up Period) was modified based on recent regulatory feedback on 
other studies of tislelizumab. Specifically, 
o Telephone contacts will be made at Day 60 and Day 90 to assess irAE and concomitant 
medications, regardless of whether or not the patient starts a new anticancer therapy 
• 
Section 3.3.4 (Survival Follow-up Period) was removed 
• 
Section 4.1 (Inclusion Criteria) was revised and the following changes were made: 


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o #7: Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN for all 
patients. The purpose of this change is to align with CTCAE Grade 
o #7: Removed coagulation inclusion criteria to align with standard sponsor language 
o #7: A new criterion “HCC patients must meet Child-Pugh A classification” was added per 
request from one ethics committee in Australia 
o General changes made to align with standard sponsor language for the study drugs 
• 
Section 4.2 (Exclusion Criteria) was revised and the following changes were made: 
o #5 “With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management” was added 
o #9: eligibility for HCC patients with a history of HBV or HCV infection were modified (also 
impacts Schedule of Assessments Appendix 1) 
o #12: two additional CV risk factors (uncontrolled hypertension and recent episode of 
syncope/seizure) were added  
o #19: changed to “Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-
CTLA-4 antibody (or any other antibody targeting T cell co-stimulation pathways)” 
o General changes made to align with standard sponsor language for the study drugs 
• 
In Section 6.1.1 (Permitted Concomitant Medications and Therapy), requirement of antiviral 
therapy in patients with active hepatitis B was added based on recent regulatory feedback on other 
studies of tislelizumab 
• 
In Section 6.2 (Prohibited or Restricted Concomitant Medications and Therapy), restrictions of 
hepatotoxic drugs, alcohol and addictive drugs in patients with HCC were added 
• 
In Section 7.3.2.1 (Ophthalmologic Examination), eye exams were added based on recent 
regulatory feedback on other studies of tislelizumab 
• 
In Section 7.3.7 (Hepatitis B and C testing), patients who have detectable HBV DNA at Screening 
will perform the viral load test every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc), at EOT visit, and 
when clinically indicated.  This was added based on recent regulatory feedback on other studies 
of tislelizumab 
• 
In Section 7.4 (Tumor and response evaluation), the following revisions were made:  
• 
Tumor response will be assessed by the investigators using RECIST v1.1 (see Appendix 9). 
Additional information on new lesions will be collected according to iRECIST (see 
Appendix 10) and sponsor will derive tumor response using iRECIST as an exploratory 
assessment 
• 
Imaging of the brain (MRI or CT) at baseline (≤ 28 days of the first dose of study drug(s)) 
is required for all patients 
• 
In Section 8.6.2 (Reporting SAE), documentation method for SAE reporting is modified.  
• 
Appendix 1 (Schedule of Assessments) was updated to align with changes in assessment 


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• 
In Appendix 1 and Appendix 2, CK and CK-MB tests were added to align with BeiGene’s safety 
monitoring guideline for the risk of myocarditis/myositis 
• 
In Appendix 2, clarification of required clinical laboratory assessments 
• 
Appendix 8 (irAE Evaluation and Management) was updated to include ASCO guideline and 
recent regulatory feedback on other studies of tislelizumab 
• 
Appendix 11 (Child-Pugh classification scoring system) was added due to the addition of 
inclusion criterion on HCC patients 
 
 


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SYNOPSIS 
Name of Sponsor: 
BeiGene, Ltd. 
Investigational Products: 
BGB-A333 and tislelizumab (BGB-A317) 
Title of Study: 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activity of Anti-PD-L1 Monoclonal 
Antibody BGB-A333 Alone and in Combination with Anti-PD-1 
Monoclonal Antibody Tislelizumab in Patients with Advanced Solid 
Tumors 
Protocol Identifier: 
BGB-900-101 
Phase of Development: 
1-2 
Study Centers: 
Up to 20 centers in Australia, New Zealand, Taiwan, Europe, and the 
United States 
Duration of Patient 
Participation: 
This study will consist of 3 periods: 
1. Screening Period is within 28 days prior to first study drug 
administration.  
2. Treatment Period starts with the first study drug administration 
and ends when the patient discontinues study treatment 
3. Safety Follow-up Period Patients who discontinue treatment for 
any reason will be asked to return to the clinic for the Safety 
Follow up Visit (to occur within 30 days [± 7 days] after the last 
dose of study drug (s) or before the initiation of a new anticancer 
treatment, whichever occurs first. In addition, telephone contacts 
with patients should be conducted to assess irAEs and 
concomitant medications (if appropriate, ie, associated with an 
irAE or is a new anticancer therapy) at 60 and 90 days (±14 days) 
after the last dose of study drug(s) regardless of whether or not 
the patient starts a new anticancer therapy.  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, or the 
patient withdraws consent. 
Study Objectives: 
Phase 1A (Dose Escalation for BGB-A333 Monotherapy) and  
Phase 1B (Dose Confirmation for BGB-A333 and Tislelizumab Combination) 
Primary: 
• 
To assess the safety and tolerability of BGB-A333 alone and in combination with 
tislelizumab (BGB-A317) in patients with advanced solid tumors 
• 
To determine the maximum tolerated dose (MTD), if any, and RP2D for BGB-A333 alone 
and in combination with tislelizumab 


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Secondary: 
• 
To assess the preliminary antitumor activity of BGB-A333 alone and in combination with 
tislelizumab 
• 
To characterize the pharmacokinetics (PK) of BGB-A333 alone and in combination with 
tislelizumab 
• 
To assess host immunogenicity to BGB-A333 alone and in combination with tislelizumab 
Exploratory: 
• 
• 
• 
Phase 2A (BGB-A333 Monotherapy Dose Expansion) and  
Phase 2B (BGB-A333 and Tislelizumab Combination Dose Expansion) 
Primary: 
• 
To assess objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 of BGB-A333 alone and in combination with tislelizumab in patients 
with selected tumor types 
Secondary: 
• 
To assess other tumor assessment outcomes ie, duration of response (DOR) progression-free 
survival (PFS), and disease control rate (DCR) per RECIST version 1.1 
• 
To characterize safety and tolerability of BGB-A333 alone and in combination with 
tislelizumab 
• 
To characterize the PK of BGB-A333 alone and in combination with tislelizumab 
• 
To assess host immunogenicity to BGB-A333 and tislelizumab 
Exploratory: 
• 
• 
• 


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Study Endpoints: 
Phase 1A (Dose Escalation for BGB-A333 Monotherapy) and  
Phase 1B (Dose Confirmation for BGB-A333 and Tislelizumab Combination) 
Primary Endpoints: 
• 
Safety and tolerability: The safety of BGB-A333 alone and in combination with tislelizumab 
will be assessed throughout the study by monitoring AEs and SAEs per National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03, 
relevant physical examination, electrocardiograms and laboratory assessments as needed 
• 
The MTD, if any, and Recommended Phase 2 Dose (RP2D) for BGB-A333 alone and in 
combination with tislelizumab will be determined based on safety, tolerability, PK, 
preliminary efficacy, and other available data 
Secondary Endpoints: 
• 
Efficacy evaluations: ORR, DOR, and DCR will be determined by investigators based on 
RECIST version 1.1  
• 
PK: Individual BGB-A333 and tislelizumab concentrations and PK parameters will be 
tabulated by dose cohort 
• 
Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be assessed by 
summarizing the number and percentage of patients by dose cohort who develop detectable 
antidrug antibodies  
Exploratory Endpoints: 
 
 
Phase 2A (BGB-A333 Monotherapy Dose Expansion) and  
Phase 2B (BGB-A333 and Tislelizumab Combination Dose Expansion) 
Primary Endpoint: 
• 
Efficacy evaluations: ORR will be determined by investigators based on RECIST version 1.1 
Secondary Endpoints: 
• 
DOR, PFS, and DCR will be determined by investigators based on RECIST version 1.1 
• 
Safety and tolerability: The safety of BGB-A333 alone and in combination with tislelizumab 
will be assessed throughout the study by monitoring AEs and SAEs per NCI-CTCAE 


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Version 4.03, relevant physical examination, electrocardiograms and laboratory assessments 
as needed 
• 
PK: Individual concentrations and PK parameters of BGB-A333 and tislelizumab 
• 
Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be assessed by 
summarizing the number and percentage of patients who develop detectable antidrug 
antibodies (ADAs) 
Exploratory Endpoints: 
Study Population 
Phase 1: Patients with histologically or cytologically confirmed advanced or metastatic, unresectable 
solid tumors who have progressed during or after the standard therapy or for which treatment is not 
available, not tolerated or refused. 
Phase 2: Arm 1: Patients with locally advanced and metastatic urothelial carcinoma who have 
progressed during or after treatment with platinum-based chemotherapy or who could not tolerate 
platinum-based chemotherapy.  
In addition, Sponsor may consider other tumor types including but not limited to non-small cell lung 
cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck 
(SCCHN), gastric cancer (GC), and microsatellite instability (MSI)-high cancer, etc. The eligibility 
criteria for patients with these tumor types will be defined in future protocol amendments.  
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, unresectable solid tumors. All patients are also required to have an ECOG PS 
score of ≤ 1, and adequate organ function. 
Test Product, Dose, and Mode of Administration: 
Phase 1A: BGB-A333 Dose Escalation 
• 
BGB-A333: approximately 3 to 5 dose levels or dosing regimens may be tested. The initial 
plan is to test 450 mg, 900 mg and 1350 mg every 3 weeks (Q3W), intravenously (IV). A 
lower dose (eg, 225 mg Q3W), intermediate doses or higher doses (eg, 1800 mg and/or 
2250 mg Q3W) may be tested based on preliminary safety, tolerability, PK, and antitumor 
activities of BGB-A333 observed in dose levels tested. Different dosing regimens every 
2 weeks (Q2W) or every 4 weeks (Q4W) may also be explored 


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Phase 1B: BGB-A333 and Tislelizumab Combination Dose Confirmation 
• 
BGB-A333: The SMC will make a recommendation on the selection of BGB-A333 dose 
based on available safety, efficacy, PK and exploratory data from Phase 1A. If this initial 
dose in combination is deemed not tolerated, lower dose(s) or alternative dosing regimens of 
BGB-A333 may be tested in combination with tislelizumab  
• 
Tislelizumab: 200 mg (Q3W, IV). Alternative dosing regiments may be explored  
Phase 2A: BGB-A333 Dose Expansion 
• 
BGB-A333: at RP2D determined in Phase 1A 
Phase 2B: BGB-A333 and Tislelizumab Combination Dose Expansion 
• 
BGB-A333 and Tislelizumab: at the dosing regimen determined in Phase 1B 
Study Design 
This is an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. This study 
consists of the following phases: 
• 
Phase 1A (BGB-A333 dose escalation): approximately 3-5 dose levels or dosing regimens 
will be tested in patients with advanced solid tumors. Additional dose levels could be tested 
if needed. The modified 3+3 design will be used in the dose escalation. At least 6 evaluable 
patients should be enrolled at the MTD level, the RP2D level or at the highest dose level 
tested if MTD is not reached. 
• 
Phase 1B (BGB-A333 and tislelizumab dose confirmation): a cohort of approximately 
6 patients with solid tumors will be treated with BGB-A333 and tislelizumab (200 mg, Q3W, 
IV). The SMC will make a recommendation on the selection of BGB-A333 dose based on 
available safety, efficacy, PK and exploratory data from Phase 1A. If the initial dose 
combination is deemed not tolerated, additional cohorts of patients may be enrolled to 
evaluate lower doses or alternative dosing regimens of BGB-A333 and tislelizumab. 
• 
Phase 2A (BGB-A333 dose expansion): approximately 20 patients with UC will be enrolled. 
In addition, Sponsor may consider enrolling 20-40 patients with other tumor types including 
but not limited to NSCLC, RCC, SCCHN, GC, MSI-high cancer, etc. The eligibility criteria 
for patients with the additional tumor types will be defined in future protocol amendments 
based upon emerging data. 
• 
Phase 2B (BGB-A333 and tislelizumab dose expansion): approximately 20 patients with UC 
will be enrolled. In addition, Sponsor may consider enrolling 20-40 patients with other tumor 
types including but not limited to NSCLC, RCC, SCCHN, GC, MSI-high cancer, etc. The 
eligibility criteria for patients with the additional tumor types will be defined in future 
protocol amendments based upon emerging data. 
All patients will receive study drug until 1) they are no longer considered to be achieving clinical 
benefit, 2) unacceptable toxicity, or 3) withdrawal of informed consent.  


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In Phase 1A (BGB-A333 monotherapy), if patients progress on BGB-A333 without other safety 
concerns, these patients may be treated with a higher dose of BGB-A333 that is deemed to be well 
tolerated by SMC. The decision to modify the dose of BGB-A333 must be discussed with the 
sponsor’s medical monitor and documented in the study records. 
In Phase 1A and Phase 2A (BGB-A333 monotherapy), if patients progress on BGB-A333 
monotherapy without other safety concerns, these patients may receive combination of BGB-A333 
and tislelizumab at doses that are deemed to be well tolerated by SMC. The decision to add 
tislelizumab to patients treated with BGB-A333 alone must be discussed with the sponsor’s medical 
monitor and documented in the study records. 
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. 
DLT Assessment 
For Phase 1A (BGB-A333 dose escalation), at least 3 patients evaluable for dose-limiting toxicity 
(DLT) assessment will be enrolled per dose level. Dose escalation will proceed to the next dose level 
if no DLT is observed in the first 3 DLT-evaluable patients. Otherwise, if a DLT has occurred, the 
cohort is expanded to at least 6 patients. If there is no additional DLT in the first 6 DLT-evaluable 
patients, dose escalation will continue to the next level. Dose escalation will stop when there are 2 or 
more DLTs in 6 patients within the same dose level. If 2 or more DLTs are reported in 6 patients at a 
dose level, a minimum of 6 patients will be enrolled on the next lower dose level, or an intermediate 
dose level may be evaluated if recommended by the SMC. The MTD dose level is defined as the 
highest dose at which < 33% of the patients experience a DLT.  At least 6 evaluable patients should 
be enrolled at the MTD level, the RP2D level or at the highest dose level tested if MTD is not 
reached. 
DLTs will be assessed among evaluable patients within 21 days after the first dose of BGB-A333. 
For dose escalation decision, only DLTs occurring within the first 21 days will be evaluated. For 
determination of MTD and RP2D, clinically significant toxicities (eg, irAE) will also be considered.  
A SMC will be established and includes both the sponsor and at least 2 investigators. The SMC will 
review all available safety, efficacy, PK and exploratory data and make recommendation on dose 
escalation, dose modification and dose selection for Phase 1B and Phase 2.  
Definition of DLT 
All toxicities or adverse events will be graded according to the NCI-CTCAE Version 4.03. The 
occurrence of any of the following toxicities within 21 days after the first dose of BGB-A333 if 
judged by the Investigator as related to BGB-A333 will be considered a DLT. 
Hematologic: 
1. Grade 4 neutropenia lasting > 7 days 
2. Grade 3 febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a 
single temperature of 38.3oC or a sustained temperature of 38oC for >1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding 
5. Grade 4 thrombocytopenia 


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6. Grade 4 anemia (life-threatening) 
Non-hematologic: 
1. Grade 4 or above toxicity 
2. Grade 3 toxicity lasting more than 7 days despite optimal supportive care 
Note: The following AEs will not be considered as DLTs: 
• 
Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• 
Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumors) 
• 
Grade 3 rash 
• 
Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical sequelae 
(eg, LDH)  
In addition, clinically important or persistent toxicities that are not included above may also be 
considered a DLT following review by SMC.  
Patients who received < two-thirds (67%) of the assigned dose of BGB-A333 (eg, because the 
infusion had to be stopped due to an infusion reaction) and did not experience a DLT will not be 
taken into account in the assessment of the overall DLT rate for the particular dose level. 
Tumor Assessments 
Radiological assessment of tumor-response status should be performed approximately every 9 weeks 
(for Q3W dosing) in the first year, then every 12 weeks thereafter. If other dosing intervals are 
explored (Q2W or Q4W), radiological assessment of tumor response will be performed 
approximately every 8 weeks.  
Tumor response will be assessed by Investigators based on the RECIST version 1.1. Additional 
information on new lesions will be collected according to iRECIST Guidelines and sponsor will 
derive tumor response using iRECIST as an exploratory assessment. 
For immune therapies, such as BGB-A333 and 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 at least 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 drug 
treatment in patients with suspected pseudoprogression:  


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• 
Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values) 
• 
Stable ECOG performance status 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) that requires urgent alternative medical intervention 
• 
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform patients that this practice is not considered standard in the treatment 
of cancer 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed with 
the sponsor’s medical monitor and documented in the study records. 
Statistical Methods 
Descriptive statistics will be used to summarize the demographic, disease characteristic, efficacy and 
safety data. No statistical hypotheses are planned in this study. 
Analysis Populations 
• 
Safety Population includes all patients who received at least 1 dose of study drug(s). It will 
be the population for the safety and efficacy analyses 
• 
Efficacy Evaluable Population includes all dosed patients who have evaluable disease at 
baseline, and at least one evaluable post-baseline tumor response assessment unless any 
clinical PD or death occurred before the first post-baseline tumor assessment 
• 
DLT Evaluable Population includes patients who received at least two-thirds (67%) of the 
assigned dose of BGB-A333 during the DLT observation period and had sufficient safety 
evaluation or patients who experienced DLT within DLT observation period 
• 
The PK analysis population includes all patients with valid PK sampling after treatment with 
study drug(s) 
Safety Analysis: 
Safety will be determined by the spontaneous reporting of adverse events and by laboratory values 
(hematology, serum chemistry, coagulation, and urinalysis). Vital signs, physical examination and 
ECG findings will also be used in determining the safety profile. The severity of adverse events will 
be graded according to the CTCAE v4.03. The incidence of DLT events, treatment-emergent AEs 
(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. 
Efficacy Analysis: 
The efficacy endpoints based on RECIST v1.1 (ie, ORR, DOR, PFS, and DCR) will be summarized 
to evaluate the antitumor activities of BGB-A333 alone or in combination with tislelizumab.  
• 
ORR is defined as the proportion of patients who had confirmed complete response (CR) or 
partial response (PR) assessed by investigator using RECIST v1.1. ORR and its 95% 
confidence interval (CI) will be summarized in the Safety Population and Efficacy Evaluable 
Population 
• 
DOR is defined as the time from the first determination of an objective response per RECIST 


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v1.1, until the first documentation of progression or death, whichever occurs first  
• 
DCR is defined as the proportion of patients with best overall response of CR, PR and SD. It 
will be summarized similarly as ORR 
• 
PFS is defined as the time from the date of the first dose of study drug(s) to the date of the 
first documentation of disease progression assessed by investigator using RECIST v1.1 or 
death, whichever occurs first 
• 
Waterfall plots of maximum tumor shrinkage per patient will be presented 
• 
Statistical methods will be described in detail in the Statistical Analysis Plan. 
Sample Size Considerations: 
The study plans to enroll approximately 58 to 168 patients. 
• 
Phase 1A (BGB-A333 dose escalation): Approximately 12 to 30 patients with advanced solid 
tumors in 3-5 dose levels or dosing regimens per modified 3+3 design 
• 
Phase 1B (BGB-A333 and tislelizumab combination): Approximately 6 patients with 
advanced solid tumors in one combination dosing regimen. An additional 12 patients may be 
enrolled to test different dosing regimens 
• 
Phase 2A (BGB-A333 dose expansion): Approximately 20 patients with UC. Additional 20-
40 patients with other tumor types (to be defined in future protocol amendments based upon 
emerging data) may be enrolled 
• 
Phase 2B (BGB-A333 and tislelizumab combination dose expansion): Approximately 20 
patients with UC. An additional 20-40 patients with other tumor types (to be defined in 
future protocol amendments based upon emerging data) may be enrolled 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the plasma concentration curve 
BOR 
best overall response 
CBC 
complete blood count 
CDC 
complement-dependent cytotoxicity 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
COPD 
chronic obstructive pulmonary disease 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
Ctrough 
trough serum concentration 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first in human 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HED  
human equivalent dose 
HIV 
human immunodeficiency virus 


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Abbreviation 
Definition 
HNSCC 
head and neck squamous cell carcinoma 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
immune-related Response Evaluation Criteria in Solid 
Tumors 
IV 
intravenous(ly) 
km 
the serum BGB-A333 concentration at which BGB-A333 is 
eliminated at 50% of Vmax 
mAB 
monoclonal antibody 
MCC 
Merkel cell carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NaF-PET 
sodium fluoride proton emission tomography 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PBMCs 
peripheral blood mononuclear cells 
PD 
pharmacodynamics; progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SMC 
Safety Monitoring Committee 


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Abbreviation 
Definition 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TK 
toxicokinetics 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma; urothelial cancer 
ULN 
upper limit of normal 
Vd 
volume of distribution  
Vmax 
the maximum elimination rate 
WHO 
World Health Organization 


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1. 
INTRODUCTION AND RATIONALES 
1.1. 
Introduction  
BGB-A333 is a humanized IgG1-variant monoclonal antibody (mAB) against programmed cell death 1-
ligand 1 (PD-L1), the ligand of an immune check point- receptor, programmed cell death-1 (PD-1). It is 
being developed for the treatment of human malignancies.  
Tislelizumab (also known as BGB-A317) is a humanized, IgG4-variant MAB against PD-1 under clinical 
development for the treatment of several human malignancies.  
Several anti-PD-1 and anti-PD-L1 agents have been approved for the treatment of a number of 
histologically distinct tumors. Tumor types selected in the Phase 2 portion of this study may include but 
are not limited to urothelial cancer (UC), non-small cell lung cancer (NSCLC), renal cell carcinoma 
(RCC), squamous cell carcinoma of the head and neck (SCCHN), gastric cancer (GC), and microsatellite 
instability (MSI)-high cancer as they are representative of tumors for which there is evidence for clinical 
responses to other immunotherapies and those for which there is supportive correlative pathologic data 
suggesting that the PD-1/PD-L1/2 pathway is important for tumor progression.  
1.2. 
BGB-A333 as a PD-L1 Blocker 
PD-L1 is expressed on various hematopoietic cells, including T cells, dendritic cells, monocytes, and in 
many nonhematopoietic tissues, including lung, vascular endothelium, liver, skin, etc. It is believed that 
PD-L1 plays an important role in immune modulation of tumor progression by inducing key inhibitory 
signaling in the T-cells and other immune cells when engages to its receptors PD-1 and B7-1 (also known 
as CD80). The PD-L1/PD-1 and PD-L1/B7-1 signaling cascades negatively regulate T-cell receptor 
activation and attenuate T-cell proliferation and functional activities, leading to T-cell exhaustion. PD-L1 
expression 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 increased 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, UC, NSCLC, RCC, SCCHN, GC, and Merkel cell carcinoma (MCC). Several 
anti-PD-L1 antibodies have been recently approved for the treatment of several cancers. Thus, PD-L1 is 
an established target for cancer immunotherapy. 
1.2.1. 
Pharmacology 
BGB-A333 binds to the extracellular domain of human PD-L1 with high specificity and affinity (KD = 
0.072 nM) as demonstrated by target binding assays and SPR characterization. It competitively blocks 
PD-L1 binding to both PD-1 and B7-1, inhibiting PD-1 mediated negative signaling in T-cells. In in vitro 
cell-based assays, BGB-A333 consistently and dose-dependently enhances the functional activities of 
human T-cells and pre-activated, primary peripheral blood mononuclear cells (PBMCs). In addition, 
BGB-A333 has demonstrated antitumor activity in several cancer xenograft models, including the 
A431 human epidermoid carcinoma model and the SK-MES-1 human squamous cell carcinoma model, 
where the PBMCs or human NK92 cells are co-transplanted with the human cancer cells A431 or 


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SK-MES-1, respectively. Similarly, the anti-murine PD-L1 surrogate antibody, Ab161, has shown 
antitumor activity in the syngeneic CT26 colon cancer model.  
BGB-A333 has been engineered in the heavy chain constant region to eliminate the Fc effector functions. 
BGB-A333 has no or very low bindings to C1q or all FcγRs, including FcγRI, FcγRIIA, FcγRIIB, and 
FcγRIIIA, in in vitro binding assays, suggesting a low or no antibody-dependent cell-mediated 
cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent 
cytotoxicity (CDC), etc. effector functions in humans. BGB-A333 does not induce ADCC or CDC in the 
cell-based assays. 
1.2.2. 
Toxicology 
BGB-A333 binds to the cynomolgus monkey and human PD-L1 with similar affinity, but does not bind to 
mouse PD-L1 due to the significant sequence divergence from human and mouse PD-L1. Therefore, the 
cynomolgus monkey is to be considered the relevant species for nonclinical safety evaluation. 
The toxicity and safety profile of BGB-A333 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. These pivotal studies were 
conducted following Good Laboratory Practice (GLP) regulations. The cytokine release assays were also 
evaluated using fresh human whole blood cells. The single dosing regimens were spanning from the 
intended human doses to more than 10-fold higher than the maximum of the intended human doses, and 
the repeat dosing regimens spanning to 5-fold higher than the maximum of the intended human doses. 
Cynomolgus monkey was the only relevant species based on the target sequence homology and 
cross-species PD-L1 binding activities.  
No apparent toxicity was noted in both mice and monkeys following a single dose up to 250 mg/kg in 
mice and in monkeys following a repeat dose up to 100 mg/kg biweekly for 13 weeks. The toxicokinetics 
(TK) profile was characterized in monkey studies and the systemic exposure appeared to be dose 
proportional without gender difference or accumulation over the dosing period. No apparent 
immunotoxicity was observed as no apparent changes in clinical pathology or histopathology were noted 
in these studies. Immunogenicity with positive antidrug antibody (ADA) against BGB-A333 was noted in 
the single dose monkey study with 1 of 2 monkeys in 30 mg/kg and 100 mg/kg dose groups and in the 
repeat dose study with 12/12, 6/12, and 3/12 of animals at doses of 10, 30, and 100 mg/kg, respectively. 
The ADAs against BGB-A333 were demonstrated to have neutralization activities in a cell based assay 
and, except for the low dose of 10 mg/kg, appeared to have no apparent impact on the systemic exposure 
in the middle (30 mg/kg) or high dose (100 mg/kg) groups.  
The tissue cross reactivity of BGB-A333 was evaluated in normal human and cynomolgus monkey frozen 
tissues using immunohistochemistry method, with appropriate positive and negative controls. Some 
staining was observed on the trophoblast cell membrane and cytoplasm of human placenta, which was 
consistent with published literature. Some staining was observed in the cytoplasm of smooth muscle in 
the human tissues as well as monkey tissues. No increase of the cytokine release from human whole blood 
cells after treatment with BGB-A333 was observed in in vitro evaluations. 


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Overall, no apparent toxicity was noted in mice and monkey toxicity studies. No relevant tissue 
cross-reactivity was found in human and monkey tissues and, no effect on cytokine release was observed 
in human whole blood assay. The TK profile was well characterized with dose proportional increases in 
systemic exposure without apparent accumulation or sex difference. Immunogenicity was observed 
without apparent immunotoxicity and effect on the systemic exposure. The no observed adverse effect 
level (NOAEL) of BGB-A333 in 13-week monkey toxicity study was to be considered 100 mg/kg. The 
safety profile of BGB-A333 is considered adequate to support first-in-human dose safely and ethically.  
Refer to the Investigator’s Brochure (IB) for more detailed information of BGB-A333. 
1.2.3. 
Comparison Between BGB-A333 and OtherAnti-PD-L1 Agents 
Three anti-PD-L1 agents (atezolizumab, avelumab, and durvalumab) have received United States Food 
and Drug Administration (FDA) approval for use in various indications. 
The binding affinity of BGB-A333 to PD- L1 is higher than atezolizumab and durvalumab and 
comparable with that of avelumab. Similar to atezolizumab and durvalumab, the heavy chain constant 
region in BGB-A333 was modified to eliminate Fc effector functions so that it does not have ADCC, 
ADCP, or CDC effects. 
Table 1. 
Comparison Between BGB-A333 and Other Anti-PD-L1 Agents 
 
IgG 
Binding Affinity, nM 
ADCC 
atezolizumab 
IgG1 variant 
1.75 
No 
avelumab 
IgG1 WT 
0.0467 
Yes 
durvalumab 
IgG1 variant 
0.667 
No 
BGB-A333 
IgG1 variant 
0.072 
No 
Abbreviations: IgG = immunoglobulin; IgG1 = immunoglobulin G1; WT = wild type. 
Sources: Package inserts for: 
atezolizumab: https://www.accessdata fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf 
avelumab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf 
durvalumab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf 
BGB-A333 IB 
1.3. 
Tislelizumab as a PD-1 Blocker 
Immune check point-inhibitory receptor, PD-1 is mainly expressed in activated T-cells including CD8+ 
cytotoxic T-lymphocytes and CD4+ T-helper lymphocytes. 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 


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stromal cells is observed in many types of solid human tumors including, but not limited to
 
 
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, IgG4-variant mAB against PD-1 under clinical development for the 
treatment of several human malignancies. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as well as 
high affinity (KD=0.15 nM). It competitively blocks binding efforts by both PD-L1 and programmed 
death-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 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.  
The IgG4 variant antibody has very low binding affinity to FcγRIIIA and Complement 1q, a subunit of 
complement 1, by in vitro assays, suggesting either low or no ADCC or CDC effects in humans 
(Labrijn 2009). 
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 studies were conducted following GLP 
regulations. The single dosing regimens spanned from the intended human doses to 10-fold higher than 
the maximum of the intended human doses, and the repeat dosing regimens spanned to 3-fold higher than 
the maximum of the intended human doses. Cynomolgus monkey was the only relevant species based on 
the target sequence homology and binding activity.  
Overall, no apparent toxicity was noted in mice and monkey toxicity studies. No tissue cross reactivity 
was found in both human and monkey tissues, nor effect on cytokine release was observed in human 
whole blood assay. The TK profile was well characterized with dose proportional increases in systemic 
exposure without apparent accumulation or sex difference. Immunogenicity was observed without 
apparent immunotoxicity and effect on the systemic exposure. The NOAEL of tislelizumab in the 
13-week monkey toxicity study was to be considered 30 mg/kg. The safety profile of tislelizumab is 
considered adequate to support first-in-human (FIH) dose safely and ethically.  
Please refer to the tislelizumab IB for more detailed information on the toxicology of tislelizumab. 


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1.3.3. 
Clinical Pharmacology 
In Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim pharmacokinetic (PK) analysis 
(cut off date 28 August 2017) was conducted by noncompartmental methods, using serum concentrations 
from patients who received doses of 0.5, 2.0, 5.0, 10 mg/kg every 2 weeks (Q2W) and 2.0 mg/kg, 
5.0 mg/kg, 200 mg every 3 weeks (Q3W) (Phase 1a Parts 1, 2, and 3, and Phase 1b in 
BGB-A317_Study_001) and patients who received doses of 200 mg Q3W in Phase 1 of Study 
BGB-A317-102 (n=19). Maximum observed plasma concentration (Cmax) and area under the plasma 
concentration curve (AUC) increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, 
both after single-dose administration at steady state. Preliminary PK data from 27 patients who were 
administered one dose of 200 mg Q3W (Phase 1a, Part 3 and Study BGB-A317-102) showed tislelizumab 
concentrations between the range of concentrations observed after for patients who were administered 
2 mg/kg and 5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first order elimination show a 
systemic CL of tislelizumab of 0.173 L/day, volume of distribution (Vd)in the central and peripheral 
compartments of 2.89 and 1.76 L, respectively, and half-life (t1/2) of approximately 19 days. Race, gender, 
and body weight were not significant covariates on the CL of tislelizumab.  
1.3.4. 
Prior Clinical Experience of Tislelizumab 
As of 28 February 2018, there are 13 ongoing studies with tislelizumab, including monotherapy and 
combination studies in solid tumors and hematological malignancies. Of the ongoing monotherapy studies 
in solid tumors, available data from BGB-A317_Study_001 and BGB-A317-102 are summarized below 
(with a data cut-off date of 28 August 2017). 
Please refer to the tislelizumab IB for more detailed information on efficacy and safety of tislelizumab. 
1.3.4.1. 
BGB-A317_Study_001 (Data cut off 28August 2017) 
Study BGB-A317_Study_001 is a two-stage study consisting of a Phase 1a dose-escalation and dose-
finding component with 3 parts to establish the maximum tolerated dose (MTD), if any, a recommended 
Phase 2 dose (RP2D[s]) for the Phase 1b, and a flat dose (fixed dose) followed by a Phase 1b component 
to investigate efficacy in select tumor types in indication expansion arms and to further evaluate safety 
and tolerability of tislelizumab.  
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens including 
0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg Q2W; 2 mg/kg or 5 mg/kg Q3W; and 200 mg Q3W. 
In Phase 1b, 323 patients had received tislelizumab in Phase 1b across 9 indication-expansion cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the population was 
male, and 65.6% of patients were white. The median number of prior anti-cancer therapy regimens was 
2 (range: 0 to 12). The median treatment exposure duration was 2.50 months (range: 0 to 23.0) and the 
median study follow-up duration was 5.56 months (range: 0.0 to 26.9). As of 28 August 2017, there were 
210 patients (47.8%) on study in Study BGB-A317_Study_001.  


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Preliminary Safety 
Of the 439 total patients in the Safety Population for BGB-A317_Study_001, 240 (54.7%) experienced at 
least 1 treatment-emergent adverse event (TEAE) assessed as related to tislelizumab by the Investigator 
and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE. The most commonly occurring related 
TEAEs for patients treated with the tislelizumab monotherapy in BGB-A317_Study_001 were fatigue 
(12.8%), rash (7.7%), nausea (6.8%), diarrhea (6.6%), and hypothyroidism (4.8%). The ≥ Grade 3 related 
TEAEs occurring in 2 or more patients were pneumonitis (6 patients, 1.4%); colitis and alanine 
aminotransferase (ALT) increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate 
aminotransferase (AST) increased (3 patients each, 0.7%); and diarrhea, gamma-glutamyltransferase 
(GGT) increased, and diabetic ketoacidosis (2 patients each, 0.5%). All other events occurred in single 
patients. Lastly, 18 patients (4.1%) experienced an infusion-related reaction; all were mild/moderate in 
severity.  
Preliminary efficacy 
For patients in Phase 1a (n=116, evaluable), there were 20 patients with a confirmed response and 
42 patients with a best overall response of SD.  
For patients in Phase 1b (n=286 evaluable), a total of 26 patients had a confirmed response. Additionally, 
there were 101 patients with a best overall response of stable disease (SD).  
1.3.4.2. 
Study BGB-A317-102 (Data cut off 28 August 2017)  
This Phase 1-2 study was a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.  
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of the 
population was male, and 100.0% of patients were Asian (Chinese). The median number of prior anti-
cancer therapy regimens was 2 (range: 0 to 9). The median treatment exposure duration was 1.78 months 
(range: 0 to 8.0) and the median study follow-up duration was also 1.78 months (range: 0.0 to 8.0). As of 
28 August 2017, there were 113 patients (91.9%) on study in Study BGB-A317-102. 
Preliminary Safety 
Of the 123 total patients in the Safety Population for Study BGB-A317-102, 69 (56.1%) experienced at 
least 1 TEAE assessed as related to tislelizumab by the Investigator and 10 (8.1%) were ≥ Grade 3 in 
severity. The most commonly TEAEs were AST increased (20 patients, 16.3%), ALT increased 
(17 patients, 13.8%), and blood bilirubin increased and anemia (13 patients each, 10.6%). The ≥ Grade 3 
related TEAEs occurring in 2 or more patients were AST increased (3 patients, 2.4%) and ALT increased 
(2 patients, 1.6%). All other events occurred in single patients including a case of retinal detachment 
(Grade 4). 
Preliminary efficacy data are not yet available. 


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1.3.4.3. 
Immune-related Reactions  
In patients treated with tislelizumab monotherapy, the following immune-related adverse events (irAEs) 
were observed: 
• 
Acute hepatitis and abnormal liver function have been reported, including 1 patient with fatal 
hepatitis. Additionally, 3.2% of patients experienced treatment-related abnormal liver function 
tests, and 1.4% of patients experienced immune-related hepatitis or hyperbilirubinemia. 
• 
Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal pneumonitis.  
• 
Colitis has been reported in approximately 2% of patients treated. Diarrhea has been reported in 
6.6% of patients.  
• 
Endocrinopathies have been reported, diabetes mellitus (including hyperglycemia and 
ketoacidosis). In addition, thyroiditis, including thyrotoxicosis and hypothyroidism have been 
reported. Furthermore, hypophysitis has been reported in < 1% of patients treated.  
• 
Other immune-related events (<1% of patients with tislelizumab monotherapy except where 
noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); hemolytic anemia, 
nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, pancreatitis, stomatitis, uveitis, 
and dry eye (1.4%).  
Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and polymyositis was 
reported in 1 patient who received a single dose of tislelizumab, in combination with paclitaxel and 
cisplatin. The patient’s initial symptoms were dyspnea and tea-colored urine 2 weeks after starting 
treatment. Elevated urine and serum cardiac markers and skeletal muscle were reported. The patient died 
of multi-organ failure 6 days later.  
1.4. 
Study Rationales 
1.4.1. 
Rationale for BGB-A333 as a Monotherapy 
BGB-A333 is an anti-PD-L1 antibody. A large body of literature supports the role of PD-L1 in immune 
modulation of tumor progression. Several anti-PD-L1 antibodies have been recently approved for the 
treatment of several cancers. BGB-A333 is expected to provide similar clinical benefit as the approved 
anti-PD-L1 antibodies. 
1.4.2. 
Rationale for Combination of BGB-A333 and Tislelizumab in the Treatment of 
Advanced Solid Tumors 
Anti-PD-1 and anti-PD-L1 monotherapies have shown clinical benefit in a variety of cancers, although 
the response rates are still somewhat low in most tumor types. The goal of combination therapy is to 
improve clinical response rate and increase duration of response. The emerging scientific evidence 
supporting the potential benefit of this combination is summarized below.  
The mechanisms of action of anti-PD-1 and anti-PD-L1 are different albeit with overlapping elements. 
Anti-PD-1 (such as tislelizumab) blocks PD-1 binding to PD-L1 and PD-L2, thus inhibiting 
PD-1-mediated negative signaling in T-cells. Besides binding to PD-1, PD-L1 also interacts with B7-1 
(also known as CD80) and this interaction can also exert inhibitory effects on immunity (Butte 2007). In 


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addition, a recent study by Hui et al. has demonstrated that CD28 is a primary target for PD-1-mediated 
immune inhibition (Hui 2017). PD-L1 inhibitors block the interaction between PD-L1 and CD80 (B7-1), 
which in turn releases inhibitory signals to T-cells, enhances T-cell expansion and prevents T-cell energy 
induction (Park 2010). Therefore, combination of anti-PD-1 and anti-PD-L1 antibodies can potentially 
elicit stronger antitumor immunity through blockade of multiple complementary immune-suppressive 
signals in tumor microenvironments. 
Several preclinical studies have demonstrated potential synergy between anti-PD-1 and anti-PD-L1 
antibodies. In the mouse MCA205 sarcoma model, combination of anti-PD-1 and anti-PD-L1 antibodies 
showed stronger tumor growth inhibition effect than administration of anti-PD-1 antibody alone 
(Hamid 2016) (Figure 1). In a recent study, mouse tumor models of anti-PD-1 sensitivity (MC38 tumor) 
and anti-PD-1 resistance (AT3 tumor) were compared (Ngiow 2015) (Figure 2). Administration of an 
anti-PD-1 antibody significantly increased PD-L1 expression on intratumor T-cells and myeloid cells in 
both anti-PD-1 sensitive and resistant tumors. However, the expression level of PD-L1 in anti-PD-1 
resistant tumors remained lower than anti-PD-1 sensitive tumors at all times (Ngiow 2015). In the 
anti-PD-1 resistant tumor model (AT3), anti-PD-L1 antibody alone or in combination with anti-PD-1 
antibodies suppressed the tumor growth. Thus, the anti-PD-L1 antibody might be an effective therapy to 
treat PD-1 resistant tumors. 
Figure 1. Combination of PD-1 and PD-L1 in Mouse MCA205 Sarcoma Model (Hamid 
2016) 
 
 


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Figure 2. Combination of PD-1 and PD-L1 inPD-1 resistant model (AT3 Tumor) (Ngiow 
2015) 
 
 
Results from an ongoing Phase 1 study of combination of MEDI0680 (an anti-PD–1 antibody) with 
durvalumab (an anti-PD-L1 antibody) showed an acceptable safety profile with evidence of antitumor 
activity in patients with advanced malignancies (Hamid 2016). In particular, in higher dose cohorts 
(10 to 20 mg/kg) of MEDI0680, objective response rate (ORR) was 50% (n=14). One CR was observed 
in urothelial carcinoma and 6 PRs were observed in mixed tumor types including RCC (3 PR), NSCLC 
(2 PR) and HNSCC (1 PR). These provide preliminary clinical evidence that the combination of PD-1 and 
PD-L1 blockers are well tolerated with notable antitumor activity. 
1.4.3. 
Rationale for Selection of BGB-A333 Starting Dose 
1.4.3.1. 
Compartmental Pharmacokinetic Model 
BGB-A333 has demonstrated a favorable toxicology and safety pharmacology profile in nonclinical 
studies. Early clinical development of BGB-A333 will be conducted in patients who have advanced 
cancer and progressed after standard-care treatment.  
The relevant species for preclinical safety evaluation is cynomolgus monkey, because BGB-A333 binds 
to and is pharmacologically active towards PD-L1 in cynomolgus monkey, but does not bind to mouse. 
The Kd for BGB-A333 binding to cynomolgus monkey PD-L1 is similar to that for human, whereas the 
binding to mouse PD-L1 is not detectable. 
Two studies (P16-050-YD, P16-050-CD) were conducted in cynomolgus monkeys to assess the PK and 
TK of BGB-A333. Three pharmacology studies were conducted in xenograft (A431, SK-MES-1) or 
syngeneic (CTG26WT) mouse tumor models to assess the pharmacodynamics (PD) of BGB-A333 and a 
surrogate PD-L1 antibody (Ab161) respectively. A PK/PD model was developed to describe the kinetics 
of BGB-A333 using PK data from cynomolgus monkeys and PD data (tumor growth inhibition) from the 
mouse studies. 


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A 2 -compartmental model describes the PK of BGB-A333. In this model, the dose was administered into 
the central compartment, from which elimination was modeled as occurring in parallel, by a first-order 
linear clearance pathway, presumably mediated by the reticuloendothelial system, and a nonlinear 
pathway, presumably by target-mediated clearance. 
PK parameters were derived from the serum concentration-time profiles of BGB-A333 from different 
dose regimens in TK studies which were conducted in cynomolgus monkeys (P16-050-YD, 
P16-050-CD). Vmax (the maximum elimination rate) and km (the serum BGB-A333 concentration at 
which BGB-A333 is eliminated at 50% of Vmax) characterized the nonlinear target-mediated clearance. 
The estimated nonlinear clearance is characterized by Vmax (0.317 mg/kg/day) and km (and 5.45 µg/mL), 
respectively. The linear clearance was estimated to be 6.39 mL/kg/day, which is consistent with the 
clearance of cynomolgus monkey reported in the literature (Deng 2011). The results demonstrated that the 
2-compartment model with linear and nonlinear clearance in parallel adequately described the PK profiles 
of BGB-A333 in cynomolgus monkey. 
1.4.3.2. 
Pharmacologically Active Dose of BGB-A333 
The minimum efficacious dose was determined by the mouse tumor models (A431, SK-MES-1, and 
CT26WT). Various weekly doses of BGB-A333 were associated with tumor growth inhibition in 
xenograft mouse models. The dose of 3 mg/kg weekly was determined to be the minimum effective dose 
with significant tumor growth inhibition, which was converted to human equivalent dose (HED) as 
approximately 3 mg/kg (FDA guidance), and with model-predicted efficacious trough levels of 
approximately 27 μg/mL.  
The PK parameters derived from monkeys were allometrically scaled to obtain the human PK parameters. 
Based on km, the nonlinear target-mediated clearance pathway is largely saturated at clinically relevant 
doses, and the nonspecific linear clearance pathway mediated by reticuloendothelial system becomes the 
major determinant for BGB-A333 clearance. The linear clearance of BGB-A333, 0.212 L/day (for 70 kg 
subject) and steady state volume of distribution of 5.95 L were subsequently used to simulate the 
multiple-dose PK profiles in human subjects (Figure 3). The projected steady state T½ of BGB-A333 in 
human is approximately 20 days. 




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Table 2. 
Predicted Safety Margins 
Proposed  
Human Doses 
Predicted Steady 
State AUCτ 
(µg·d/mL) 
Predicted Steady 
State Cmax  
(µg/mL) 
Safety Margin 
AUC 
Cmax 
450 mg  
Q3W 
2030 
202 
11.6 
15.9 
900 mg  
Q3W 
4146 
408 
5.68 
7.89 
1350 mg 
Q3W 
6262 
613 
3.76 
5.25 
1800 mg  
Q3W 
8378 
819 
2.81 
3.93 
Abbreviations: Q3W = every 3 weeks; AUCτ: area under the serum concentration-time curve within the 
interval; AUC-based safety margin = AUC14,cyno,Day71 × 
3
2  ÷ AUC21,human,SS = 15708.8 µg∙day/mL × 
3
2  ÷ 
AUC21,human,SS; Cmax = calculated or observed maximum serum concentration of steady state;  
Cmax,cyno,Day71 ÷ Cmax,human,SS = 3221.7 mg/mL ÷ Cmax,human,SS  
Following multiple doses of 450 mg IV BGB-A333 Q3W, this dosing regimen is predicted to produce: 
• 
An AUC with a 11.6-fold safety margin relative to the observed exposure in cynomolgus 
monkeys and a Cmax with a 15.9-fold safety margin relative to the observed Cmax in cynomolgus 
monkeys, based on the NOAEL of 100 mg/kg IV BGB-A333 Q2W (total 7 doses) in Study 
P16-050-CD 
• 
A 2.81-fold and 3.93-fold safety margin on AUC and Cmax, respectively, relative to the highest 
dose, 1800 mg IV Q3W, based on a NOAEL of 100 mg/kg IV BGB-A333 Q2W (total 7 doses) in 
Studies P16-050-CD 
A fixed dose regimen is chosen to reduce dosing errors and to ensure ease of preparation. Published data 
shows that PK variability is similar for fixed dose dosing regimens and body weight-based dose regimens 
(Zhang 2011; Wang 2009). The 3-weekly schedule is chosen based on the projected steady state t½ of 
BGB-A333 in humans (20 days) and maintained steady state trough levels above minimum efficacious 
level. This selection of dose range will allow for optimal characterization of the BGB-A333 PK/PD and 
safety. 
The Safety Follow-up Period is determined based on the predicted PK profile of proposed doses of 
BGB-A333. The Follow-up Period is anticipated to be at minimum 5 times the elimination half-life of 
compounds with a linear PK; the serum half-life of BGB-A333 is estimated to be 20 days. A 90-day 
follow-up time is chosen to allow for adequate safety coverage as the highest dose of BGB-A333 
(1800 mg IV) will fall below the sub-therapeutic level. 
1.4.4. 
Rationale for Selection of Tislelizumab Dose 
The PK, safety, and efficacy data obtained from FIH 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 IV Q3W was selected for further evaluation. 


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Rates of treatment-related AEs and serious adverse events (SAEs) observed in patients receiving 2 mg/kg 
and 5 mg/kg Q2W and Q3W 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 Q2W 
ranged between 10% and 15%, compared to a range of 15% to 38% for patients treated at 2 mg/kg and 
5 mg/kg Q3W. 
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).  
Additionally, no unexpected treatment-related AEs occurred in the 200 mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n = 13), 3 patients (23%) had a best overall response (BOR) of partial response 
(PR), 4 patients (31%) had a BOR of stable disease (SD), and 6 patients (46%) had a BOR of progressive 
disease (PD). Therefore, clinical activity with a manageable and tolerable safety profile is expected to be 
maintained in patients receiving tislelizumab 200 mg Q3W. 
In conclusion, tislelizumab 200 mg Q3W is the recommended initial dose for combination with 
BGB-A333. Additional dosing regimens may be explored.  
1.5. 
Benefit-Risk Assessment 
Urothelial carcinoma is the ninth most common cancer overall worldwide. Platinum-based chemotherapy 
is the standard of care in previously untreated patients with metastatic urothelial carcinoma, and is 
associated with an overall survival of around 9–15 months (von der Maase 2005, De Santis 2012). The 
prognosis for patients who relapse after platinum-based chemotherapy is poor, with median survival 
ranging from 5 to 7 months (Bellmunt 2009). Anti-PD-L1 agents (atezolizumab, durvalumab and 
avelumab) showed good tolerability in this patient population and the objective response rate is higher in 
patients with PD-L1 expression (Hahn 2017, Powles 2017, and Apolo 2017).  
More than 500 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 4 irAEs have been observed, 
which are generally reversible and manageable with study drug interruption and/or steroid treatment. For 
further discussion on safety profile of tislelizumab, please refer to the tislelizumab IB. 
Given the unmet medical need in patients with advanced UC, the benefit/risk assessment based on 
available tislelizumab Phase 1 data and the publication from other PD-1 or PD-L1 inhibitors is considered 
favorable.  
A Safety Monitoring Committee (SMC) will be established and will review regularly monitor the safety 
and activity of BGB-A333 alone and in combination with tislelizumab. SMC will review all available 
safety, efficacy, PK and exploratory data and make recommendation on dose selection and safety 
management throughout the study. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives for Phase 1A (Dose Escalation for BGB-A333 Monotherapy) and 
Phase 1B (Dose Confirmation for BGB-A333 and Tislelizumab Combination) 
2.1.1. 
Primary Objectives 
• 
To assess the safety and tolerability of BGB-A333 alone and in combination with 
tislelizumab in patients with advanced solid tumors 
• 
To determine the MTD, if any, and RP2D for BGB-A333 alone and in combination with 
tislelizumab 
2.1.2. 
Secondary Objectives 
• 
To assess the preliminary antitumor activity of BGB-A333 alone and in combination with 
tislelizumab 
• 
To characterize the PK of BGB-A333 alone and in combination with tislelizumab 
• 
To assess host immunogenicity to BGB-A333 alone and in combination with tislelizumab 
2.1.3. 
Exploratory Objectives 
•
•
•
2.2. 
Study Objectives for Phase 2A (BGB-A333 Monotherapy Dose Expansion) and 
Phase 2B (BGB-A333 and Tislelizumab Combination Dose Expansion) 
2.2.1. 
Primary Objectives 
• 
To assess ORR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
of BGB-A333 alone and in combination with tislelizumab in patients with selected tumor 
types 
2.2.2. 
Secondary Objectives 
• 
To assess other tumor assessment outcomes (ie, duration of response [DOR], 
progression-free survival [PFS], and disease control rate [DCR]) per RECIST v1.1 
• 
To characterize safety and tolerability of BGB-A333 alone and in combination with 
tislelizumab 
• 
To characterize the PK of BGB-A333 alone and in combination with tislelizumab 
• 
To assess host immunogenicity to BGB-A333 and tislelizumab 
2.2.3. 
Exploratory Objectives 
• 


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• 
• 
2.3. 
Study Endpoints for Phase 1 
2.3.1. 
Primary Endpoints 
• 
Safety and tolerability: The safety of BGB-A333 alone and in combination with 
tislelizumab will be assessed throughout the study by monitoring AEs and SAEs per the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCI-CTCAE Version 4.03, relevant physical examination, electrocardiograms (ECGs) 
and laboratory assessments as needed 
• 
The MTD, if any, and RP2D for BGB-A333 alone and in combination with tislelizumab 
will be determined based on safety, tolerability, PK, preliminary efficacy, and other 
available data 
2.3.2. 
Secondary Endpoints 
• 
Efficacy evaluations: ORR, DOR, and DCR will be determined by investigators based on 
RECIST version 1.1  
 
ORR is defined as the proportion of patients who had confirmed complete 
response (CR) or partial response (PR) assessed by investigator using RECIST 
version 1.1. ORR and its 95% confidence interval (CI) will be summarized in the 
Safety Population and Efficacy Evaluable Population 
 
DOR is defined as the time from the first determination of an objective response 
per RECIST version 1.1, until the first documentation of progression or death, 
whichever occurs first 
 
DCR is defined as the proportion of patients with best overall response of CR, 
PR and SD. It will be summarized similarly as ORR 
• 
PK: Individual BGB-A333 and tislelizumab concentrations and PK parameters will be 
tabulated by dose cohort 
• 
Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be 
assessed by summarizing the number and percentage of patients by dose cohort who 
develop detectable antidrug antibodies 
2.3.3. 
Exploratory Endpoints 
• 
• 
• 


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2.4. 
Study Endpoints for Phase 2 
2.4.1. 
Primary Endpoint 
• 
Efficacy evaluations: ORR will be determined by investigators based on RECIST 
version 1.1. The ORR is defined as the proportion of patients who had confirmed CR or 
PR assessed by investigator using RECIST version 1.1. ORR and its 95% CI will be 
summarized in the Safety Population and Efficacy Evaluable Population  
2.4.2. 
Secondary Endpoints 
• 
DOR, PFS, and DCR will be determined by investigators based on RECIST version 1.1 
o PFS is defined as the time from the date of the first dose of study drug(s) to the date 
of the first documentation of disease progression assessed by investigator using 
RECIST v1.1 or death, whichever occurs first 
• 
Safety and tolerability: The safety of BGB-A333 alone and in combination with 
tislelizumab will be assessed throughout the study by monitoring AEs and SAEs per 
NCI-CTCAE Version 4.03, relevant physical examination, ECGs, and laboratory 
assessments as needed 
• 
PK: Individual concentrations and PK parameters of BGB-A333 and tislelizumab 
• 
Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be 
assessed by summarizing the number and percentage of patients who develop detectable 
ADAs 
2.4.3. 
Exploratory Endpoints 
 
•
•
•


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design  
This is an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. The study design 
schematic is presented in Figure 4. For all study procedures see Section 7 and Appendix 1. 
This study consists of the following phases: 
• 
Phase 1A (BGB-A333 dose escalation): approximately 3-5 dose levels will be tested in patients 
with advanced solid tumors. Additional dose levels or dosing regimens could be tested if needed. 
The modified 3+3 design will be used in the dose escalation. At least 6 evaluable patients should 
be enrolled at the MTD level, the RP2D level or at the highest dose level tested if MTD is not 
reached 
• 
Phase 1B (BGB-A333 and tislelizumab dose confirmation): a cohort of approximately 6 patients 
with solid tumors will be treated with BGB-A333 and tislelizumab (200 mg, Q3W, IV). The 
SMC will make a recommendation on the selection of BGB-A333 dose based on available safety, 
efficacy, PK and exploratory data from Phase 1A. If the initial dose combination is deemed not 
tolerated, additional cohorts of patients may be enrolled to evaluate lower doses or alternative 
dosing regimens of BGB-A333 and tislelizumab 
• 
Phase 2A (BGB-A333 dose expansion): approximately 20 patients with UC will be enrolled. In 
addition, Sponsor may consider other tumor types including but not limited to NSCLC, RCC, 
SCCHN, GC, MSI-high cancer, etc. The eligibility criteria for patients with the additional tumor 
types will be defined in future protocol amendments based upon emerging data 
• 
Phase 2B (BGB-A333 and tislelizumab dose expansion): approximately 20 patients with UC will 
be enrolled. In addition, Sponsor may consider other tumor types including but not limited to 
NSCLC, RCC, SCCHN, GC, MSI-high cancer, etc. The eligibility criteria for patients with the 
additional tumor types will be defined in future protocol amendments based upon emerging data 
All patients will receive study drug until 1) they are no longer considered to be achieving clinical benefit, 
2) unacceptable toxicity, or 3) withdrawal of informed consent.  
In Phase 1A (BGB-A333 monotherapy), if patients progress on BGB-A333 without other safety concerns, 
these patients may be treated with a higher dose of BGB-A333 that is deemed to be well tolerated by 
SMC. The decision to modify the dose of BGB-A333 must be discussed with the sponsor’s medical 
monitor and documented in the study records. 
In Phase 1A and Phase 2A (BGB-A333 monotherapy), if patients progress on BGB-A333 monotherapy 
without other safety concerns, these patients may receive combination of BGB-A333 and tislelizumab at 
doses that are deemed to be well tolerated by SMC. The decision to add tislelizumab to patients treated 
with BGB-A333 alone must be discussed with the sponsor’s medical monitor and documented in the 
study records. 


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Figure 4. 
Study Schema 
 
Abbreviations: GC = gastric cancer; NSCLC = non-small cell lung carcinoma; UC = urothelial carcinoma; RCC = 
renal cell carcinoma; SCCHN = squamous cell carcinoma of the head and neck; MSI = microsatellite instability-
high; Q3W = every 3 weeks; TBD = to be determined. 
3.1.1. 
Phase 1A (BGB-A333 Dose Escalation) 
For Phase 1A (BGB-A333 dose escalation), at least 3 patients evaluable for dose-limiting toxicity (DLT) 
assessment will be enrolled per dose level. Dose escalation will proceed to the next dose level if no DLT 
is observed in the first 3 DLT-evaluable patients. Otherwise, if a DLT has occurred, the cohort is 
expanded to at least 6 patients. If there is no additional DLT in the first 6 DLT-evaluable patients, dose 
escalation will continue to the next level. Dose escalation will stop when there are 2 or more DLTs in 6 
patients within the same dose level. If 2 or more DLTs are reported in 6 patients at a dose level, a 
minimum of 6 patients will be enrolled on the next lower dose level, or an intermediate dose level may be 
evaluated if recommended by the SMC. The MTD dose level is defined as the highest dose at which 
< 33% of the patients experience a DLT. At least 6 evaluable patients should be enrolled at the MTD 
level, the RP2D level or at the highest dose level tested if MTD is not reached. 


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DLTs will be assessed among evaluable patients within 21 days after the first dose of BGB-A333. For 
dose escalation decision, only DLTs occurring within the first 21 days will be evaluated. For 
determination of MTD and RP2D, clinically significant toxicities (eg, irAE) will also be considered.  
The SMC will review all available safety, efficacy, PK, and exploratory data and make a recommendation 
on dose escalation and dose selection for Phase 1B and Phase 2. 
3.1.2. 
Phase 1B (BGB-A333 and Tislelizumab Combination Dose Confirmation) 
After completion of Phase 1A, a cohort of approximately 6 patients with solid tumors will be treated with 
BGB-A333 and tislelizumab (200 mg, Q3W, IV). The SMC will make a recommendation on the selection 
of BGB-A333 dose based available safety, efficacy, PK, and exploratory data.  
• 
If 2 or more DLTs are reported in these 6 patients, a minimum of 6 patients will be enrolled to a 
lower dose level (DL-1) if recommended by an SMC 
• 
Similarly, if 2 or more DLTs are reported at DL-1, a minimum of 6 patients will be enrolled to a 
next lower dose level (DL-2) if recommended by an SMC 
The SMC will review all available safety, efficacy, PK, and exploratory data and make a recommendation 
on dose selection for Phase 2B. 
3.1.3. 
Phase 2A (BGB-A333 Dose Expansion) 
Approximately 20 patients with UC will be enrolled. In addition, Sponsor may consider other tumor types 
including but not limited to NSCLC, RCC, SCCHN, GC, MSI-high cancer, etc. The eligibility criteria for 
patients with the additional tumor types will be defined in future protocol amendments based upon 
emerging data.  
Eligible patients will receive BGB-A333 and tislelizumab that are deemed to be well tolerated in 
Phase 1A.  
3.1.4. 
Phase 2B (BGB-A333 and Tislelizumab Dose Expansion) 
Approximately 20 patients with UC will be enrolled. In addition, Sponsor may consider other tumor types 
including but not limited to NSCLC, RCC, SCCHN, GC, MSI-high cancer, etc. The eligibility criteria for 
patients with the additional tumor types will be defined in future protocol amendments based upon 
emerging data. 
Eligible patients will receive BGB-A333 and tislelizumab that are deemed to be well tolerated in 
Phase 1B.  
3.2. 
Enrollment Priority 
The first priority is to enroll patients to Phase 1A. After completion of Phase 1A and the RP2D for 
BGB-A333 monotherapy has been determined, Phase 2A (patients with UC) and Phase 1B (advanced 
solid tumors) will be open for enrollment in parallel. Phase 2B will be open after completion of Phase 1B.  


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3.3. 
Study Periods 
This study consists of the following 3 periods. See Section 7 and Appendix 1 for study procedures to be 
conducted in each period.  
3.3.1. 
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 (refer to Appendix 1 for details). Patients who are suspected to have serious respiratory 
concurrent illness or exhibit significant respiratory symptoms unrelated to underlying cancer will take a 
pulmonary function test (refer to Appendix 1 for details). Screening evaluations may be repeated as 
needed within the Screening Period; the investigator is to assess patient eligibility according to the latest 
screening assessment results. 
Archival tumor tissues (if available) must be collected for the purpose of biomarker analysis. If no 
archival samples are available, a fresh tumor biopsy at baseline is highly recommended. Refer to 
Section 7.6 for details. 
3.3.2. 
Treatment Period 
After completing all screening activities, patients confirmed to be eligible by the sponsor will be treated 
with BGB-A333 alone or in combination with tislelizumab. 
All patients will receive study drug until 1) they are no longer considered to be achieving clinical benefit, 
2) unacceptable toxicity, or 3) withdrawal of informed consent.  
The End of Treatment (EOT) Visit is conducted when the Investigator determines that study drug(s) will 
no longer be used. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 
7 days before the End of Treatment Visit, these tests need not be repeated. Tumor assessment is not 
required at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last 
assessment. 
An optional biopsy will be taken at the end of treatment visit for patients who have confirmed disease 
progression during the study from accessible tumor sites to obtain samples to explore resistance 
mechanism (written informed consent is required prior to obtaining fresh tumor biopsies). 
3.3.3. 
Safety Follow-Up Period 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the Safety 
Follow-up Visit (to occur within 30 [±7 days] after last dose of the study drug(s) or before initiation of a 
new anticancer treatment, whichever occurs first). In addition, telephone contacts with patients should be 
conducted to assess irAEs and concomitant medications (if appropriate, ie, associated with an irAE or is a 
new anticancer therapy) at 60 days and 90 days (±14 days) after the last dose of study drug(s) regardless 
of whether or not the patient starts a new anticancer therapy. 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, or the patient withdraws consent. 


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All adverse events, including SAEs, will be collected as described in Section 8.7.  
The End of Treatment visit at which a response assessment showed progressive disease, resulting in 
patient discontinuation, may be used as the Safety Follow-up visit, provided that it occurred 30 days (± 7 
days) after the last study treatment. Patients who discontinue study treatment prior to disease progression 
will have their tumors assessed as outlined in Section 7.4. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
3.4. 
Patient Discontinuation and Study Completion 
3.4.1. 
Patient Discontinuation from Study Treatment 
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients who 
discontinue study treatment for reasons other than disease progression, should be followed for 
assessments of antitumor activity and safety. 
Every effort should be made to obtain information on patients who discontinue the study treatment. The 
primary reason for discontinuation from the study treatment should be documented on the appropriate 
eCRF.  
Patients must discontinue study treatment for reasons, which include, but are not limited to, the following:  
• 
Patient withdrawal of consent 
• 
Pregnancy 
• 
Any medical condition that the investigator or sponsor determines may jeopardize the patient’s 
safety, if he or she were to continue the study treatment  
• 
Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal medicine and 
Chinese patent medicines] for the treatment of cancer) 
• 
Patient noncompliance 
3.4.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) 
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• 
Patient withdrawal of consent 
• 
Death 
• 
Lost to follow up 
• 
Patients have completed all study assessments 
3.4.3. 
Study Completion or Termination 
The study completion is defined as the timepoint when the final data for the study were collected after the 
last patient has made the final visit to the study location.  


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The sponsor has the right to terminate this study at any time. Reasons for terminating the study early may 
include, but are not limited to, the following:  
• 
The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to patients  
• 
Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this be 
necessary, prematurely discontinued patients should be seen as soon as possible for an EOT visit and 
Safety Follow-up visit. 
The investigators may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs/Independent Ethics Committees (IECs) of the early termination of the 
trial. 
The sponsor has the right to close a site at any time. The site will be notified of the decision in advance. 
Reasons for closing a site may include but are not limited to the following:  
• 
Excessively slow recruitment  
• 
Poor protocol adherence  
• 
Inaccurate or incomplete data recording  
• 
Good Clinical Practice (GCP) noncompliance 
• 
Study activity is completed (ie, all patients have completed and all obligations have been 
fulfilled).  
3.5. 
DLT Definition 
All toxicities or AEs will be graded according to the NCI-CTCAE Version 4.03. The occurrence of any of 
the following toxicities within 21 days after the first dose of BGB-A333 if judged by the Investigator as 
related to BGB-A333 will be considered a DLT.  
Hematologic: 
1. Grade 4 neutropenia lasting >7 days 
2. Grade 3 febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a single 
temperature of 38.3oC or a sustained temperature of 38oC for >1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding 
5. Grade 4 thrombocytopenia 
6. Grade 4 anemia (life-threatening) 
Non-hematologic: 
1. Grade 4 or above toxicity 


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2. Grade 3 toxicity lasting more than 7 days despite optimal supportive care 
Note: The following AEs will not be considered as DLTs: 
• 
Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• 
Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors) 
• 
Grade 3 rash 
• 
Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical sequelae (eg, 
LDH)  
In addition, clinically important or persistent toxicities that are not included above may also be considered 
a DLT following review by SMC.  
Patients who received <two-thirds (67%) of the assigned dose of BGB-A333 (eg, because the infusion 
had to be discontinued due to an infusion reaction) and did not experience a DLT will not be taken into 
account in the assessment of the overall DLT rate for the particular dose level. 


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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 comply with the requirements of 
the study 
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the jurisdiction in which 
the study is taking place) 
3. For Phase 1 only: patients with histologically or cytologically confirmed advanced or metastatic, 
unresectable solid tumors who have progressed during or after standard therapy or for which 
treatment is not available, not tolerated or refused 
4. For Phase 2 only: 
a. Arm 1: Patients with locally advanced and metastatic urothelial carcinoma who have 
progressed during or after treatment with platinum-based chemotherapy or who could not 
tolerate platinum-based chemotherapy.  
b. Sponsor may consider other tumor types including but not limited to NSCLC, RCC, SCCHN, 
GC, MSI-high cancer, etc. The eligibility criteria for patients with these tumor types will be 
defined in future protocol amendments 
5. Patient must have at least one measurable lesion as defined per RECIST v1.1 
Note: The target lesion(s) selected have not been previously treated with local therapy or the target 
lesion(s) selected that are within the field of prior local therapy have subsequently progressed as 
defined by RECIST v1.1. 
6. Has Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 
7. Has adequate organ function as indicated by the following laboratory values: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 75 × 109/L, hemoglobin 
≥ 90 g/L. Note: Patients must not have required a blood transfusion or growth factor support 
≤ 14 days before sample collection 
b. Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or estimated GFR ≥ 60 mL/min/1.73 m2 
by Chronic Kidney Disease Epidemiology Collaboration equation (Appendix 7) 
c. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN 
d. Serum total bilirubin ≤ 1.5 X ULN (total bilirubin must be < 3 X ULN for patients with Gilberts 
syndrome)  
e. For hepatocellular carcinoma (HCC) patients only, patient must meet the Child-Pugh A 
classification for liver function as assessed within 7 days before the first dose of study drug(s) 
(Appendix 11). 
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 drug (s), and have a negative 
urine or serum pregnancy test ≤ 7 days of the first dose of study drug(s)  


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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 drug(s) 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible to enroll  
1. Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal findings or 
with confirmed brain metastases are eligible for enrollment provided they are asymptomatic and 
radiologically stable without the need for corticosteroid treatment for at least 4 weeks prior to the first 
dose of study drug(s).  
2. Active autoimmune diseases or history of autoimmune diseases that may relapse 
Note: Patients with the following diseases are not excluded and may proceed to further screening: 
a. Controlled type 1 diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering factors 
3. Any active malignancy ≤ 2 years before the first dose of study drug(s), 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) 
4. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before administration of 
study drug 
Note: Patients who are currently or have previously been on any of the following steroid regimens are 
not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)  
b. Topical, ocular, intra-articular, intranasal, or inhalational 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) 
5. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management  
6. With significant pulmonary disease (ie, chronic obstructive pulmonary disease [COPD], emphysema 
or chronic bronchitis) or with history of interstitial lung disease, noninfectious pneumonitis or 
uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc. 
7. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral 
therapy, including tuberculosis infection, etc. Note: antiviral therapy is permitted for patients with 
hepatocellular carcinoma 
8. A known history of HIV infection 
9. A known history of HBV or HCV infection, except for patients with HCC 


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Note: For patients with HCC only: patients with detectable HBsAg or detectable HCV antibody at 
screening must be excluded unless their HBV DNA titers < 500 IU/mL or HCV RNA polymerase 
chain reaction test is negative respectively. In addition, patients with detectable 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 the first dose of study drug (s) and should continue 
treatment for 6 months after the last dose of study drug(s). 
10. Any major surgical procedure ≤ 28 days before the first dose of study drug(s) 
11. Prior allogeneic stem cell transplantation or organ transplantation 
12. Any of the following cardiovascular criteria: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, 
≤ 28 days before the first dose of study drug(s) 
b. Symptomatic pulmonary embolism ≤ 28 days before the first dose of study drug(s) 
c. Any history of acute myocardial infarction ≤ 6 months before the first dose of study drug(s) 
d. Any history of heart failure meeting New York Heart Association Classification (NYHA) III or 
IV (Appendix 6) ≤ 6 months before the first dose of study drug(s) 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of 
study drug(s) 
f. Any history of cerebrovascular accident ≤ 6 months before the first dose of study drug(s) 
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg 
despite anti-hypertension medications ≤ 28 days before the first dose of study drug(s) 
h. Any episode of syncope or seizure ≤ 28 days before the first dose of study drug(s) 
13. A history of severe hypersensitivity reactions to other mAbs 
14. Has received any chemotherapy, radiotherapy, immunotherapy (eg, interleukin, interferon, thymoxin, 
etc.) or any investigational therapies within 28 days or 5 half-lives (whichever is shorter) of the first 
study drug (s) administration. 
Has received any Chinese herbal medicine or Chinese patent medicines used to control cancer within 
14 days of the first study drug administration 
15. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline 
or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific 
laboratory abnormalities) 
16. Was administered a live vaccine ≤ 4 weeks prior to study drug administration 
Note: seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal 
vaccines are live vaccines, and are not allowed 
17. Underlying medical conditions, laboratory abnormality, or alcohol or drug abuse or dependence that, 
in the investigator’s opinion, will be unfavorable for the administration of study drug or affect the 
explanation of drug toxicity or adverse events; or insufficient compliance during the study according 
to investigator’s judgement 
18. Concurrent participation in another therapeutic clinical trial 
19. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody (or any 
other antibody targeting T cell co-stimulation pathways). 


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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling 
5.1.1. 
BGB-A333 
BGB-A333 is a mAB formulated for IV injection in a single-use glass vial (USP type I), containing a total 
of 450 mg antibody in 18 mL of isotonic solution. BGB-A333 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 label will include at a minimum, drug name, dose strength, contents, sponsor, protocol number, lot 
number, directions for use, storage conditions, caution statements, retest or expiry date, and space to enter 
the patient number and name of investigator. 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. BGB-A333 drug 
product does not contain any preservatives and must be stored at temperatures between 2 oC and 8oC. 
Protect from light until time to use. Observations to date support drug stability for at least 18 months 
under this storage condition.  
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and disposal. 
Please also refer to the IB for other details regarding BGB-A333. 
5.1.2. 
Tislelizumab 
Tislelizumab is a mAB 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 label will include at a minimum, drug name, dose strength, contents, sponsor, protocol number, 
kit number, lot number, directions for use, storage conditions, caution statements, retest or expiry date, 
and space to enter the patient number and name of investigator. 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. Tislelizumab must be 
stored at temperatures between 2oC and 8oC and protected from light.  
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, Administration, and Compliance 
Planned dose levels for BGB-A333 and tislelizumab are provided in Table 3. All patients will be 
monitored continuously for AEs. Treatment modifications (eg, dose delay or discontinuation) will be 
based on specific laboratory and AE criteria, as described in Section 5.5. 


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Table 3. 
Planned Dose Levels for BGB-A333 and Tislelizumab 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of 
Treatment 
BGB-A333 
450 mg,  
900 mg, 
1350 mg, 
1800 mg 
(optional), 
2250 mg 
(optional) 
Every 3 weeks 
(additional dose levels or dosing 
regimens may be explored) 
Intravenous  
See Section 3.3.2 
Tislelizumab 200 mg 
Every 3 weeks 
(additional dose levels or dosing 
regimens may be explored) 
Intravenous  
See Section 3.3.2 
The initial dosing regimen for BGB-A333 and tislelizumab (in Phase 1B and Phase 2B only) will be 
administered on D1 of each 21-day cycle (ie, Q3W). Other dosing regimens may be explored based on 
safety, PK and antitumor activities observed in dose levels completed.  
BGB-A333 and tislelizumab will be administered by IV infusion through an IV line containing a sterile, 
non-pyrogenic, low-protein-binding filter. Specific instructions for product preparation and administration 
are provided in the Pharmacy Manual. BGB-A333 and tislelizumab must not be concurrently 
administered with any other drug (refer to Section 6). 
For BGB-A333 monotherapy (Phase 1A and Phase 2A), on C1D1, C2D1 and C3D1, the infusion of 
BGB-A333 will be delivered over 60 (± 5) minutes. After infusion of BGB-A333, patients must be 
monitored for at least 120 minutes in an area with resuscitation equipment and emergency agents.  
If BGB-A333 infusion is well tolerated in the first three cycles, on C4D1 and subsequent cycles, 
BGB-A333 may be administered over 30 (± 5) minutes and, after infusion of BGB-A333, patients must 
be monitored for at least 30 minutes in an area with resuscitation equipment and emergency agents. 
The infusion rate may be decreased or infusion may be stopped in the event of infusion-related reactions. 
See Section 8.7 for details.  
For BGB-A333 and tislelizumab combination arms (Phase 1B and Phase 2B), on C1D1 and C2D1, 
Tislelizumab will be administered first over 60 (± 5) minutes followed by the administration of 
BGB-A333 over 60 (± 5) minutes. After infusion of BGB-A333, patients must be monitored for at least 
120 minutes in an area with resuscitation equipment and emergency agents. 
If infusions of tislelizumab and BGB-A333 are well tolerated in the first two cycles, on C3D1, 
tislelizumab may be administered over 30 (± 5) minutes followed by the administration of BGB-A333 
over 60 (± 5) minutes and, after infusion of BGB-A333, patients must be monitored for at least 
120 minutes in an area with resuscitation equipment and emergency agents. 
If infusions of tislelizumab and BGB-A333 are well tolerated in the first three cycles, on C4D1 and 
subsequent cycles, tislelizumab may be administered over 30 (± 5) minutes followed by the 
administration of BGB-A333 over 30 (± 5) minutes and, after infusion of BGB-A333, patients must be 
monitored for at least 30 minutes in an area with resuscitation equipment and emergency agents. 


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The infusion rate may be decreased or infusion may be stopped in the event of infusion-related reactions. 
See Section 8.7 for details.  
Table 4. 
Administration of BGB-A333 and Tislelizumab and Monitoring Time 
Cycle 
BGB-A333 monotherapy 
BGB-A333 and Tislelizumab combination 
C1D1 
and 
C2D1 
• 
BGB-A333 infusion over 60 (± 5) 
minutes  
• 
Patient monitoring for at least 120 
minutes 
• 
Tislelizumab infusion over 60 (± 5) 
minutes  
• 
BGB-A333 infusion over 60 (± 5) 
minutes  
• 
Patient monitoring for at least 120 
minutes 
C3D1 
• 
BGB-A333 infusion over 60 (± 5) 
minutes;  
• 
Patient monitoring for at least 120 
minutes 
• 
Tislelizumab infusion over 30 (± 5) 
minutes  
• 
BGB-A333 infusion over 60 (± 5) 
minutes  
• 
Patient monitoring for at least 120 
minutes 
C4D1 
onwards 
• 
BGB-A333 infusion over 30 (± 5) 
minutes  
• 
Patient monitoring for at least 30 
minutes 
• 
Tislelizumab infusion over 30 (± 5) 
minutes  
• 
BGB-A333 infusion over 30 (± 5) 
minutes  
• 
Patient monitoring for at least 30 
minutes 
Abbreviations; C1D1 = Cycle 1, Day 1; C2D1 = Cycle 2, Day 1; C3D1 = Cycle 3, Day 1; C4D1 = Cycle 4, Day 1 
* The infusion rate may be decreased or infusion may be stopped in the event of infusion-related reactions. See 
Section 8.7 for details.  
Guidelines for dose modification, treatment interruption, or discontinuation and for the management of 
infusion-related reactions and irAEs are provided in detail in Section 5.4, Section 8.7.1, and Appendix 8. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and administration. 
5.3. 
Overdose of Tislelizumab and Incorrect Administration of BGB-A333 
Any overdose of tislelizumab (defined as ≥ 600 mg in a 24-hour period) or incorrect administration of 
BGB-A333 should be noted in the patient’s chart and on the study drug administration electronic case 
report form (eCRF).  


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Adverse events associated with an incorrect administration of study drug will be recorded on the adverse 
event eCRF. If an incorrect administration of study treatment takes place and adversely affects the 
patient’s safety, the sponsor or designee is required to be notified within 24 hours of awareness via 
SAE reporting process described in Section 8.6.2. Supportive care measures should be administered as 
appropriate. 
5.4. 
Dose Delay and Modification  
5.4.1. 
Dose Modification 
There will be no dose reduction for BGB-A333 or tislelizumab within a given patient in this study.  
In Phase 1A (BGB-A333 monotherapy), if patients progress on BGB-A333 without other safety concerns, 
these patients may be treated with a higher dose of BGB-A333 that is deemed to be well tolerated by 
SMC. The decision to modify the dose of BGB-A333 must be discussed with the sponsor’s medical 
monitor and documented in the study records. 
In Phase 1A and Phase 2A (BGB-A333 monotherapy), if patients progress on BGB-A333 monotherapy 
without other safety concerns, these patients may receive combination of BGB-A333 and tislelizumab at 
doses that are deemed to be well tolerated by SMC. The decision to add tislelizumab to patients treated 
with BGB-A333 alone must be discussed with the sponsor’s medical monitor and documented in the 
study records.  
5.4.2. 
Dose Delay 
Dose delays or interruptions less than 12 weeks will be permitted. The tumor assessment schedule will 
not be altered even if the administration of study drug(s) is delayed. 
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. 
Patients may temporarily suspend study treatment if they experience toxicity that is considered related to 
study drug(s) and requires a dose to be withheld. The patients should resume study drug treatment as soon 
as possible after the AEs recover to baseline or Grade 1 (whichever is more severe) within 12 weeks after 
last dose of study drug(s).  
If the patient is unable to resume study drug treatment within 12 weeks after the last dose of study drug, 
then the patient should be discontinued from study drug treatment. 
In case a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with sponsor medical monitor. 
Dose modification related to irAEs and infusion-related reactions are described in Appendix 8 and 
Section 8.7.1, respectively.  


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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, anti-diarrheals) and 
in a patient’s interest are allowed. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids. 
All concomitant medication received within 30 days before the first dose of study treatment and 30 days 
after the last dose of study treatment should be recorded. In addition, telephone contacts with patients 
should be conducted to assess irAEs and concomitant medications (if appropriate, ie, associated with an 
irAE or is a new anticancer therapy) at 60 and 90 days (±14 days) after the last dose of study drugs 
regardless of whether or not the patient starts a new anticancer therapy. 
Systemic corticosteroids given for the control of irAEs must be tapered gradually (see Appendix 8) and be 
at non-immunosuppressive 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.  
Bisphosphonates and RANK-L inhibitors are allowed for bone metastases if initiated prior to enrollment 
and at a stable dose. Bisphosphonates are permitted during the trial only for a nonmalignant indication. 
HBV or HCV treatment should be according to local guidelines. Anti-viral therapy given for prevention 
of HBV reactivation must be started 2 weeks prior to first dose of study drug(s) and continued for 6 
months after the last dose of study drug(s). 
Patients with active hepatitis B, defined as either detectable HBsAg or HBV DNA at baseline, must 
initiate treatment 2 weeks prior to the first dose of study drug(s) and continue until 6 months after the last 
dose of study drug(s).  Patients should continue effective antiviral treatment during the study to decrease 
potential viral re-activation risk.  Tenofovir and entecavir are recommended in the American Association 
for the Study of Liver Disease (AASLD) guideline because they lack resistance with long-term use 
(Terrault 2016; Chung 2015).  The Investigator may 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.   
Patients with active hepatitis C are not required to receive antiviral therapy.  However, patients with 
detectable HCV RNA and who are receiving treatment at screening should remain on continuous, 
effective antiviral therapy during the study.  Investigators may consider treatment with sofosbuvir alone 
or in combination with other antivirals following the AASLD guideline or the local guidelines as 
appropriate.  However, interferon-based therapy for either HBV or HCV is not permitted on study.  
Patients who are given antiviral therapy must initiate treatment at least 2 weeks prior to the first dose of 
study drug(s).   


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Palliative radiation therapy is permitted, but only for pain control or prophylaxis of bone fracture to sites 
of bone disease present at baseline provided the following criteria are met: 
• 
Repeat imaging demonstrates no new sites of bone metastases 
• 
The lesion being considered for palliative radiation is not a target lesion for RECIST v1.1 
• 
The case is discussed with sponsor medical monitor, who agrees that the conditions required to 
receive palliative radiation are met 
Whenever possible, these patients should have a tumor assessment of the lesion(s) before receiving the 
radiotherapy in order to rule out progression of disease. 
6.2. 
Prohibited or Restricted Concomitant Medications and Therapy 
The following medications are prohibited or restricted during the study: 
• 
Immunosuppressive agents (except to treat a drug-related AE) 
• 
Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or control a 
drug-related AE or for short-term use as prophylactic treatment 
• 
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, or 
standard or investigational agents [including Chinese herbal medicine and Chinese patent 
medicines] for the treatment of cancer) is not allowed 
• 
Radiation therapy except for palliative radiation therapy described in Section 6.1.1 
• 
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) 
• 
Herbal remedies with immune-stimulating properties (ie, mistletoe extract) or that are known to 
potentially interfere with liver or other major organ functions (ie, hypericin). Patients must notify 
the investigator of all herbal remedies used during the study 
• 
For patients with HCC only, patients should avoid alcohol completely and should avoid other 
addictive drugs during the study. Use of potentially hepatotoxic drugs in patients with impaired 
hepatic function should be carefully monitored. Patients must notify the investigator of all 
concurrent medications used during the study 
• 
Interferon-based therapy for either HBV or HCV is not permitted during the study 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant Medications 
The potential for drug-drug interaction between the study drugs (BGB-A333 and tislelizumab) and 
small-molecule drug products is very low, given BGB-A333 and tislelizumab are therapeutic mAB. 
Because BGB-A333 and tislelizumab are expected to be degraded into amino acids and recycle into other 
proteins, it is unlikely to have an effect on drug metabolizing enzymes or transporters. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely monitored for 
safety and tolerability throughout the study. All assessments must be performed and documented in the 
medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be available 
before any dosing) have been reviewed and found to be acceptable per protocol guidelines.  
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to the first dose of study drug(s). Patients 
who agree to participate will sign the ICF prior to undergoing any screening procedure (refer to 
Appendix 1 for details). Patients who are suspected or known to have serious respiratory concurrent 
illness or exhibit significant respiratory symptoms unrelated to underlying cancer should take a 
pulmonary function test (refer to Appendix 1 for details). Screening evaluations may be repeated as 
needed within the Screening Period; the investigator is to assess patient eligibility according to the latest 
screening assessment results.  
Results of standard of care tests or examinations performed prior to obtaining informed consent and 
≤ 28 days prior to the first dose of the study drug(s) may be used for the purposes of screening rather than 
repeating the standard of care tests unless otherwise indicated. 
Procedures conducted during the Screening Visit only are described in this section. For the description of 
other assessments that are conducted at Screening as well as throughout the study, refer to Safety 
Assessments (Section 7.3), Tumor and Response Evaluation (Section 7.4), Pharmacokinetic Assessment 
(Section 7.5) and Biomarkers (Section 7.6). The PK sampling schedule is shown in Appendix 1 (C-F).  
Rescreening under limited conditions (eg, when a patient narrowly misses a laboratory criterion and it is 
correctable and not due to rapidly deteriorating condition or disease progression) may be allowed after 
consultation with Sponsor medical monitor. Rescreening is allowed only once. 
7.1.1. 
Demographic Data and Medical History 
Demographic data will include age or date of birth, gender, and self-reported race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never); and all medications (eg, prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 30 days before the first dose of study drug(s).  
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. 


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7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer to 
Appendix 5 for contraception guidelines and definitions of “women of childbearing potential” and 
“no childbearing potential”. 
7.1.3. 
Informed Consent and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before performing 
any study-specific procedures. Informed consent forms for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility 
criteria before the first dose of study drug(s). The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
7.1.4. 
Pulmonary Function Tests 
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant 
respiratory symptoms unrelated to the underlying cancer will undergo pulmonary function testing which 
may include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
Screening period to assist the determination of suitability on the study. 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility 
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 a Treatment 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’s 
approval 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 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, 


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6) gastrointestinal, and 7) neurological systems. Any abnormality identified during screening will be 
graded according to NCI-CTCAE v 4.03 and recorded on the Medical History eCRF with appropriate 
disease/condition terms.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations will be 
performed. Changes from baseline will be recorded. New or worsened clinically significant abnormalities 
are to be recorded as adverse events on the Adverse Event eCRF. Refer to Section 8.3 regarding AE 
definitions and reporting and follow-up requirements. 
7.3.2.1. 
Ophthalmologic Examination 
Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) will be 
assessed by an appropriate specialist at Screening. Eye exam, visual acuity test, and optical coherence 
tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to 
obtaining written informed consent and within 28 days of the first dose of the study drug(s) may be used 
for the Screening evaluation. Patients will undergo repeat assessments by an appropriate specialist 
approximately every 15 weeks (± 7 days) during study treatment and a final assessment < 30 days 
(± 7 days) after the last dose of study treatment.  
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 (see Appendix 8). 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status  
Eastern Cooperative Oncology Group Performance Status (Appendix 3) will be assessed during the study.  
7.3.4. 
Laboratory Safety Test 
Local and/or central laboratory assessments on hematology, serum chemistry, coagulation, and urinalysis 
will be conducted, of which certain elements will be collected as specified in Appendix 2.  
If laboratory tests at screening are not performed within 96 hours prior to the administration of study 
drug(s) on C1D1, these tests should be repeated and reviewed within 72 hours before study drug(s) 
administration. Hematology and serum chemistry (including liver function tests) as specified in 
Appendix 2 should be performed weekly for the first 3 cycles and at the beginning of subsequent cycles. 
After Cycle 1, laboratory safety results should be reviewed within 72 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:  
• 
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 Q3W or 
monthly during treatment and at Safety Follow-up. A serum pregnancy test must be performed if 


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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. 
• 
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 Safety Follow-up 
Visit. 
7.3.5. 
Electrocardiograms 
A centralized ECG laboratory may be used in this study in selected study sites. Calibrated ECG machines 
will be provided to these sites and ECG collected from these sites will be reviewed centrally. In other 
sites, local ECG machines will be used.  
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.  
At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to 
determine the mean QTcF interval.  
7.3.6. 
Adverse Events 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 4.03 
(NCI-CTC, June 2010). Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6.  
7.3.7. 
Hepatitis B and C Testing 
In patients with HCC only, hepatitis serology and viral load will be tested at Screening.  Patients who 
have detectable HBsAg or HCV antibody at screening must not be enrolled unless HBV DNA titers < 500 
IU/mL or HCV RNA polymerase chain reaction test is negative respectively. Patients who have 
detectable HBV DNA at Screening will perform the viral load test every 4 cycles (ie, Day 1 of Cycle 5, 9, 
13, etc), at EOT visit, and when clinically indicated. 
In other patients, blood samples for hepatitis serology and viral load will be collected at Screening and 
may be tested if patients have hepatic AE (Grade ≥3) during the study. Testing will include HBV/HCV 
serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load assessment (HBV DNA and HCV 
RNA). 
7.4. 
Tumor and Response Evaluations 
Tumor imaging will be performed within 28 days prior to the first study treatment. 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 9 weeks (± 7 days) (for 
Q3W dosing) or every 8 weeks (± 7 days (for Q2W or Q4W dosing) in the first year and thereafter 
approximately every 12 weeks (± 7 days).  


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Screening assessments and each subsequent assessment must include computed tomography (CT) scans 
(with oral/IV contrast, unless contraindicated) or magnetic resonance imaging (MRI) of the chest, 
abdomen, and pelvis. Other known or suspected sites of disease must be included in the imaging 
assessments (neck, brain, etc). 
Tumor assessments must include CT scans (with oral/IV contrast, unless contraindicated) or MRI, with 
preference for CT, of the chest, abdomen, and pelvis. All measurable and evaluable lesions should be 
assessed and documented at the screening visit and reassessed at each subsequent tumor evaluation. The 
same radiographic procedure used to assess disease sites at Screening are 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. 
• 
Imaging of the brain (MRI or CT) at baseline (≤ 28 days of the first dose of study drug(s)) is 
required for all patients  
• 
If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed 
• 
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast diagnostic CT 
scan 
• 
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at Screening if clinically indicated. If bone metastases are present at Screening and 
cannot be seen on CT or MRI scans afterwards, TC-99m or NaF-PET bone scans should be 
conducted when a CR is suspected in target lesion. In addition, TC-99m or NaF-PET bone scans 
may be conducted when progression in bone is suspected 
• 
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 by the investigators using RECIST v1.1 (see Appendix 9). Additional 
information on new lesions will be collected according to iRECIST (see Appendix 10) and sponsor will 
derive tumor response using iRECIST as an exploratory assessment. 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 BGB-A333 and 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 at least 4 weeks later but not exceeding 8 weeks from the date of initial 


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documentation of PD. The following criteria must be met in order to continue study drug treatment in 
patients with suspected pseudoprogression:  
• 
Absence of clinical symptoms and signs of disease progression (including clinically significant 
worsening of laboratory values) 
• 
Stable ECOG performance status ≤ 1 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (eg, 
cord compression) that requires urgent alternative medical intervention 
• 
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform patients that this practice is not considered standard in the treatment of 
cancer 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed with the 
sponsor’s medical monitor and documented in the study records. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments following the original plan until the patient begins a 
subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to follow-up, 
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 and Antidrug Antibody Testing 
BGB-A333 and tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response will be closely monitored. Validated screening and confirmatory assays will be employed to 
detect ADAs at multiple time points throughout the study (see Appendix 1 [C-F]). An optional PK sample 
may be collected if a patient experiences an adverse event that requires understanding of drug exposure at 
the time of event. 
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy (Koren et al 2008; 
Worobec and Rosenberg 2004a; Worobec and Rosenberg 2004b) to characterize ADA responses to 
BGB-A333 and tislelizumab in support of the clinical development program. 
The following assessments will be performed at a central laboratory:  
• 
ADA assays: serum samples will be tested for the presence of ADAs to BGB-A333 and 
tislelizumab using a validated immunoassay.  
• 
PK assay: serum samples will be assayed for BGB-A333 and tislelizumab concentration with use 
of a validated immunoassay. 
Shipping, storage, and handling of samples for the assessment of BGB-A333 and tislelizumab PK and 
ADA assays will be managed through a central laboratory. Instruction manuals and supply kits will be 
provided for all central laboratory assessments.  


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7.6. 
Biomarkers 
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue for the 
assessment of biomarkers will be managed through a central laboratory. Refer to the laboratory manual 
for details of sample handling.  
Archival tumor tissues (formalin-fixed paraffin-embedded block [FFPE] with tumor tissue or 
approximately 15 [≥7] unstained slides) need to be sent to central laboratory for central 
immunohistochemistry assay of PD-L1 status. In addition to PD-L1 expression, other exploratory 
predictive biomarkers, such as TIL assessment, tumor mutation load and gene expression profiling, that 
are related to response or clinical benefit of BGB-A333 and tislelizumab may also be evaluated. If no 
archival samples are available, a fresh tumor biopsy at baseline is highly recommended.  
For fresh biopsy specimens, acceptable samples include core needle biopsies for deep tumor tissue or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
The optional biopsy will also be taken at the end of treatment visit for the patients who have confirmed 
disease progression during the study from accessible tumor sites to obtain samples, the resistance 
mechanism will be explored by NGS-based gene sequencing. If feasible, any follow up biopsy should be 
ideally taken from the same tumor lesion as the baseline biopsy. Written patient informed consent is 
required before obtaining fresh tumor biopsies. 
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.  
Around 5 mL peripheral blood samples will be collected at specified times in Phase 1 as described in the 
schedule of assessments to be used for the evaluation of PD measurements, such as, but not limited to, 
effects of BGB-A333 on immune cell subtypes. 
7.7. 
Safety Follow-Up Visit 
Patients will return for a follow-up visit at approximately 30 (±7) days after last dose of the study drug(s). 
In addition, telephone contacts with patients should be conducted to assess irAEs and concomitant 
medications at 60 and 90 days (±14 days) after the last dose of study drugs regardless of whether or not 
the patient starts a new anticancer therapy. SAEs and irAEs are collected up to 90 days. Beyond 90 days, 
investigators should report any SAEs or irAEs that are believed to be related to study drug(s) if they 
become aware of them. Patients who discontinue study drug(s) due to a drug-related AE will be followed 
until the resolution of the AE (to Grade 0 to Grade 1, baseline, stabilization) or initiation of a new 
treatment, whichever comes first.  
Any end-of-treatment (EOT) visit at which a response assessment showed PD, resulting in patient 
discontinuation, may be used as the Safety Follow-up visit, if appropriate. Patients who discontinue study 
treatment prior to disease progression will have their tumors assessed as outlined in Section 7.4. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 


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7.8. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see Appendix 1). 
All assessments will be performed on the day of the specified visit unless an acceptable time window is 
specified. Assessments scheduled on the day of study treatment administration (Day 1) of each cycle 
should be performed prior to study treatment unless otherwise noted. Laboratory results are required to be 
reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other events, the 
visit should be scheduled on the nearest feasible date, with subsequent visits conducted according to the 
original schedule calculated from Cycle 1 Day 1.  
7.9. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and may 
include review of AE, concomitant medications and procedures; assessments of vital signs, physical 
examination, ECOG performance status, laboratory safety tests, ECG, and radiographic assessments.  
The date and reason for the unscheduled visit must be recorded in the source documentation.  
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then diagnostic 
tests may be performed based on investigator assessment as appropriate, and the results of these tests 
should be entered on the unscheduled visit eCRF. 
7.10. 
Site Closure 
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:  
• 
Excessively slow recruitment  
• 
Poor protocol adherence  
• 
Inaccurate or incomplete data recording  
• 
Good Clinical Practice (GCP) noncompliance  
• 
Study activity is completed (ie, all patients have completed and all obligations have been 
fulfilled) 
 


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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 BGB-A333 and Tislalizumab 
BGB-A333 and tislelizumab are investigational agents that are currently in clinical development. No 
clinical information is available for BGB-A333 whereas limited safety data for tislelizumab are available 
in patients and the full safety profile has not been characterized. The following recommendation is based 
on results from nonclinical studies of BGB-A333 and non-clinical and clinical studies with tislelizumab 
and published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the 
risk of irAEs, specifically the induction or enhancement of autoimmune conditions. AEs observed with 
anti-PD-1 therapy are presented in Section 8.7. 
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 8. 
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 BGB-A333 and tislelizumab, clinical data with tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered. Specifically, patients at risk 
for study-emergent active autoimmune diseases or history of autoimmune diseases that may relapse, and 
patients who have received a live vaccine within 28 days before administration of study drug(s) are 
excluded from the study (see Section 4.2).  
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all adverse events, defined and graded 
according to NCI-CTCAE v4.03. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to the start of 
each cycle.  
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs, physical examinations, laboratory measurements (hematology, chemistry, 
etc.), and other assessments. In addition, patients will be closely monitored for the development of any 
signs or symptoms of autoimmune conditions and infection.  
Serum samples will be drawn for determination of ADAs to BGB-A333 in all patients and to tislelizumab 
in patients for Phase 1B and Phase 2B only. Administration of study drug(s) will be performed in a setting 


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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 adverse events 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 adverse event. 
Immune-related AEs will be recorded until up to 90 days after the last dose of study treatment, regardless 
of whether or not 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 events (includes pregnancy-related AEs).  
The potential safety issues anticipated in this trial, 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:  
• 
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  
• 
New conditions detected or diagnosed after study drug administration even though it may have 
been present before the start of the study  
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction  
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug(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 
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8.3.2. 
Assessment of Severity 
The investigator will make an assessment of severity for each AE and SAE reported during the study. 
AEs and SAEs should be assessed and graded based upon the NCI-CTCAE v4.03. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)  
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL  
• 
Grade 4: Life-threatening consequences; urgent intervention indicated  
• 
Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity (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 BGB-A333 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 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 in light of 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:  
• 
Temporal relationship of the AE to the administration of study treatment/study procedure  
• 
Whether an alternative etiology has been identified  
• 
Mechanism of action of the study drug  
• 
Biological plausibility  


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An AE should be considered “related” to study drug if any of the following are met:  
• 
There is clear evidence to suggest a causal relationship, and other possible contributing factors 
can be ruled out  
• 
There is evidence to suggest a causal relationship, and the influence of other factors is unlikely  
• 
There is some evidence to suggest a causal relationship (eg, the AE occurred within a reasonable 
time after administration of the study drug). However, the influence of other factors may have 
contributed to the AE (eg, the patient’s clinical condition or other concomitant AEs)  
An AE should be considered “unrelated” to study drug if any of the following are met:  
• 
An unreasonable temporal relationship between administration of the product and the onset on the 
AE (eg, the AE occurred either before, or too long after administration of the product for it to be 
considered product-related)  
• 
A causal relationship between the product and the AE is biologically implausible (eg, death as a 
passenger in an automobile accident)  
• 
A clearly more likely alternative explanation for the AE is present (eg, typical adverse reaction to 
a concomitant drug and/or typical disease-related AE) 
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 post mortem 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 
Only abnormal laboratory findings (eg, serum chemistry, complete blood count (CBC), coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE 


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(as defined in Section 8.3) or an SAE (as defined in Section 8.4). Clinically significant abnormal 
laboratory findings or other abnormal assessments that are detected during the study or are present at 
baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. 
However, clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more severe than expected 
for the patient’s condition, or that are present or detected at the start of the study and do not worsen, will 
not be reported as AEs or SAEs.  
8.4. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose:  
• 
Results in death 
• 
Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in which the 
patient was at risk of death at the time of the AE. It does not refer to an AE, which hypothetically 
might have caused death, if it were more severe 
• 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually involving at least 
an overnight stay) to the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting 
• 
Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere or prevent everyday life functions, 
but do not constitute a substantial disruption 
• 
Is a congenital anomaly/birth defect 
• 
Is considered a significant medical AE by the investigator based on medical judgement (eg, may 
jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
The following are NOT considered SAEs: 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• 
Hospitalization for social/convenience considerations 
• 
Scheduled therapy for the target disease of the study, including admissions for transfusion support 
or convenience 


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8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets the definition 
of an SAE/serious adverse drug reaction (ADR), the specificity or severity of which is not consistent with 
those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
8.6.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be reported 
until either 30 days after last dose of study drug or initiation of new anticancer therapy, whichever occurs 
first. Immune-related adverse events (serious or non-serious) should be reported until 90 days after the 
last dose of study drug(s), regardless of whether or not the patient starts a new anticancer therapy. The 
investigator should report any SAEs that are assessed as related to study drug(s), at any time after 
treatment discontinuation. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the event must 
be reported promptly to the sponsor or designee as described in Table 5. 
Table 5. Time Frames and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making 
Follow-Up 
Report 
Documentation 
Method 
All SAEs  
Within 24 hours of 
first knowledge of 
the AE 
SAE report 
As 
expeditiously as 
possible 
SAE report 
   Abbreviations: AE = adverse event; SAE = serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.1. The SAE report will 
always be completed as thoroughly as possible with all available details of the event, and forwarded to the 
sponsor or designee within the designated time frames.  


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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 at the time of the initial report as 
described in Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures detailed 
in Section 8.6.2.1 and Section 8.6.2.2. The sponsor has a legal responsibility to notify, as appropriate, 
both the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with the applicable 
local regulatory requirements related to the reporting of SAEs to regulatory authorities and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities and 
investigators for tislelizumab and BGB-A333 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:  
• 
How are you feeling?  
• 
Have you had any medical problems since your last visit?  
• 
Have you taken any new medicines since your last visit?  
8.6.4. 
Recording Disease Progression 
Disease progression is expected in this study population, and the term “disease progression” should not be 
reported as an AE term. When disease progression is identified, the AE that is associated with the disease 
progression should be reported as the AE term. For instance, for a patient who has a seizure that is 
determined to be associated with a brain metastasis, the term “seizure” should be recorded as the AE 
instead of disease progression or brain metastasis. Deaths that are assessed by the investigator as likely 
due to disease progression should be recorded in the eCRF. The term “death” should not be reported as an 
AE or SAE term, but rather as an outcome of an event. 


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8.6.5. 
Recording Deaths 
When recording a death as an SAE, the symptomatic deterioration and AE that caused or contributed to 
fatal outcome should be recorded in the eCRF. If the cause of death is unknown and cannot be ascertained 
at the time of reporting, record “unexplained death.” 
8.6.6. 
Recording Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving investigational 
therapy or within 120 days after the last dose of tislelizumab or BGB-A333, a pregnancy report form is 
required to be completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, follow up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of 
the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective termination 
of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drug 
should be recorded and reported as an SAE. 
8.6.7. 
Recording Post-Study Adverse Events  
A poststudy AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period that is 
defined in Section 8.6.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discontinued from 
the study, and he/she considers the SAE related to the study drug, the investigator will notify the sponsor.  
8.6.8. 
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: 
• 
BGB-A333 and tislelizumab IB 
8.6.9. 
Assessing and Recording Immune-Related Adverse Events 
Since treatment with anti-PD-1 or anti-PD-L1 therapy can cause autoimmune disorders, AEs considered 
by the investigator to be immune-related (see Section 8.7.3) should be classified as irAEs and identified 
as such in the eCRF AE page until 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 8. 


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An extensive list of potential irAEs appears in Section 8.7.3, Table 7. 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 8. 
8.7. 
Management of AE of Special Interest 
As a routine precaution, after infusion of BGB-A333 alone or in combination with tislelizumab, patients 
must be monitored in an area with resuscitation equipment and emergency agents. The infusion time and 
monitoring time are shown in Table 4. 
The management of infusion-related reactions, severe hypersensitivity reactions and irAEs according to 
the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Infusion-Related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, angioedema, 
hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness or hypertension. 
Severe reactions may include acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock. Patients should be closely monitored for such reactions. Immediate 
access to an Intensive Care Unit (ICU) or equivalent environment and appropriate medical therapy 
(including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen) must be available 
to treat infusion-related reactions.  
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is provided in 
Table 6. 
Table 6. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for BGB-A333 and 
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 hours 
Stop infusion. Infusion may be resumed at 50% 
of previous rate once infusion-related reactions 
has resolved or decreased to Grade 1 in severity. 
Any worsening is closely monitored. Proper 
medical management should be instituted as 
described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 


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Table 6. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) 
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 
IV: intravenous; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
Once the BGB-A333 and/or 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 BGB-A333 and/or tislelizumab treatment. 
CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted, as indicated 
per type of the reaction. This includes but is not limited to an anti-histamine (eg, diphenhydramine or 
equivalent), anti-pyretic (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.  
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, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available medical 
practice as described in the complete guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK). 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 


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respiratory difficulty; cutaneous manifestations such as pruritus and urticaria with/without edema; and 
gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea), the 
infusion must be immediately stopped and the patient discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if hypersensitivity 
reaction is observed and then the patient should be placed on monitor immediately and ICU should be 
alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs(s) infusion. Alternative 
treatments for fever (ie, paracetamol) may be given to patients at the discretion of the investigator. 
8.7.3. 
Immune-Related Adverse Events  
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, 
disease progression) 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 list of potential irAEs is shown below in Table 7. All conditions similar to those listed should be 
evaluated in patients receiving BGB-A333 alone or in combination with tislelizumab to determine 
whether they are immune-related.  
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 8. For any 
adverse events not included in Appendix 8, please refer to ASCO Clinical Practice Guideline (Brahmer et 
al 2018) for further guidance on diagnostic evaluation and management of immune-related toxicities.  
 
 




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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. Data will be listed and summarized using SAS® Version 9.3 or higher 
(SAS Institute, Inc., Cary, North Carolina) per sponsor agreed reporting standards, where applicable. 
Details of the statistical analyses will be included in a separate Statistical Analysis Plan (SAP).  
Efficacy and safety data will be summarized by phase and tumor type where appropriate. 
9.1. 
Statistical Analysis 
9.1.1. 
Randomization Methods 
Not applicable. 
9.1.2. 
Analysis Populations 
The Safety Population includes all patients who received at least 1 dose of study drug; it will be the 
population for the safety and efficacy analyses. 
Efficacy Evaluable Population includes all dosed patients who have evaluable disease at baseline, and at 
least 1 evaluable post-baseline tumor response assessment unless any clinical PD or death occurred before 
the first post-baseline tumor assessment.  
DLT Evaluable Population for BGB-A333 monotherapy includes patients who received at least two-thirds 
(67%) of the assigned dose of BGB-A333 during the DLT observation period and had sufficient safety 
evaluation or patients who experienced DLT within DLT observation period.  
DLT Evaluable Population for BGB-A333 and tislelizumab combination includes patients who received 
at least two-thirds (67%) of the assigned dose of BGB-A333 and tislelizumab during the DLT observation 
period and had sufficient safety evaluation or patients who experienced DLT within DLT observation 
period.  
The PK analysis population includes all patients with valid PK sampling after treatment with study 
drug(s). 
9.1.3. 
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 and/or study discontinuation will be 
summarized according to the categories in the eCRF. The end of study status (alive, dead, withdrew 
consent or lost to follow-up) at the data cut-off date will be summarized using the data from the eCRF.  
Major protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety Population using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial cancer 


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diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables include prior 
number of systemic treatment, gender, ECOG, country, race, and metastatic site. 
9.1.5. 
Prior and Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization (WHO) 
Drug Dictionary drug codes. Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical (ATC) code indicating therapeutic classification. Prior and 
concomitant medications will be summarized and listed by drug and drug class in the Clinical Study 
Report (CSR) for this protocol. Prior medications will be defined as medications that stopped before the 
first dose of study drug. Concomitant medications will be defined as medications that (1) started before 
the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started 
on or after the date of the first dose of study drug up to 30 days after the patient’s last dose. In addition, 
telephone contacts with patients should be conducted to assess irAEs and concomitant medications (if 
appropriate, ie, associated with an irAE or is a new anticancer therapy) at 60 and 90 days (±14 days) after 
the last dose of study drugs regardless of whether or not the patient starts a new anticancer therapy.  
9.2. 
Efficacy Analyses 
Safety and MTD/RP2D determination are the primary objectives in the Phase 1 part. Evaluation of ORR 
of BGB-A333 alone and in combination with tislelizumab in the selected tumor types is the primary 
objective in Phase 2 part.  
The efficacy per RECIST 1.1 (ie, ORR, DOR, PFS, and DCR) will be summarized to evaluate antitumor 
activities of BGB-A333 alone or in combination with tislelizumab in patients with measurable disease at 
baseline. Efficacy summary will be provided by tumor type. 
9.2.1. 
Primary Efficacy Analysis in Phase 2 
ORR and its 95% CI will be summarized in the Safety and Efficacy Evaluable Populations. ORR in Phase 
2 will be presented by tumor type. 
9.2.2. 
Secondary Efficacy Analysis in Phase 2 
PFS will be estimated using the Kaplan-Meier (KM) method. The median PFS and landmark PFS at every 
3 months will be calculated and presented with 2-sided 95% CIs. PFS censoring rule will follow FDA 
Guidance. The PFS censoring rule will follow United States (US) Food and Drug Administration (FDA) 
Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and Biologics (2007) (FDA 
Guidance for Industry 2007). 
DOR will be analyzed in the responders. 
Best overall response is defined as the best response recorded from administration of study drug(s) until 
data cut or the start of new anticancer treatment. Patients with no post-baseline response assessment (due 
to any reason) will be considered non-responders for best overall response (BOR). The proportion and its 
corresponding Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be 
presented. 


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DCR will be analyzed similarly to ORR in the Safety and Efficacy Evaluable Populations.  
Waterfall plots of maximum tumor shrinkage per patient will be presented. 
9.2.3. 
Exploratory Efficacy Analysis 
9.3. 
Safety Analyses 
Safety will be determined by the spontaneous reporting of adverse events and by laboratory values 
(hematology, serum chemistry, coagulation, and urinalysis). Vital signs, physical examination and ECG 
findings will also be used in determining the safety profile. The severity of adverse events will be graded 
according to the CTCAE v4.03. The incidence of DLT events, treatment-emergent AEs (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 data will be summarized in the Safety Population, and by study phase or tumor type if necessary. 
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 interruption, dose delay, and drug discontinuation due 
to AEs will be summarized for each study drug.  
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®). Adverse events will be coded to MedDRA 
(Version 18.1 or higher) lower level term, preferred term and primary system organ class (SOC). 
DLT will be summarized at each dose cohort in Phase 1A and Phase 1B. 
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 also includes immune-related AEs 
recorded up to 90 days after the last dose of study drug.  Only those AEs that were treatment-emergent 
will be included in summary tables. All AEs, treatment emergent or otherwise, will be presented in 
patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by SOC and 
PT. A patient will be counted only once by the highest severity grade per NCI-CTCAE v.4.03 within an 


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SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC and PT. The 
number (percentage) of patients with TEAEs will also be summarized by relationship to the study drug. 
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, 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 by patient. 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 post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v.4.03 will be summarized by NCI-CTCAE grade. 
In the summary of laboratory parameters by NCI-CTCAE grade, parameters with NCI-CTCAE grading in 
both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) will be summarized 
separately. 
9.3.4. 
Vital Signs 
Descriptive statistics for vital sign parameters and changes from baseline will be presented by visit. Vital 
signs will be listed by patient and visit. 
9.3.5. 
Ophthalmologic Examination 
Ophthalmologic examination results will be listed by patient. 
9.4. 
Pharmacokinetic Analysis  
In Phase 1, BGB-A33 PK variables (eg, Cmax, Tmax, trough serum concentration [Ctrough], AUC, Cl, and Vd) 
will be calculated as appropriate using noncompartmental methods and summary statistics will be 
provided. BGB-A333 serum concentration data and PK parameters will be tabulated and summarized for 
each cycle at which pharmacokinetics are to be measured in Phase 1 and Phase 2. Descriptive statistics 
will include means, medians, ranges, and SDs, as appropriate. Mean serum concentrations will also be 
plotted against time for each dose level. Additional PK analyses may be conducted as appropriate. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. Results 
of such analyses may be reported separately from the CSR. 
Tislelizumab serum concentration data will be tabulated and summarized for each cycle at which PK are 
to be measured. 


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9.5. 
Immunogenicity Analyses 
Samples to assess anti-BGB-A333 antibodies as well as anti-tislelizumab antibodies will be collected only 
in patients who receive the treatment. 
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 
9.7. 
Sample Size Consideration 
The study plans to enroll approximately 58 to 168 patients. 
• 
Phase 1A (BGB-A333 dose escalation): Approximately 12 to 30 patients with advanced solid 
tumors in 3-5 dose levels or dosing regimens per modified 3+3 design.  
• 
Phase 1B (BGB-A333 and tislelizumab combination): Approximately 6 patients with advanced 
solid tumors in one combination dosing regimen. An additional 12 patients may be enrolled to 
test different dosing regimens.  
• 
Phase 2A (BGB-A333 dose expansion): Approximately 20 patients with UC. Additional 20-40 
patients with other tumor types (to be defined in future protocol amendments based upon 
emerging data) may be enrolled.  
• 
Phase 2B (BGB-A333 and tislelizumab combination dose expansion): Approximately 20 patients 
with UC. An additional 20-40 patients with other tumor types (to be defined in future protocol 
amendments based upon emerging data) may be enrolled.  
In Phase 2, approximately 20 patients per cohort will be enrolled to evaluate the preliminary efficacy.  
No formal hypothesis testing will be performed in the efficacy evaluation. With 20 patients, the 
probabilities of observing at least one responder under different underlying ORR assumptions are 
summarized in Table 8, indicating the proposed sample size is adequate to detect any preliminary anti-
cancer activities of the treatment. The 95% CIs of the ORR estimate when observing 1 to 6 responders are 
included in Table 9, depicting the precision achieved with 20 patients.  
 


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Table 8. 
Time Probabilities of Observing at least One Responder in 20 Patients under 
Various ORR Assumptions 
ORR 
0.10 
0.20 
0.30 
0.40 
Probability (observing 
≥ 1 responder) 
0.88 
0.99 
> 0.99 
> 0.99 
 
Table 9. 
95% CI (%) when Observing 1 to 6 Responders in 20 Patients 
# of 
responders 
1 
2 
3 
4 
5 
6 
95% CI 
(0.1, 24.8) 
(1.2, 31.7) 
(3.2, 37.9) 
(5.7, 43.7) 
(8.7, 49.1) 
(11.9, 54.3) 
9.8. 
Interim Analyses 
Not applicable. 


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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Safety Monitoring Committee 
SMC will be established and includes both the sponsor and at least 2 investigators. The SMC will review 
all available safety, efficacy, PK, and exploratory data and make recommendation on dose escalation, 
dose modification, and dose selection for Phase 1B and Phase 2. 
10.2. 
Communication 
Sponsor plans to have regular communications with all study sites (study investigators and coordinators) 
regarding: 
• 
Study enrollment status  
• 
Any significant safety findings  
• 
Decisions on dose escalation  
• 
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 International Council on Harmonisation (ICH) GCP guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data recorded in 
the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The monitor should have access to any patient records needed to verify the entries on the 
eCRFs. The investigator agrees to cooperate with the monitor to ensure that any problems detected during 
these monitoring visits are resolved. 
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 GCP and all applicable regulatory requirements, the sponsor may conduct a 
quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant 
documents and to allocate his/her time and the time of his/her personnel to the auditor/inspector to discuss 
findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard operating 
procedures, working practice documents, and applicable regulations and guidelines. Site audits may be 
made periodically by the sponsor’s or the contract research organization’s (CRO’s) qualified compliance 
auditing team, which is an independent function from the study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, patients’ 
medical records, and eCRFs. The investigator is to permit national and local health authorities; sponsor 
study monitors, representatives, and collaborators; and IRB/IEC members to inspect all facilities and 
records relevant to this study.  
12.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of all 
used and unused study drug. This includes acknowledgment of receipt of each shipment of study product 
(quantity and condition), patient drug dispensation records and returned or destroyed study product. 
Dispensation records will document quantities received from BeiGene’s designated depot and quantities 
dispensed to patients, including lot or batch number, date dispensed, patient identifier number, patient 
initials, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction to ensure that it complies with BeiGene requirements. At the end of the study, or at 
appropriate times during the conduct of the study, following drug inventory reconciliation by the monitor, 
the study site will dispose of and/or destroy all unused study drug supplies, including empty containers, 
according to these procedures. If the site cannot meet BeiGene’s requirements for disposal, arrangements 
will be made between the site and BeiGene or its representative for destruction or return of unused study 
drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study. 


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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1. 
Ethical Standard 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the principles 
of the Declaration of Helsinki or the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting information 
must be submitted to the institutional review board (IRB)/independent ethics committee (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 adverse events to the sponsor, 
investigators must comply with requirements for reporting serious adverse events to the local health 
authority and IRB/IEC. Investigators may receive written investigation 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 sponsor 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 trial. 
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 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 only be disclosed to third 
parties as permitted by the signed ICF (or a separate authorization for the use and disclosure of personal 
health information that has been signed by the patient), unless permitted or required by law.  
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated by this study must be available for inspection upon request by representatives of the 
US FDA, China FDA, 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 
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 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 local regulations to allow the sponsor to submit complete disclosure or certification the 
absence of certain financial interest of 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 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 the EDC system.  
Data collection in the eCRF must follow the instructions described in the eCRF Completion Guidelines 
(eCCGs). The investigator has ultimate responsibility for the collection and reporting of all clinical data 
entered in the eCRF. The investigator or designee as identified on Form FDA 1572 must provide an 
e-signature in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available in any 
form to third parties without written permission from BeiGene, except for authorized representatives of 
BeiGene or appropriate regulatory authorities.  
14.1.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored by BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to produce 
queries and maintenance of an audit file which includes all database modifications) will be followed to 
support accurate data collection. Data will be reviewed for outliers, logic, data inconsistencies and 
completeness. 
During the course of the study, a study monitor (clinical research associate [CRA]) will make site visits to 
review protocol compliance, compare eCRFs against individual patient’s medical records and ensure that 
the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs for 
completeness, clarity and cross checking with source documents is required to monitor the progress of the 
study. Direct access to source data is also required for inspections and audits, and will be carried out 
giving due consideration to data protection and medical confidentiality. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) Version 18.1 or 
higher. Concomitant medications and medical history will be coded using the World Health Organization 
Drug Dictionary.  
14.2. 
Data Integrity 
Due to the open-label design of the study, access to the unblinded patient level clinical data in the 
Electronic Data Capture (EDC) system will only be assigned to predefined study personnel. 
Functions/persons with access to the EDC system shall be prohibited from using the EDC system to 
generate unnecessary listings/summaries that may introduce unwanted bias, or share such outputs or the 
unblinded data from the EDC system with other functions/persons who do not have access to the EDC. 


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Although the trial is open-label, analyses or summaries generated by treatment assignment and actual 
treatment received will be limited and documented. 
14.3. 
Study Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 
into at least one of the following 2 categories: (1) investigator’s study file, and (2) patient clinical source 
documents. 
The investigator’s study file will contain the protocol/amendments, blank 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. 
Patient clinical source documents (usually defined by the project in advance to record key efficacy/safety 
parameters independent of the eCRFs) would include (although not be limited to) the following: patient 
hospital/clinic records, physician’s and nurse’s notes, appointment book, original laboratory reports, 
electrocardiogram, 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 back up of these reproductions and that 
an acceptable quality control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that study center for the study, as dictated by any institutional requirements or local laws or 
regulations, or the sponsor’s standards/procedures; otherwise, the retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, but not 
limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event 
the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the investigator and BeiGene to store these in 
sealed containers outside of the site so that they can be returned sealed to the investigator in case of a 
regulatory audit. When source documents are required for the continued care of the patient, appropriate 
copies should be made for storage outside of the site. 


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14.4. 
Protocol Deviations 
The investigator is responsible for ensuring 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.  
14.5. 
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 regulator guidance, and 
the need to protect the intellectual property of BeiGene (sponsor), regardless of the outcome of the trial. 
The data generated in this clinical trial are the exclusive property of the sponsor and are confidential. For 
multicenter studies, 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. 
After conclusion of the study and without prior written approval from BeiGene, investigators in this study 
may communicate, orally present, or publish in scientific journals or other scholarly media only after the 
following conditions have been met: 
• 
The results of the study in their entirety have been publicly disclosed by or with the consent of 
BeiGene in an abstract, manuscript, or presentation form; or 
• 
The study has been completed at all study sites for at least 2 years 
• 
No such communication, presentation, or publication will include BeiGene’s confidential 
information 
• 
Each investigator agrees to submit all manuscripts or congress abstracts and posters/presentations 
to the sponsor at least 30 days prior to submission. This allows the sponsors to protect 
confidential information, provide comments based on information from other studies that may not 
yet be available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the investigator’s clinical study agreement 
14.6. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction with the 
investigator or study center personnel, as appropriate: 
• 
Return of all study data to the sponsor 


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• 
Resolve and close all data queries 
• 
Accountability, reconciliation, and arrangements for unused study drug(s) 
• 
Review of study records for completeness 
• 
Return of treatment codes to the sponsor 
• 
Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend 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. 
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 all unused study drug(s) in accordance with the applicable sponsor 
procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the agreement 
established between the investigator and the sponsor. 
14.7. 
Information Disclosure and Inventions 
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) is the sole property of the sponsor. 
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) 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: 
• 
Information which becomes publicly available through no fault of the investigator or study center 
personnel 


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• 
Information which is necessary to disclose in confidence to an IEC/IRB solely for the evaluation 
of the study 
• 
Information which is necessary to disclose in order to provide appropriate medical care to a 
patient 
• 
Study results which may be published as described in Section 14.5 
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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carcinoma (mUC): pooled analysis from 2 cohorts of phase 1b JAVELIN solid tumor study. Abstract for 
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Atezolizumab (TECENTRIQ®) [Package Insert]. US Prescribing Information, TECENTRIQ® 
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BeiGene Investigator’s Brochure, TISLELIZUMAB. Edition 5.0, Feb 2018. 
BeiGene Investigator’s Brochure, BGB-A333 Edition 1.0, July 2017. 
Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared 
with best supportive care alone after a platinum-containing regimen in patients with advanced transitional 
cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27: 4454–61. 
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients 
treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical 
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Butte, MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-
1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27, 111-22. 
Chung RT, Davis GL, Jensen DM, Masur H, Saag MS, Thomas DL, et al. Hepatitis C guidance: AASLD-
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Hepatology 2015; Sep;62(3):932-54. 
Common Toxicity Criteria Version 4.03. Cancer Therapy Evaluation Program. 14 June 2010.  
Deng R, Iyer S, Theil FP, et al. Projecting human pharmacokinetics of therapeutic antibodies from 
nonclinical data: What have we learned? mAbs 2011; 3(1): 61-66. 
De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin 
and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for 
cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012; 30: 191–99. 
durvalumab (Imfinzi) [Package Insert]. US Prescribing Information, Imfinzi (durvalumab). AstraZeneca 
UK Limited, Cambridge, England. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf. Accessed 10 July 2017. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009; 45:228-247. 
FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(2007). 
Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 
1;28(suppl_4):iv119-iv142. doi: 10.1093/annonc/mdx225. 
Hahn NM, Powles T, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally 
advanced or metastatic urothelial carcinoma. Abstract for ASCO 2017. 


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Hamid, O, Chow, L.Q., Sanborn R.E. et al. Combination of MEDI0680, an anti-PD-1 antibody, with 
durvalumab, an anti-PD-L1 antibody: A phase 1, open-label study in advanced malignancies. Ann 
Oncology 2016; 27 (6): 359-378.  
Hui, E., Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated 
inhibition. Science. 2017; 355 (6332), 1428-33. 
International Committee of Medical Journal Editors. Uniform requirements for manuscripts or stricter 
local criteria. 2013. 
Koren E, Smith HW, Shores E, et al. Recommendations on risk-based strategies for detection and 
characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1 2):1-9. 
Labrijn, A.F., Buijsse AO, van den Bremer ET, et al., Therapeutic IgG4 antibodies engage in Fab-arm 
exchange with endogenous human IgG4 in vivo. Nature Biotechnology 2009; 27(8): 767-771.  
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of 
adults on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637. 
Ngiow, S.F., Young A, Jacquelot N, et al. A threshold level of intratumor CD8+ T-cell PD1 expression 
dictates therapeutic response to anti-PD1. Cancer Res. 2015; 75 (18), 3800-11. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-55. 
Park, J.J., Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and 
maintenance of peripheral T-cell tolerance. Blood 2010; 116, 1291-8. 
Powles T, Loriot Y, Durán I, et al. IMvigor211: A Phase III Randomized Study Examining Atezolizumab 
Versus Chemotherapy for Platinum-Treated Advanced Urothelial Carcinoma. Abstract for EAS 2017. 
Pugh RNH, Murray-Lyon IN, Dawson DL, Pietroni MC, and Williams R. Transection of the esophagus 
for bleeding esophageal varices. Brit J Surgery. 1973;60:646-645. 
Seymour L, Bogaerts J, Perrone A et al. RECIST working group. iRECIST: guidelines for response 
criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017 Mar;18(3):e143-e152. 
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for 
treatment of chronic hepatitis B. Hepatology 2016; 63(1): 261–283. 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion. N 
Engl J Med. 1996;274(9):473-481. 
von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial 
comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in 
patients with bladder cancer. J Clin Oncol 2005; 23: 4602–08. 
Wang DD, Zhang S, Zhao H, et al. Fixed Dosing Versus Body Size-Based Dosing of Monoclonal 
Antibodies in Adult Clinical Trials. J Clin Pharmacol 2009; 49:1012 24. 
Worobec AS and Rosenberg AS. A Risk-Based Approach to Immunogenicity Concerns of Therapeutic 
Protein Products, Part 1: Considering Consequences of the Immune Response to a Protein. BioPharm Intl. 
2004a;17(11). http://www.biopharminternational.com/risk-based-approach-immunogenicity-concerns-
therapeutic-protein-products-part-1-considering-conseque. Accessed 01 August 2017. 
Worobec AS and Rosenberg AS. A Risk-Based Approach to Immunogenicity Concerns of Therapeutic 
Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting 
Immunogenicity. BioPharm Intl. 2004b;17(12). http://www.biopharminternational.com/risk-based-


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approach-immunogenicity-concerns-therapeutic-protein-products-part-2-considering-host-spe. Accessed 
01 August 2017. 
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in Adults. J Clin Pharmacol, 2011. 
 


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16. 
APPENDICES 
 






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Abbreviations: AE = adverse event; C1D1 = Cycle 1, Day 1; C1D8 = Cycle 1, Day 8; C1D15 = Cycle 1, Day 15; C3D1 = Cycle 3, Day 1; C5D1 = Cycle 5, Day 1; CK = 
Creatine kinase; CK-MB = Creatine kinase-cardiac muscle isoenzyme; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; HBV = hepatitis B virus; HCV = hepatitis C virus; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks; x = to be performed. 
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 Cycle 1 Day 1 may be used for screening assessments rather than repeating such tests. 
2. In Cycles 1 to 3, patients will receive study drug on Day 1 and return to study sites for assessments on Day 8. In addition, patients on Q3W, Q4W or longer intervals will 
return to study sites on Day 15.  
3. The End of Treatment Visit is conducted when the investigator determines that study drug(s) will no longer be used. If routine laboratory tests (eg, hematology, serum 
chemistry) are completed within 7 days before the End of Treatment Visit, tests need not be repeated. Tumor assessment is not required at the End of Treatment Visit 
provided that less than 6 weeks have passed since the last assessment. 
4. The Safety Follow-up Visit and Phone calls: Patients who discontinue treatment for any reason will be asked to return to the clinic for the Safety Follow up Visit (to 
occur within 30 days [± 7 days] after the last dose of study drug or before the initiation of a new anticancer treatment, whichever occurs first. In addition, telephone contacts 
with patients should be conducted to assess irAEs and concomitant medications (if appropriate, ie, associated with an irAE 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. 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, or the 
patient withdraws consent. 
5. Demographic data, medical history and prior medications will be collected during screening (see Section 7.1.1 for details).  
6. Vital signs collected on study include temperature, pulse, and blood pressure (systolic and diastolic) while the patient is in a seated position after resting for 10 minutes. 
In the first cycle, vital signs should be collected within 60 minutes before the infusion of the study drug(s), and within 30 minutes after the infusion of the study drug(s). 
In the subsequent cycles, vital signs should be collected within 60 minutes before infusion and as clinically indicated. Height and weight should only be measured and 
recorded at screening only.  
7. Complete physical examination including an evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 5) respiratory, 6) 
gastrointestinal, and 7) neurological systems is required to be performed at Screening. At subsequent visits (or as clinically indicated), limited, symptom-directed 
physical examinations will be performed.  
8. ECOG Performance Status (Appendix 3) will be assessed at Screening, Day 1 of each treatment cycle, EOT visit and the Safety Follow-up Visit. 
9. 12-lead ECG will be collected during screening, on C1D1, C2D1 and C5D1 at approximately 30 min before and approximately 30 min after dosing of BGB-A333. In 
addition, 12-lead ECG will be collected any time on C1D8, C1D15 (only in Q3W or longer dosing intervals), at EOT and the Safety Follow-up visits, and as clinically 
indicated. At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine the mean QTcF interval. 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. For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
10. Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 4.03. 
11. All concomitant medication received within 30 days before the first dose of study treatment, 30 days after the last dose of study treatment, and at 60 or 90 days of 
follow up (if appropriate, ie, associated with a new adverse event or is a new anticancer therapy) should be recorded.  
12. Hematology and serum chemistry as specified in Appendix 2 should be performed at screening and weekly for the first 3 cycles and at the beginning of subsequent 
cycles, EOT visit, Safety Follow-up visit and when clinically indicated. If these tests at screening are not performed within 96 hours prior to the administration of study 
drug(s) on C1D1, these tests should be repeated and reviewed within 72 hours before study drug(s) administration. After Cycle 1, test results should be reviewed within 


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72 hours before study drug administration. Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory 
abnormalities. 
CK and CK-MB will be conducted at Screening, scheduled visits during the first 3 treatment cycles, and all pre-dose assessments from Cycle 4 onward, EOT visit, 
Safety Follow-up and when clinically indicated. If CK-MB fractionation is not available, troponin I and/or troponin T should be assessed instead. 
13. Coagulation tests as specified in Appendix 2 are required at Screening, Day 1 of each treatment cycle, EOT visit, the Safety Follow-up Visit and as clinically indicated. 
14. Urinalysis as specified in Appendix 2 will be conducted at Screening and the Safety Follow-up Visit and as clinically indicated.  
15. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative within 7 
days prior to administration of study drug(s). Urine or serum pregnancy tests will be performed before study drug administration at each cycle and at Safety Follow-up. 
A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. A negative pregnancy test (by urine or serum) must be completed and 
recorded before administration of study drug(s) at each cycle. 
16. Thyroid function tests include analysis of free T3, free T4 and TSH. Testing will be performed at Screening and every three cycles thereafter (eg, Cycles 4, 7, 10, etc.), 
and at the Safety Follow-Up Visit (see Section 7.3.4 for details).  
17. HBV/HCV tests: In patients with HCC only, hepatitis serology and viral load will be tested at Screening.  Patients who have detectable HBV DNA at Screening will 
perform the viral load test every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc), at EOT visit, and when clinically indicated. In other patients, blood samples for hepatitis 
serology and viral load will be collected at Screening and may be tested if patients have hepatic AE (Grade ≥ 3) during the study (see Section 7.3.7 for details).  
18. Pulmonary function test: Patients who have a history of serious or severe pulmonary disease or are suspected to have serious or severe respiratory concurrent illness or 
exhibit significant respiratory symptoms should take a pulmonary function test at screening and as clinically indicated during study treatment (see Section 7.1.4 for details). 
19. Optical coherence tomography (or equivalent diagnostic test) and visual acuity tests: Eye exam, visual acuity test, and optical coherence tomography (or equivalent 
diagnostic test for retinal examination) will be assessed by an appropriate specialist at Screening. Patients will undergo repeat assessments by an appropriate specialist 
approximately every 15 weeks (± 7 days) during study treatment after Cycle 1 and a final assessment within 30 days after the last dose of study treatment.  
20. Tumor imaging will be performed within 28 days prior to C1D1 and while on study approximately every 9 weeks ± 7 days after C1D1 (for Q3W dosing) or every 8 weeks 
± 7 days after C1D1 (for Q2W or Q4W dosing) in the first 12 months and approximately every 12 weeks ± 7 days thereafter. All measurable and evaluable lesions should 
be assessed and documented at the screening visit. 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 at least 4 weeks (≥ 4 weeks) after the first response or at the next scheduled assessment time point. Progressive disease suspected as 
pseudoprogression needs to be confirmed by repeated imaging at least 4 weeks later but not exceeding 8 weeks from the date of initial documentation of PD. Patients who 
stop treatment prior to documentation of progressive disease will undergo repeated imaging for tumor response assessments (see Section 7.4 for details). 
21. Bone scan is only required if disease is suspected or has been documented previously (see Section 7.4 for details).  
22. Archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] blocks or approximately 15 [≥7] unstained FFPE slides) will be collected if available. 
23. Fresh biopsy: In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 28 days before Cycle 1 Day 1) is highly recommended. An 
optional biopsy will also be taken from patients who have confirmed disease progression during the study from accessible tumor sites to obtain samples to explore resistance 
mechanism (written inform consent is required prior to obtaining fresh tumor biopsies). 
24. BGB-A333 administration (see Section 5.2 for details).  
25. Tislelizumab and BGB-A333 administration (see Section 5.2 for details). 
26. PD biomarker (Phase 1 only): Around 5 mL peripheral blood will be collected pre-dose at the following timepoints: C1D1, C1D15 (only for Q3W or longer dosing 


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intervals); C2D1, C3D1.  


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Appendix 1B. Pharmacokinetic and Immunogenicity Sampling Schedule for BGB-A333 (Q3W) 
 
Cycle 
Week 
Day 
PK Assessment 
ADA Assessment 
Treatment Period 
1 
1 
1 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
6-hr (± 2 hr) (Phase 1 only) 
Day 2 (± 2 hr) (Phase 1 only) 
Day 4 (± 2 hr) (Phase 1 only) 
Day 8 (Phase 1 only) 
Day 15 (Phase 1 only) 
Predose 
2 
4 
22 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Predose 
5 
13 
85 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Day 8 (Phase 1 only) 
Day 15 (Phase 1 only) 
Predose 
6 
16 
106 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
9 
25 
169 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
13 
37 
253 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
17 
49 
337 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
25 
73 
505 
Predose (-60 min to predose) 
Predose 
33 
97 
673 
Predose (-60 min to predose) 
Predose 
33  
+8. 
97 
+24. 
Predose every 6 months after 
Predose 
Safety Follow-up 
(30 Days ± 7 Days after last dose) 
Abbreviations: ADA = antidrug antibody; EOI = end of infusion; PK = pharmacokinetic; Q3W = every 3 weeks. 
Note: Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection for PK 
and ADA should be from a different site. Window: ± 30 minutes for EOI and ± 60 minutes for all other timepoints. 
 
 


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Appendix 1C. Pharmacokinetic and Immunogenicity Sampling Schedule for BGB-A333 (Q2W) 
 
Cycle 
Week 
Day 
PK Assessment 
ADA Assessment 
Treatment Period 
1 
1 
1 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
6-hr (± 2 hr) (Phase 1 only) 
Day 2 (± 2 hr) (Phase 1 only) 
Day 4 (± 2 hr) (Phase 1 only) 
Day 8 (Phase 1 only) 
Predose 
2 
3 
15 
Predose (-60 min to predose) 
 
3 
5 
29 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Predose 
7 
13 
85 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Day 8 (Phase 1 only) 
Predose 
8 
15 
99 
Predose (-60 min to predose) (Phase 1 only) 
Predose 
13 
25 
169 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
19 
37 
253 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
25 
49 
337 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
37 
73 
505 
Predose (-60 min to predose) 
Predose 
37  
+8. 
73  
+24. 
 
Predose every 6 months after 
Predose 
Safety Follow-up 
(30 Days ± 7 Days after last dose) 
Abbreviations: EOI = end of infusion; PK = pharmacokinetic; Q2W = every 2 weeks. 
Note: Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection for PK 
& ADA should be from a different site. Window: ± 30 minutes for EOI and ± 60 minutes for all other timepoints. 


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Appendix 1D. Pharmacokinetic and Immunogenicity Sampling Schedule for BGB-A333 (Q4W) 
 
Cycle 
Week 
Day 
PK Assessment 
ADA Assessment 
Treatment Period 
1 
1 
1 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
6-hr (± 2 hr) (Phase 1 only) 
Day 2 (± 2 hr) (Phase 1 only) 
Day 4 (± 2 hr) (Phase 1 only) 
Day 8 (Phase 1 only) 
Day 15 (Phase 1 only) 
Day 21 (Phase 1 only) 
Predose 
2 
5 
29 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Predose 
4 
13 
85 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Day 8 (Phase 1 only) 
Day 15 (Phase 1 only) 
Day 21 (Phase 1 only) 
Predose 
5 
17 
113 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) 
Predose 
7 
25 
169 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
10 
37 
253 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
13 
49 
337 
Predose (-60 min to predose) 
End of infusion (Within 30-min after EOI) (Phase 1 only) 
Predose 
19 
73 
505 
Predose (-60 min to predose) 
Predose 
25 
97 
673 
Predose (-60 min to predose) 
Predose 
25 +8. 
97 +24. 
Predose every 6 months after 
Predose 
Safety Follow-up 
(30 Days ± 7 Days after last dose) 
Abbreviations: ADA = antidrug antibody; EOI = end of infusion; PK = pharmacokinetic; Q4W = every 4 weeks. 
Note: Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection for PK 
& ADA should be from a different site. Window: ± 30 minutes for EOI and ± 60 minutes for all other timepoints.  
 


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Appendix 1E. Pharmacokinetic and Immunogenicity Sampling for Tislelilzumab 
 
Cycle 
Week 
Day 
PK Assessment 
ADA Assessment 
Treatment Period 
1 
1 
1 
Predose (-60 min to predose) 
End of infusion (End infusion to 30 min after EOI) 
Predose 
2 
4 
22 
Predose (-60 min to predose) 
 
Predose 
5 
13 
85 
Predose (-60 min to predose) 
End of infusion (End infusion to 30 min after EOI 
Predose 
6 
16 
106 
Predose (-60 min to predose) 
 
9 
25 
169 
Predose (-60 min to predose) 
 
Predose 
13 
37 
253 
Predose (-60 min to predose) 
 
Predose 
17 
49 
337 
Predose (-60 min to predose) 
 
Predose 
25 
73 
505 
Predose (-60 min to predose) 
Predose 
33 
97 
673 
Predose (-60 min to predose) 
Predose 
33  
+8. 
97  
+24. 
Predose every 6 months after 
Predose 
Safety Follow-up 
(30 Days ± 7 Days after last dose) 
Abbreviations: ADA = antidrug antibody; EOI = end of infusion; PK = pharmacokinetic. 
Note: Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection for PK 
& ADA should be from a different site. Window: ± 30 minutes for EOI and ± 60 minutes for all other timepoints. 
 


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APPENDIX 2. 
CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
Hematology 
Coagulationb 
Urinalysis 
Alkaline phosphatase 
RBC count 
Prothrombin time 
Glucose  
Alanine aminotransferase 
Hematocrit 
Partial thromboplastin time 
Protein 
Aspartate aminotransferase 
Hemoglobin 
International normalized ratio 
Blood  
Albumin 
Platelet counts 
 
Ketones  
Total bilirubin 
WBC 
count 
with 
differential 
 
24-hour proteinc 
Direct bilirubin 
Neutrophil count 
 
pH 
Blood urea nitrogen or urea 
Lymphocyte count 
 
Specific gravity 
Potassium 
Monocyte count 
 
 
Sodium 
Basophil count 
 
 
Calcium 
Eosinophil count 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Testosteronea 
Creatine kinase 
Creatine kinase-cardiac 
muscle isoenzyme 
(CK-MB)d 
 
 
 
Abbreviations: aPTT = activated partial thromboplastin time; INR = International Normalized Ratio WBC = white 
blood cell. 
a. 
Testosterone test is only applied for patients with mCRPC. However, the testosterone levels do not need to be 
checked if the patient has undergone surgical castration for > 4 months. Patients receiving chemical castration 
should have testosterone levels checked at baseline and confirmed to be in the castrate levels (< 0.5 ng/mL or 
1.735 nM). 
b. Coagulation tests are required at baseline and subsequently as clinically indicated (eg, patients with underlying 
coagulation disorder) 
c. 
On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein 
and a random urine sample for total protein and creatinine to determine a protein to creatinine ratio 
d. If CK-MB fractionation is not available, troponin I and/or troponin T should be assessed instead. 
In addition, the following tests will be conducted in this study:  
• 
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 before study drug administration at each cycle 
and at Safety Follow-up. A serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal. A negative pregnancy test (by urine or serum) must be completed and recorded before 
administration of study drug(s) at each cycle 
• 
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 Safety Follow-up Visit (see 
Section 7.3.4 for details). 
 


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APPENDIX 3. 
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 4. 
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 sponsor medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
 


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APPENDIX 5. 
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 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized male partner 
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of 
exposure associated with the study treatment) 
 
NOTE: Total sexual abstinence should only be used as a contraceptive  
method if it is in line with the patient’s usual and preferred lifestyle.  
   Periodic abstinence (eg, calendar, ovulation, symptothermal,  
post-ovulation methods), declaration of abstinence for the duration of exposure to study drug, and 
withdrawal are not acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is not 
considered a highly effective method of contraception and if used, this method must be combined with 
another acceptable method listed above. 
Definitions of “Women of Childbearing Potential", “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of the 
following criteria: 
• 
Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) 
• 
Postmenopausal, defined as: 
o ≥ 55 years of age with no spontaneous menses for ≥12 months OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with a postmenopausal 
follicle-stimulating hormone concentration > 30 IU/mL 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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APPENDIX 6. 
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, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart 
and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and 
Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 
1964, p 114.  


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APPENDIX 7. 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from serum 
creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the 
Modification of Diet in Renal Disease (MDRD) Study equation. NKDEP’s calculators rely on creatinine 
determinations which are isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be 
using creatinine methods calibrated to be IDMS traceable.  
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. This 
equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1 209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 body surface 
area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-
calculators.aspx 
Source: Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150(9):604-12). 


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APPENDIX 8. 
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, disease progression, and adverse effects of 
concomitant drugs. In addition to the results of these tests, the following factors should be considered 
when making an irAE diagnosis:  
• 
What was the temporal relationship between initiation of tislelizumab and the adverse event? 
• 
How did the patient respond to withdrawal of tislelizumab? 
• 
Did the event recur when tislelizumab was reintroduced? 
• 
Was there a clinical response to corticosteroids? 
• 
Is the event an autoimmune endocrinopathy? 
• 
Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field associated with 
the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of Possible  
Immune-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  


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Recommended Diagnostic Tests in the Management of Possible  
Immune-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a patient 
experiences bleeding, pain or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.  
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a hepatologist 
and consider liver biopsy.  
Renal toxicity 
Review hydration status and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to nephrology for further management assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology 
referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB (if CK-MB fractionation is not 
available, troponin I and/or troponin T should be assessed instead), and refer to a 
cardiologist. 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANA = antinuclear antibody; AST = aspartate 
aminotransferase; CK = creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS = central nervous system; 
CRP = C-reactive protein; CT = computed tomography; DLCO = diffusing capacity for carbon monoxide; ECG = 
electrocardiogram; ESR = erythrocyte sedimentation rate; FBC = full blood count; HIV = human immunodeficiency 
virus; INR = international normalized ratio; LCI = liver cytosolic antigen; LFT = liver function test; LKM = liver 
kidney microsomal antibody; LP = liver pancreas antigen; MRA = magnetic resonance angiogram; MRI = magnetic 
resonance imaging; PCR = polymerase chain reaction; SLA = soluble liver antigen; SMA = smooth muscle 
antibody; T4 = thyroxine; TFT = thyroid function tests; TSH = thyroid-stimulating hormone; UEC = urea 
electrolytes and creatinine. 


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Treatment of Immune-related Adverse Events 
• Immune-related AEs can escalate quickly; study treatment interruption, close monitoring, 
timely diagnostic work-up and treatment intervention, as appropriate, with patients is 
required 
• Immune-related AEs should improve promptly after introduction of immunosuppressive 
therapy. If this does not occur, review the diagnosis, seek further specialist advice and 
contact the study medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after consultation 
with the study medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy 
 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
µg/kg/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. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
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. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. Initiate 
pulse IV methylprednisolone 1 
mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation. Convert to 
oral prednisolone and taper over at 
least 1 month. Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen. 
Consider Pneumocystis infection 
prophylaxis. Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 2 
months. Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day. Taper over at least 
4 weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms. Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids over 
2-4 weeks, consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
symptoms 
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. 
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. 
3 
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:  
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day. When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed IV methylprednisolone 
• 
If on IV, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
Hold study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Creatinine > 3X baseline 
or > 3X-6X ULN 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 4 
weeks. 
investigated.  
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline. Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9- 
13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week. Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management. Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose value 
> 500 mg/dL; > 27.8 
mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment. Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the study medical 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management. Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
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 study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management. Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider IV corticosteroids if 
not contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. If symptoms do not 
improve add immunosuppressant 
therapy. Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
<2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms. Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 1-
2 mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BSA = 
body surface area; CHF = congestive heart failure; CK = creatine kinase; CK-MB = creatine kinase cardiac 
isoenzyme; INR = international normalized ratio; IV = intravenous; LFT = liver function test; MMF = 
mycophenolate mofetil; NYHA = New York Heart Association; T4 = thyroxine; TB = tuberculosis; TFT = 
thyroid function test; TSH = thyroid-stimulating hormone; U&E = urea and electrolytes; ULN = upper limit of 
normal. 


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APPENDIX 9. 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference:  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (Version 1.1). Eur J Cancer. 2009;45:228-247. 
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: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and 
a minimum of 10 mm). 
• 
10 mm caliper measurement by clinical examination (when superficial). 
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
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: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 


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Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area patiented 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 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”). 


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


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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. 
 
 


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RESPONSE CRITERIA 
Evaluation of Target Lesions 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.  
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if 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. 
• 
Target lesions that become “too small to measure”. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure”.  
 
When this occurs, it is important that a value be recorded on the eCRF. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
• 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 


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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. 
• 
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). 
• 
PD: Unequivocal progression (as detailed below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression.) 
• 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
• 
When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
 
• 
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 
apply here as noted above, however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a measurable 
lesion).  
Examples include an increase in a pleural effusion from “trace” to “large”, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”. If “unequivocal progression” is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (for example, some “new” bone lesions may be simply healing or flare of pre-existing 


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lesions). This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals metastases. 
The patient’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible “new” disease). New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on a 
new lesion. 
• 
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 best overall response is the best response recorded from the start of the study drug treatment until the 
end of treatment taking into account any requirement for confirmation. On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment assessments 
are to be considered in determination of best overall response. Protocols must specify how any new 
therapy introduced before progression will affect best response designation. The patient’s best overall 
response assignment will depend on the findings of both target and 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 
“best overall response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall 
response of PR). When SD is believed to be best response, it must also meet the protocol specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments. For example, a patient who 
has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best 


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response of PD. The same patient lost to follow-up after the first SD assessment would be considered 
inevaluable. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD 
= stable disease. 
 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” size (< 
10 mm), they may still have a measurement reported on scans. This measurement should be recorded 
even though the nodes are normal in order not to overstate progression should it be 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 disease progression at that time should be reported as “symptomatic deterioration”. 
Every effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping trial 
therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and should be 
clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of 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 


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circumstance should be prospectively described in the protocol and supported by disease specific medical 
literature for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 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 progression-free survival are influenced 
by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define a 
standard follow-up frequency. The frequency should take into account many parameters including disease 
types and stages, treatment periodicity, and standard practice. However, these limitations of the precision 
of the measured endpoint should be taken into account if comparisons between trials are to be made. 
 
 
 


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APPENDIX 10. 
IRECIST CRITERIA 
Table 1: Comparison of RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definition of measurable 
and non-measurable 
disease; numbers and site 
of target disease 
Measurable lesions are ≥10 mm in 
diameter (≥ 15mm for nodal lesions); 
maximum of five lesions (two per organ); 
all other disease is considered non-target 
(must be ≥10 mm in short axis for 
nodal disease) 
No change from RECIST 1.1; however, 
new lesions are assessed as per 
RECIST 1.1 but are recorded separately 
on the case report form (but not 
included in the sum of lesions for target 
lesions identified at baseline) 
Complete response, partial 
response, or stable disease 
Cannot have met criteria for progression 
before complete response, partial 
response, or stable disease 
Can have had iUPD (one or more 
instances), but not iCPD, before iCR, 
iPR, or iSD 
Confirmation of complete 
response or partial 
response 
Only required for non-randomized trials 
As per RECIST 1.1 
Confirmation of stable 
disease 
Not required 
As per RECIST 1.1 
New lesions 
Result in progression; recorded but not 
measured 
Results in iUPD but iCPD is only 
assigned on the basis of this category if 
at next assessment additional new 
lesions appear or an increase in size of 
new lesions is seen (≥5 mm for sum of 
new lesion target or any increase in 
new lesion non-target); the appearance 
of new lesions when none have 
previously been recorded, can also 
confirm iCPD 
Independent blinded 
review and central 
collection of scans 
Recommended in some circumstances-
eg, in some trials with progression-based 
endpoints planned for marketing 
approval 
Collection of scans (but not 
independent review) recommended for 
all trials 
Confirmation of 
progression 
Not required (unless equivocal) 
Required  
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is considered when 
deciding whether treatment is 
continued after iUPD 
“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation Criteria in Solid Tumors. 
iUPD=unconfirmed progression. iCPD=confirmed progression. iCR=complete response. iPR=partial response. 
iSD=stable disease. 
Source: Seymour L et al, 2017.  


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Table 2: Assignment of Timepoint Response Using iRECIST 
 
Timepoint response 
with no previous 
iUPD in any 
category 
Timepoint response with previous iUPD in any 
category* 
Target lesions: iCR; non-target 
lesions: iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target 
lesions: non-iCR/non-iUPD; 
new lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target 
lesions: non-iCR/non-iUPD; 
new lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target 
lesions: non-iCR/non-iUPD; 
new lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease 
from last timepoint; non-target 
lesions: iUPD with no change, 
or decrease from last 
timepoint; new lesions: yes 
Not applicable 
New lesions confirm iCPD if new lesions were 
previously identified and they have increased in size 
(≥5 mm in sum of measures for new lesion target or 
any increase for new lesion non-target) or number; if 
no change is seen in new lesions (size or number) 
from last timepoint, assignment remains iUPD 
Target lesions: iSD, iPR, iCR; 
non-target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in the size of non-target disease 
(does not need to meet RECIST 1.1 criteria for 
unequivocal progression) 
Target lesions: iUPD; non-
target lesions: non-iCR/non-
iUPD, or iCR; new lesions: no 
iUPD 
 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in sum of measures ≥5 mm; 
otherwise, assignment remains iUPD 
Target lesions: iUPD; non-
target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed based on a 
further increase in previously identified target lesion 
iUPD in sum of measures ≥5 mm or non-target lesion 
iUPD (previous assessment need not have shown 
unequivocal progression) 
Target lesions: iUPD; non-
target lesions: iUPD; new 
lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in previously identified target 
lesion iUPD sum of measures ≥5 mm, previously 
identified non-target lesion iUPD (does not need to be 
unequivocal), or an increase in the size or number of 
new lesions previously identified 
Target lesions: non-iUPD or 
progression; non-target 
lesions: non-iUPD or 
progression; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of an increase in the size or number of new lesions 
previously identified 


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Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no 
pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete response, partial response, and stable 
disease would be the same. *Previously identified in assessment immediately before this timepoint. “i” indicates 
immune responses assigned using iRECIST. iCR=complete response. iPR=partial response. iSD=stable disease. 
iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither CR nor PD have been met. iCPD=confirmed 
progression. RECIST=Response Evaluation Criteria in Solid Tumors. 
Source: Seymour L et al, 2017. 
 
Table 3: Scenarios of Assignment of Best Overall Response Using iRECIST 
 
 
Timepoint 
response 1 
Timepoint 
response 2 
Timepoint 
response 3 
Timepoint 
response 4 
Timepoint 
response 5 
iBOR 
Example 1 
iCR 
iCR, iPR, 
iUPD, or NE 
iCR, iPR, 
iUPD, or NE 
iUPD 
iCPD 
iCR 
Example 2 
iUPD 
iPR, iSD, or 
NE 
iCR 
iCR, iUPD, 
or NE 
iCR, iPR, 
iSD, iUPD, 
iCPD, or NE 
iCR 
Example 3 
iUPD 
iPR 
iPR, iSD, 
iUPD, or NE 
iPR, iSD, 
iUPD, NE, or 
iCPD 
iPR, iSD, 
iUPD, NE, or 
iCPD 
iPR 
Example 4 
iUPD 
iSD or NE 
iPR 
iPR, iSD, 
iUPD, or NE 
iPR, iSD, 
iUPD, iCPD, 
or NE 
iPR 
Example 5 
iUPD 
iSD 
iSD, iUPD, or 
NE 
iSD, iUPD, 
iCPD, or NE 
iSD, iUPD, 
iCPD, or NE 
iSD 
Example 6 
iUPD 
iCPD 
Any 
Any 
Any 
iCPD 
Example 7 
iUPD 
iUPD (no 
iCPD) 
iCPD 
Any 
Any 
iCPD 
Example 8 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
 Eight examples are presented for patients with target disease at baseline, but many more scenarios exist following 
the same principles. Table assumes a randomized study in which confirmation of complete 
response or partial response is not required. For patients with non-target disease only at baseline, only iCR or non-
complete response or non-progression of disease can be assigned at each timepoint (not shown 
in the table for ease of presentation). “i” indicates immune responses assigned using iRECIST. iBOR=best overall 
response. iCR=complete response. iPR=partial response. NE=not evaluable. iUPD=unconfirmed 
progression. iCPD=confirmed progression. iSD=stable disease. RECIST=Response Evaluation Criteria in Solid 
Tumors. 
Source: Seymour L et al, 2017.  
 
 
 
 


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Figure 1: RECIST 1.1 and iRECIST: an example of assessment 
 
Prefix “i” indicates immune responses assigned using iRECIST; others without “i” are confirmed by RECIST 1.1. 
RECIST=Response Evaluation Criteria in Solid Tumors. 
iCR=complete response. iCPD=complete progression. iPR=partial response. iSD=stable disease. 
iUPD=unconfirmed progression. TP=timepoint. 
Source: Seymour L et al, 2017. 
 
 
 


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APPENDIX 11. 
CHILD-PUGH CLASSIFICATION SCORING SYSTEM 
The information presented here has been obtained from the Washington University Medical 
Center, with sources as follows: 
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for 
placement of adults on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637 
Pugh RNH, Murray-Lyon IN, Dawson DL, Pietroni MC, and Williams R. Transection of the 
esophagus for bleeding esophageal varices. Brit J Surgery. 1973;60:646-645 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood 
transfusion. N Engl J Med. 1996;274(9):473-481 
Child-Pugh classification is either Grade A (mild: score 5 to 6 points), B (moderate: from 7 to 9 
points), or C (severe: from 10 to 15 points) and is determined by both clinical and biochemical 
parameters (as shown below). 
Clinical/Biochemical Parameter 
Score (Anomaly Severity) 
1 
2 
3 
Hepatic encephalopathy (NCI-CTCAE grade)a 
0b 
1c or 2d 
3e or 4f 
Ascites (presence and severity) 
None 
Mild 
Moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prolonged prothrombin time (seconds) 
or 
Activated partial thromboplastin time 
(INRg) 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
a. 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion.  
N Engl J Med. 1996;274(9):473-481. 
b. Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c. 
Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5CPS waves. 
d. Grade 2: Lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e. 
Grade 3: Drowsiness, coma, orientation disorder, over-reflection, stiff/slow wave. 
f. 
Grade 4: Cannot wake up from coma, no independent personality/behavior, irrational, slow 2-3CPS Delta 
activity. 
g. Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637. 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events. 
 
 
 
 

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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-900-101 
Study Protocol 
Title: 
Phase 1/2 Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Anti-PD-L1 Monoclonal Antibody 
BGB-A333 Alone and in Combination with Anti-PD-1 Monoclonal 
Antibody Tislelizumab in Patients with Advanced Solid Tumors   
 
Date: 
October 12, 2020 
Version: 
Version 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SIGNATURE PAGE 
                
 
 
 
 
 
Signature 
Date:  ______________ 
 
 
 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date: ________________ 
 
 
 
 
 
Signature 
Date: ________________ 
 
 
 
 
Signature 
Date: ________________ 
 


 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
6 
2 
STUDY OVERVIEW 
6 
2.1 
Overview 
6 
2.2 
Study Assessments 
9 
Adverse Events 
9 
3 
STUDY OBJECTIVES 
11 
3.1 
Primary Objectives 
11 
3.2 
Secondary Objectives 
11 
3.3 
Exploratory Objectives 
12 
4 
STUDY ENDPOINTS 
12 
4.1 
Primary Endpoints 
12 
4.2 
Secondary Endpoints 
13 
5 
SAMPLE SIZE CONSIDERATIONS 
13 
6 
STATISTICAL METHODS 
14 
6.1 
Analysis Populations 
14 
6.2 
Data Analysis General Considerations 
14 
6.2.1 
Definitions and Computations 
14 
6.2.2 
Conventions 
15 
6.2.3 
Handling of Missing Data 
16 
6.2.3.1 
Date of medication missing or partially missing 
16 
6.2.3.2 
Onset date of adverse event missing or partially missing 
16 
6.2.3.3 
Relationship of adverse event to study treatment 
16 
6.2.3.4 
Severity (grade) of adverse event 
16 
6.2.4 
Adjustment for Covariates 
16 
6.2.5 
Multiplicity Adjustment 
16 
6.2.6 
Data Integrity 
16 
6.3 
Subject Characteristics 
17 
6.3.1 
Patient Disposition 
17 
6.3.2 
Protocol Deviations 
17 
6.3.3 
Demographic and Other Baseline Characteristics 
17 
6.3.4 
Disease History and Baseline Disease Characteristics 
17 
6.3.5 
Prior Anti-Cancer Drug Therapies and Radiotherapies 
17 
6.3.6 
Prior and Concomitant Medications 
17 
6.3.7 
Medical History 
18 
6.4 
Efficacy Analysis 
18 
6.4.1 
Primary Efficacy Endpoints 
18 
6.4.2 
Secondary Efficacy Endpoints 
18 
6.5 
Safety Analyses 
19 
6.5.1 
Extent of Exposure 
19 
6.5.2 
Adverse Events 
20 


 
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6.5.3 
Laboratory Values  
21 
6.5.4 
Vital Signs 
22 
6.5.5 
Electrocardiograms (ECG) 
22 
6.5.6 
Eastern Cooperative Oncology Group (ECOG) 
22 
6.6 
Pharmacokinetic Analyses 
22 
6.7 
Immunogenic Analyses 
22 
7 
INTERIM ANALYSIS 
22 
8 
CHANGES IN THE PLANNED ANALYSIS 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
A317 
BGB-A317 
A333 
BGB-A333 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
FDA 
Food and Drug Administration 
irAE 
immune-related adverse event 
iRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamics; progressive disease 
PD-1 
programmed cell death protein-1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time; preferred term 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
UC 
urothelial carcinoma; urothelial cancer 
 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to pre-specify the procedures and the 
statistical methods (before the database lock) that will be used to analyze data and report results 
for Study BGB-900-101: a Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activity of Anti-PD-L1 Monoclonal Antibody BGB-A333 Alone and 
in Combination with Anti-PD-1 Monoclonal Antibody Tislelizumab in Patients with Advanced 
Solid Tumors. This SAP is for the final analyses of the final study protocol (Protocol amendment 
2.0). Supporting documents and references are included in Appendices. 
The analyses to the sample data of pharmacokinetics (PK), pharmacodynamics (PD), 
pharmacogenomics (ADA) and biomarkers, are not covered in this document and they will be 
described in separate documents.  
2 
STUDY OVERVIEW 
2.1 
OVERVIEW 
This is an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. This study 
consists of the following phases: 
 
• 
Phase 1A (BGB-A333 dose escalation): approximately 4-5 dose levels or dosing 
regimens will be tested in patients with advanced solid tumors. Additional dose levels 
could be tested if needed. The modified 3+3 design will be used in the dose escalation. At 
least 6 evaluable patients should be enrolled at the MTD level, the RP2D level or at the 
highest dose level tested if MTD is not reached. 
• 
Phase 1B (BGB-A333 and tislelizumab dose confirmation): a cohort of approximately 6 
patients with solid tumors will be treated with BGB-A333 and tislelizumab (200 mg, 
Q3W, IV). The SMC will make a recommendation on the selection of BGB-A333 dose 
based on available safety, efficacy, PK and exploratory data from Phase 1A. If the initial 
dose combination is deemed not tolerated, additional cohorts of patients may be enrolled 
to evaluate lower doses or alternative dosing regimens of BGB-A333 and tislelizumab. 
• 
Phase 2B (BGB-A333 and tislelizumab dose expansion): approximately 20 patients with 
UC may be enrolled.  
 
All patients will receive study drug until 1) they are no longer considered to be achieving clinical 
benefit, 2) unacceptable toxicity, or 3) withdrawal of informed consent. 
 
In Phase 1A (BGB-A333 monotherapy), if patients progress on BGB-A333 without other safety 
concerns, these patients may be treated with a higher dose of BGB-A333 that is deemed to be 
well tolerated by SMC. The decision to modify the dose of BGB-A333 must be discussed with 
the sponsor’s medical monitor and documented in the study records. 
 
In Phase 1A (BGB-A333 monotherapy), if patients progress on BGB-A333 monotherapy without 
other safety concerns, these patients may receive combination of BGB-A333 and tislelizumab at 
doses that are deemed to be well tolerated by SMC. The decision to add tislelizumab to patients 


 
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treated with BGB-A333 alone must be discussed with the sponsor’s medical monitor and 
documented in the study records. 
 
Planned dose levels for BGB-A333 and tislelizumab are provided in Table 1. All patients will be 
monitored continuously for AEs. Treatment modifications (eg, dose delay or discontinuation) 
will be based on specific AE criteria, as described in Section 5.4 of the protocol. Reasons for 
dose modifications or delay or treatment discontinuation will be documented in the patients’ 
chart and recorded in the eCRF. 
 
Table 1. Planned Dose Levels for BGB-A333 and Tislelizumab 
Study Drug  
Dose  
Frequency of  
Administration  
Route of  
Administration  
BGB-A333  
450 mg,  
900 mg,  
1350 mg,  
1800 mg,  
2250 mg 
(optional)  
Every 3 weeks  
(additional dose 
levels or dosing 
regimens may be 
explored)  
Intravenous  
Tislelizumab  
200 mg  
Every 3 weeks  
(additional dose 
levels or dosing 
regimens may be 
explored)  
Intravenous  
 
BGB-A333 and tislelizumab will be administered by IV infusion through an IV line containing a 
sterile, non-pyrogenic, low-protein-binding filter.  
 
For BGB-A333 monotherapy (Phase 1A), on C1D1, C2D1 and C3D1, the infusion of BGB-
A333 will be delivered over 60 (± 5) minutes. After infusion of BGB-A333, patients must be 
monitored for at least 120 minutes in an area with resuscitation equipment and emergency 
agents. 
 
If BGB-A333 infusion is well tolerated in the first three cycles, on C4D1 and subsequent cycles, 
BGB-A333 may be administered over 30 (± 5) minutes and, after infusion of BGB-A333, 
patients must be monitored for at least 30 minutes in an area with resuscitation equipment and 
emergency agents. 
 
For BGB-A333 and tislelizumab combination arms (Phase 1B and Phase 2B), tislelizumab 
will be administered first followed by the administration of BGB-A333. 
• On C1D1 and C2D1, tislelizumab will be administered over 60 (± 5) minutes followed by 
the administration of BGB-A333 over 60 (± 5) minutes. After infusion of BGB-A333, 
patients must be monitored for at least 120 minutes in an area with resuscitation 
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• If infusions of tislelizumab and BGB-A333 are well tolerated in the first two cycles, on 
C3D1, tislelizumab may be administered over 30 (± 5) minutes followed by the 
administration of BGB-A333 over 60 (± 5) minutes and, after infusion of BGB-A333, 
patients must be monitored for at least 60 minutes in an area with resuscitation equipment 
and emergency agents. 
• If infusions of tislelizumab and BGB-A333 are well tolerated in the first three cycles, on 
C4D1 and subsequent cycles, tislelizumab may be administered over 30 (± 5) minutes 
followed by the administration of BGB-A333 over 30 (± 5) minutes and, after infusion of 
BGB-A333, patients must be monitored for at least 30 minutes in an area with 
resuscitation equipment and emergency agents. 
The infusion rate may be decrease or infusion may be stopped in the evet of infusion-related 
reactions. 
 
Figure 1 Study Schema 
 
Abbreviations: UC = urothelial carcinoma; Q3W = every 3 weeks. 
 


 
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A Sponsor decision was made not to pursue A333 as a monotherapy treatment beyond the 
completion of dose escalation in Phase 1A.  As such, Phase 2A was not initiated nor conducted 
in the study.  For Phase 2B, only one cohort was opened for dose expansion and a total of 12 
patients were treated in the metastatic urothelial carcinoma arm (mUC).  
 
2.2 
STUDY ASSESSMENTS 
DLT Assessment 
For Phase 1A (BGB-A333 dose escalation), at least 3 patients evaluable for dose-limiting 
toxicity (DLT) assessment will be enrolled per dose level. Dose escalation will proceed to the 
next dose level if no DLT is observed in the first 3 DLT-evaluable patients. Otherwise, if a DLT 
has occurred, the cohort is expanded to at least 6 patients. If there is no additional DLT in the 
first 6 DLT-evaluable patients, dose escalation will continue to the next level. Dose escalation 
will stop when there are 2 or more DLTs in 6 patients within the same dose level. If 2 or more 
DLTs are reported in 6 patients at a dose level, a minimum of 6 patients will be enrolled on the 
next lower dose level, or an intermediate dose level may be evaluated if recommended by the 
SMC. The MTD dose level is defined as the highest dose at which < 33% of the patients 
experience a DLT.  At least 6 evaluable patients should be enrolled at the MTD level, the RP2D 
level or at the highest dose level tested if MTD is not reached. 
DLTs will be assessed among evaluable patients within 21 days after the first dose of BGB-
A333. For dose escalation decision, only DLTs occurring within the first 21 days will be 
evaluated. For determination of MTD and RP2D, clinically significant toxicities (e.g., irAE) will 
also be considered.  
Adverse Events 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, 
version 4.03 (NCI-CTC, June 2010). Characterization of toxicities will include severity, 
duration, and time to onset. 
All toxicities or adverse events will be graded according to the NCI-CTCAE Version 4.03.  
Definition of DLT 
The occurrence of any of the following toxicities within 21 days after the first dose of BGB-
A333 if judged by the Investigator as related to BGB-A333 will be considered a DLT. 
Hematologic: 
1. Grade 4 neutropenia lasting > 7 days 
2. Grade 3 febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a 
single temperature of 38.3oC or a sustained temperature of 38oC for >1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding 
5. Grade 4 thrombocytopenia 


 
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6. Grade 4 anemia (life-threatening) 
Non-hematologic: 
1. Grade 4 or above toxicity 
2. Grade 3 toxicity lasting more than 7 days despite optimal supportive care 
Note: The following AEs will not be considered as DLTs: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumors) 
• Grade 3 rash 
• Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical sequelae 
(eg, LDH)  
In addition, clinically important or persistent toxicities that are not included above may also be 
considered a DLT following review by SMC.  
Patients who received < two-thirds (67%) of the assigned dose of BGB-A333 (eg, because the 
infusion had to be stopped due to an infusion reaction) and did not experience a DLT will not be 
taken into account in the assessment of the overall DLT rate for the particular dose level. 
Tumor Assessments 
Radiological assessment of tumor-response status should be performed approximately every 9 
weeks (for Q3W dosing) in the first year, then every 12 weeks thereafter. If other dosing 
intervals are explored (Q2W or Q4W), radiological assessment of tumor response will be 
performed approximately every 8 weeks.  
Tumor response will be assessed by Investigators based on the RECIST version 1.1.  
For immune therapies, such as BGB-A333 and 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 at least 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 drug treatment in patients with suspected pseudoprogression:  


 
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• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values) 
• Stable ECOG performance status 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment beyond radiologic 
disease progression and inform patients that this practice is not considered standard in the 
treatment of cancer 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed 
with the sponsor’s medical monitor and documented in the study records. 
 
3 
STUDY OBJECTIVES 
Study objectives are presented by study phase in this section. 
3.1 
PRIMARY OBJECTIVES  
Primary Objectives for Phase 1A (Dose Escalation for BGB-A333 Monotherapy) and Phase 1B 
(Dose Confirmation for BGB-A333 and Tislelizumab Combination) 
• To assess the safety and tolerability of BGB-A333 alone and in combination with 
BGBA317 in patients with advanced solid tumors 
• To determine the maximum tolerated dose (MTD), if any, and RP2D for BGB-A333 
alone and in combination with tislelizumab 
Primary Objectives for Phase 2B (BGB-A333 and Tislelizumab Combination Dose Expansion) 
To assess objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 of BGB-A333 alone and in combination with tislelizumab in patients with 
selected tumor types 
 
3.2 
SECONDARY OBJECTIVES  
Secondary Objectives for Phase 1A and Phase 1B: 
• To assess the preliminary antitumor activity of BGB-A333 alone and in combination with 
tislelizumab 
• To characterize the PK of BGB-A333 alone and in combination with tislelizumab  
• To assess host immunogenicity to BGB-A333 alone and in combination with tislelizumab 
Secondary Objectives for Phase 2B: 
• To assess other tumor assessment outcomes (ie, duration of response [DOR], 
progression-free survival [PFS] and disease control rate [DCR]) per RECIST version 1.1  
• To characterize safety and tolerability of BGB-A333 alone and in combination with 
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• To characterize the PK of BGB-A333 alone and in combination with tislelizumab 
• To assess host immunogenicity to BGB-A333 and tislelizumab 
3.3 
EXPLORATORY OBJECTIVES 
4 
STUDY ENDPOINTS 
Study endpoints, separated as the primary, secondary and exploratory endpoints, are explained in 
this section.   
4.1 
PRIMARY ENDPOINTS 
Primary endpoints for Phase 1A and Phase 1B:   
 
• 
Safety and tolerability: The safety of BGB-A333 alone and in combination with tislelizumab will 
be assessed throughout the study by monitoring AEs and SAEs per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03, relevant 
physical examination, electrocardiograms and laboratory assessments as needed 
• 
The MTD, if any, and Recommended Phase 2 Dose (RP2D) for BGB-A333 alone and in 
combination with tislelizumab will be determined based on safety, tolerability, PK, preliminary 
efficacy, and other available data 
Primary endpoints for Phase 2B:   
• 
Efficacy evaluations: ORR will be determined based on investigators assessment per RECIST 
version 1.1. The ORR is defined as the proportion of patients who had confirmed CR or PR 
assessed by investigator using RECIST version 1.1. ORR and its 95% CI will be summarized in 
the Safety Population 


 
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4.2 
SECONDARY ENDPOINTS 
Secondary endpoints for Phase 1A and Phase 1B: 
• Efficacy evaluations: ORR, DOR, and DCR based on investigator assessment per 
RECIST version 1.1.   
o ORR is defined as the proportion of patients who had confirmed complete 
response (CR) or partial response (PR) assessed by investigator using RECIST 
version 1.1. ORR and its 95% confidence interval (CI) will be summarized in the 
Safety Population and Efficacy Evaluable Population 
o DOR is defined as the time from the first determination of an objective response 
per RECIST version 1.1, until the first documentation of progression or death, 
whichever occurs first 
o DCR is defined as the proportion of patients with best overall response of CR, PR 
and SD. It will be summarized similarly as ORR 
• PK: Individual BGB-A333 and tislelizumab concentrations and PK parameters will be 
tabulated by dose cohort 
• Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be 
assessed by summarizing the number and percentage of patients by dose cohort who 
develop detectable antidrug antibodies  
Secondary endpoints for Phase 2B: 
• DOR, PFS, and DCR based on investigator assessment per RECIST version 1.1. 
o PFS is defined as the time from the date of the first dose of study drug(s) to the 
date of the first documentation of disease progression assessed by investigator 
using RECIST v1.1 or death, whichever occurs first 
• Safety and tolerability: The safety of BGB-A333 in combination with tislelizumab will be 
assessed throughout the study by monitoring AEs and SAEs per NCI-CTCAE Version 
4.03, relevant physical examination, electrocardiograms and laboratory assessments as 
needed 
• PK: Individual concentrations and PK parameters of BGB-A333 and tislelizumab 
• Immunogenicity: Immunogenic responses to BGB-A333 and tislelizumab will be 
assessed by summarizing the number and percentage of patients who develop detectable 
antidrug antibodies (ADAs) 
5 
SAMPLE SIZE CONSIDERATIONS 
The study plans to enroll approximately 98 to 128 patients. 
• 
Phase 1A (BGB-A333 dose escalation): Approximately 12 to 30 patients with advanced solid 
tumors in 4 to 5 dose levels or dosing regimens per modified 3+3 design 
• 
Phase 1B (BGB-A333 and tislelizumab combination): Approximately 6 patients with advanced 
solid tumors in one combination dosing regimen. An additional 12 patients may be enrolled to 
test different dosing regimens 
• 
Phase 2B (BGB A333 and tislelizumab combination dose expansion): Approximately 20 patients 
with UC 


 
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In Phase 2, approximately 20 patients per cohort will be enrolled to evaluate the preliminary efficacy.  
No formal hypothesis testing will be performed in the efficacy evaluation. With 20 patients, the 
probabilities of observing at least one responder under different underlying ORR assumptions are 
summarized in Table 2, indicating the proposed sample size is adequate to detect any preliminary 
anti-cancer activities of the treatment. The 95% CIs of the ORR estimate when observing 1 to 6 
responders are included in Table 3, depicting the precision achieved with 20 patients.  
Table 2. 
Time Probabilities of Observing at least One Responder in 20 Patients under 
Various ORR Assumptions 
ORR 
0.10 
0.20 
0.30 
0.40 
Probability (observing ≥ 
1 responder) 
0.88 
0.99 
> 0.99 
> 0.99 
 
Table 3. 
95% CI (%) when Observing 1 to 6 Responders in 20 Patients 
# of 
responders 
1 
2 
3 
4 
5 
6 
95% CI 
(0.1, 24.8) 
(1.2, 31.7) 
(3.2, 37.9) 
(5.7, 43.7) 
(8.7, 49.1) 
(11.9, 54.3) 
 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
Safety Population includes all patients who received at least 1 dose of study drug. It is the 
population for the safety and efficacy analyses.  
 
The PK analysis population includes all patients with valid PK sampling after treatment with 
study drug(s) 
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
All the reporting of data analyses, including summary tables and listings, is presented by phase 
and cohort (per dose level for Phase 1A and Phase 1B, or tumor type for Phase 2B). All data will 
be listed as well. 
All efficacy and safety analyses will be performed for safety population. The analyses of ORR 
and its 95% confidence interval will be repeated for efficacy evaluable population as well. All 
listings will be presented for safety population unless otherwise specified.   
6.2.1 
Definitions and Computations 
Reference date: is the first date of any study drug (A333 or A317)  taken per patient. This date is 
noted as Day 1 of Cycle 1.   


 
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Study day: is the relative day of an assessment (for any event or observation) in reference to a 
patient’s date of first dose of study drug, calculated as (assessment date – reference date +1) for 
any assessment conducted on or after the reference date, or as (assessment date – reference date) 
for any assessment conducted before the reference date. So, the study day for the first dose is 1, 
noted as study day 1 (also, as explained above, as Day 1 of Cycle 1). Correspondingly, the study 
month of an assessment if needed is defined as the study day of the assessment divided by 
365.25 and by 12 (i.e., 365.25/12), rounded to 2 decimal places. When the event date is partial or 
missing, the date will appear partial or missing in the listings.  
Baseline assessment: is the last non-missing assessment collected prior to the first study drug.    
6.2.2 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 
• Summary analyses for continuous endpoints or variables will include n, mean, standard 
deviation, median, and range (minimum and maximum); summary analyses for 
categorical or discrete endpoints or variables will be in number (%) of patients reached 
the endpoint or variable, unless otherwise specified. For the second, the denominator to 
be used for the percentage will be the total number of patients by cohort of the analysis 
population, unless otherwise specified. 
• 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal place. 
• 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 decimal place. 
• Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
• Duration of event endpoints will be based on the actual date of event obtained rather than 
the associated visit date. 
• Missing efficacy or safety data will not be imputed unless otherwise specified.  
• For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
• For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator, unless otherwise specified. 
Unscheduled measurements will not be included but will contribute to the worst if 
required in the analyses. Listings will include all, the scheduled and the unscheduled.  
• Data will be presented to the original number of decimal places. The mean and medians 
will be presented to 1 more decimal place than the raw data. The standard deviations will 
be presented to 2 more decimal places than the raw data.  


 
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6.2.3 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified in the footnote of an output. Missing 
data will not be included in any analysis unless otherwise specified as well. When relevant, the 
number of patients with missing data will be presented. 
6.2.3.1 
Date of medication missing or partially missing  
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and cannot be determined whether it was taken prior or 
concomitantly, it will be considered concomitant. 
6.2.3.2 
Onset date of adverse event missing or partially missing 
When an AE has a missing or partially onset date, if the missing or partially onset date does not 
indicate that the AE started prior to the study treatment or after the 30th day post last study 
treatment, it will be classified conservatively as the treatment-emergent AE (TEAE, defined in 
Section 6.5.2). This data handling is just for the determination of treatment emergent adverse 
events and no imputation will be performed to AE start/end dates in datasets and listings. 
 
6.2.3.3 
Relationship of adverse event to study treatment 
If the assessment of the relationship of an AE to study drug is missing, the event will be 
considered related to the study drug. This handling is only for the classification and no 
imputation will be done at the data level. 
6.2.3.4 
Severity (grade) of adverse event 
If a severity is missing for an AE interested, and the maximal severity on the remaining 
occurrences of this AE is mild or moderate, then the worst severity of the event cannot be 
determined. Therefore, whenever a summary of AEs by severity is to be presented, this event 
will be in a separate “missing” category. 
 
6.2.4 
Adjustment for Covariates 
Not applicable. 
6.2.5 
Multiplicity Adjustment 
No multiplicity adjustments will be made. 
6.2.6 
Data Integrity 
Before final statistical, the integrity of the data should be reviewed to assure fit-for-purpose.  The 
data set for analysis should be an accurate and complete representation of the patients' relevant 
outcomes from the clinical database.  All data should be complete and reviewed up to data cutoff 
date.  Consistency checks and appropriate source data verification should be complete. 


 
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6.3 
SUBJECT CHARACTERISTICS 
6.3.1 
Patient Disposition 
The number of patients treated, discontinued from study drug and/or study and those with major 
protocol deviations will be summarized. The primary reason for study drug and/or study 
discontinuation will be summarized according to the categories in the eCRF. The end of study 
status (alive, dead, withdrew consent, lost to follow-up or compassionate use ) at the data cut-off 
date will be summarized using the data from the eCRF.  
6.3.2 
Protocol Deviations 
Major protocol deviations/violations will be summarized by category. All major protocol 
deviations/violations will be listed. 
6.3.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for the Safety Population 
using descriptive statistics. Continuous variables include age, weight, vital signs, etc. Categorical 
variables include race, gender, ECOG, country etc. 
6.3.4 
Disease History and Baseline Disease Characteristics 
Disease history and baseline characteristics include time since initial cancer diagnosis to date of 
signed consent, type of solid tumor at initial diagnosis, metastatic disease status at initial 
diagnosis, and metastatic disease status at study entry.  
 
Cancer associated symptoms at baseline will also be summarized by System Organ Class (SOC), 
preferred term. 
 
6.3.5 
Prior Anti-Cancer Drug Therapies and Radiotherapies 
The number (%) of prior anti-cancer drug therapies and prior radiotherapies will be summarized. 
The systemic therapies with the same sequence/regimen number are counted as one prior 
therapy. 
For prior anti-cancer drug therapy, number of regimens, time from end of last systemic therapy 
to study entry, best response for last therapy, and reason for therapy discontinuation will be 
summarized.  
6.3.6 
Prior and Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
(WHO) Drug Dictionary drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical Therapeutic Chemical (ATC) code indicating therapeutic classification. 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) class and WHO drug preferred term for the safety population. 
 


 
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Prior medications are defined as medications that stopped before the first dose of study drug. 
Concomitant medications are defined as medications that (1) started before the first dose of study 
drug and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to 30 days after the patient’s last dose.  
6.3.7 
Medical History 
Medical History will be coded using MedDRA (version 20.0 or newer). The number (%) of 
patients reporting a history of any medical condition, as recorded on the CRF, will be 
summarized by system organ class and preferred term for safety population.  
6.4 
EFFICACY ANALYSIS 
The efficacy per RECIST 1.1 (ie, ORR, DOR, PFS, and DCR) will be summarized by dose 
cohort in Phase 1A and Phase 1B. Efficacy will be summarized by tumor type in Phase 2B.  
All efficacy analyses will be performed for safety population. All time-to-event endpoints (PFS, 
DOR) will be analyzed by Kaplan-Meier (KM) method.  
6.4.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the objective response rate (ORR) for Phase 2B. Objective 
response rate is defined as proportion of patients with best overall response (BOR) of CR or PR. 
Confirmation of CR or PR is required for BOR of CR or PR. Patients without BOR of CR or PR 
will be considered as non-responders.  
The analyses will include number (%) of patients achieved the confirmed overall response as CR 
or PR and the 2-sided 95% confidence interval (CI) to the ORR by Clopper-Pearson method.  
ORR for Phase 1A and Phase 1B will also be summarized similarly by cohort. 
Best overall response is defined as the best response recorded from administration of study 
drug(s) until data cut or the start of new anticancer treatment. Patients with no post-baseline 
response assessment (due to any reason) will be considered as not evaluable for best overall 
response (BOR). The proportion of response categories (CR, PR, SD, and PD) will be presented. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints, including progression-free survival (PFS), duration of 
response (DOR), disease control rate (DCR), and clinical benefit rate (CBR). All the analyses 
will be performed for safety population.  
PFS will be estimated using the Kaplan-Meier (KM) method. The median PFS and landmark 
PFS at every 3 months will be calculated and presented with 2-sided 95% CIs.  
 
PFS is defined as the time from the date of first dose of study drug to the date of PD or death, 
whichever occurs first. Patients without PD/death will be censored at date of last adequate tumor 
assessment. The PFS censoring rule will follow United States Food and Drug Administration 


 
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(FDA) Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and 
Biologics (2007) (FDA Guidance for Industry 2007). 
 
DOR will be analyzed for the responders. DOR is defined as the time from the date of first 
response to the date of PD or death, whichever occurs first.   DOR analysis will follow the same 
censoring rule as used for PFS. 
 
Disease control rate (DCR) is defined as the proportion of patients who achieve the best overall 
response of CR, PR, or SD.   
 
Clinical benefit rate (CBR) is defined as the proportion of patients who achieve the best overall 
response of CR, PR, or durable SD [BOR of SD with duration ≥ 24 weeks].   
 
The DCR and CBR will be analyzed the same way as for ORR.  
 
In addition, the best change in sum of diameters of target lesions (i.e., the maximum tumor 
shrinkage) will be plotted using waterfall plot.   
 
6.5 
SAFETY ANALYSES 
Safety will be determined by the spontaneous reporting of adverse events and by laboratory 
values (hematology, serum chemistry, coagulation, and urinalysis). Vital signs, physical 
examination and ECG findings will also be used in determining the safety profile. The severity 
of adverse events will be graded according to the CTCAE v4.03. The incidence of DLT events, 
treatment-emergent AEs (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 data will be summarized in the Safety Population by study phase and cohort.  
6.5.1 
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. 
• Treatment duration = date of last exposure – date of first dose + 21.  
• The number of cycles received defined as the number of cycles with non-missing doses 
(dose>0) will be summarized by phase and cohort.  
• Dose intensity = cumulative total dose (mg) / (duration of exposure (day)/21).   
Relative 
dose 
intensity 
= 
Dose 
intensity 
/ 
planned 
dose 
intensity.  
The planned dose intensity = Total planned dose in a cycle.  


 
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• Cumulative total dose (mg) per subject will be computed as the sum of all of the doses 
received in each cycle for each study drug. 
 
The number (percentage) of patients requiring dose interruption, dose delay will be 
summarized for each cohort. 
6.5.2 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA®). Adverse events will be coded to 
MedDRA (Version 18.1 or higher) lower level term, preferred term and primary system organ 
class (SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(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 also 
includes immune-related AEs recorded up to 90 days after the last dose of study drug. Only those 
AEs that were treatment-emergent will be included in summary tables. All AEs, treatment 
emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest severity grade per NCI-CTCAE 
v.4.03 within an SOC and PT, even if the patient experienced more than 1 TEAE within a 
specific SOC and PT. The number (percentage) of patients with TEAEs will also be summarized 
by relationship to the study drug. 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 AEs, and TEAEs that led to treatment 
discontinuation, dose interruption, or dose delay will be summarized. 
The AE summary analyses will include: 
1) An overview summary table will be provided for TEAEs.   
2) TEAEs will be summarized by SOC and PT. TEAEs will also summarized by PT in 
descending frequency.  
3) Treatment-related AEs will be summarized by SOC and PT. 
4) Treatment-emergent SAEs, treatment-related SAEs will be summarized by SOC and PT.  
5) AEs with fatal outcomes will be summarized by SOC and PT. 
6) AEs leading to treatment discontinuation/dose modification will be summarized by SOC and 
PT.  
7) irAEs will be summarized by SOC and PT. 


 
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6.5.3 
Laboratory Values  
 Clinical laboratory (eg. hematology and serum chemistry) values will be evaluated for each 
laboratory parameter by patient. 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labor
atory 
parameters that are graded in NCI-CTCAE v.4.03 will be summarized by NCI-CTCAE grade. In 
the summary of laboratory parameters by NCI-CTCAE grade, parameters with NCI-CTCAE 
grading in both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) 
will be summarized separately. The graded laboratory parameters (ALP, ALT, AST, total 
bilirubin, albumin, hemoglobin, platelet counts, WBC count, neutrophil and lymphocyte) will be 
summarized by grade shift from baseline to maximum post-baseline grades.   
Serum Chemistry 
Hematology 
Alkaline phosphatase 
RBC count 
Alanine aminotransferase 
Hematocrit 
Aspartate aminotransferase 
Hemoglobin 
Albumin 
Total bilirubin 
Direct  bilirubin 
Platelet counts 
WBC count with differential 
Creatine kinase 
Creatine kinase-cardiac muscle isoenzyme 
(CK-MB) 
Neutrophil count 
Lymphocyte count 
Blood urea nitrogen or urea 
Testosterone 
Monocyte count 
Creatinine 
Basophil count 
Calcium 
Neutrophil count 
Chloride 
Lymphocyte (Absolute) 
Phosphate 
Monocyte (Absolute) 
Phosphorus 
Basophil (Absolute) 
Glucose 
Eosinophil (Absolute) 
Lactate dehydrogenase 
 
Total Protein 
  
Potassium 
  
Sodium 
  
 
 


 
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6.5.4 
Vital Signs 
Descriptive statistics for vital sign parameters and changes from baseline will be presented by 
visit.  
6.5.5 
Electrocardiograms (ECG) 
A centralized ECG laboratory may be used in this study in selected study sites. Calibrated ECG 
machines will be provided to these sites and ECG collected from these sites will be reviewed 
centrally. In other sites, local ECG machines will be used. 
 
Abnormal post-baseline ECG parameters will be summarized by cohort. QTcF results will be 
categorized with the following categories: increase of >30 msec, increase of > 60 msec, value of 
> 450 msec, value of > 480 msec, value of > 500. 
6.5.6 
Eastern Cooperative Oncology Group (ECOG) 
The ECOG Performance Status will be summarized by study cohort. A shift table from baseline 
to worst post-baseline in ECOG performance score will be provided.  
6.6 
PHARMACOKINETIC ANALYSES 
Refer to a separate PK analysis plan.  
6.7 
IMMUNOGENIC ANALYSES 
Refer to a separate analysis plan. 
7 
INTERIM ANALYSIS 
Not applicable.   
8 
CHANGES IN THE PLANNED ANALYSIS 
Due to the limitation of data collection and development of study program, Sponsor will not plan 
exploratory analyses specified in protocol in line of the exploratory objectives.