Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Various Combinations of BGB-A425 and LBL-007 With Tislelizumab in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Locally Advanced or Metastatic Solid Tumors for Phase 1, Dose Escalation and Phase 2 Safety Lead-in, HNSCC for Phase 2 Dose Expansion, NSCLC for Phase 2 Dose Expansion
Sponsor: BeiGene

BGB-900-102 
BeiGene 
Protocol Amendment 7.0  
14 December 2022 
 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title:  
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activity of Various Combinations of 
BGB-A425 and LBL-007 with Tislelizumab in Patients with Advanced 
Solid Tumors 
Protocol Identifier: 
BGB-900-102 
Phase: 
1-2 
Investigational Products: 
BGB-A425, LBL-007, and Tislelizumab 
Reference Number 
NCT03744468 
IND: 139200 
EU CT Number: 2022-500694-14-00 
Indication: 
Advanced Solid Tumors 
Sponsor:  
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive, 3rd Floor 
San Mateo, CA 94404 
USA 
Sponsor Medical Monitor: 
, PhD 
BeiGene co, Ltd.  
 
Email: 
 
Original Protocol: 
10 May 2018 (Final) 
Amendment 1.0: 
03 July 2018 
Amendment 2.0: 
13 March 2019 
Amendment 3.0: 
31 January 2020 
Amendment 4.0: 
11 January 2021 
Amendment 5.0 
26 October 2021 
Amendment 6.0 
06 June 2022 
Amendment 7.0 
14 December 2022 
 
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. 
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FINAL PROTOCOL APPROVAL SHEET  
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor 
Activity of Various Combinations of BGB-A425 and LBL-007 with Tislelizumab in Patients 
with Advanced Solid Tumors 
 
BeiGene, Ltd. Approval: 
____ 
PhD 
Sponsor Medical Monitor 
___
__________
Date 
 
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INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Various Combinations of BGB-A425 
and LBL-007 with Tislelizumab in Patients with Advanced Solid Tumors 
Protocol Identifier: 
BGB-900-102 
 
This protocol is a confidential communication of BeiGene, Ltd. and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval from 
BeiGene, Ltd. or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name of 
the center in which the study will be conducted.  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator:  
Date: 
Printed Name: 
Printed Name: 
Name/Address of Center: 
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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
STUDY SYNOPSIS ......................................................................................................................14 
LIST OF ABBREVIATIONS AND TERMS ................................................................................23 
1. 
INTRODUCTION AND RATIONALES ..................................................................26 
1.1. 
Introduction .................................................................................................................26 
1.2. 
BGB-A425 as a TIM-3 Inhibitor ................................................................................27 
1.2.1. 
Pharmacology .............................................................................................................28 
1.2.2. 
Toxicology ..................................................................................................................28 
1.2.3. 
Current Treatment Landscape of TIM-3 Inhibitors ....................................................30 
1.2.4. 
Prior Clinical Experience with BGB-A425 ................................................................30 
1.2.4.1. 
Preliminary Safety ......................................................................................................31 
1.2.4.2. 
Pharmacokinetics in Humans .....................................................................................34 
1.3. 
LBL-007 as a LAG-3 Inhibitor ...................................................................................34 
1.3.1. 
Pharmacology .............................................................................................................35 
1.3.2. 
Toxicology ..................................................................................................................35 
1.3.3. 
Current Landscape of LAG-3 Inhibitors .....................................................................36 
1.3.4. 
Clinical Pharmacology ................................................................................................37 
1.3.5. 
Prior Clinical Experience With LBL-007 ...................................................................38 
1.4. 
Tislelizumab as a PD-1 Inhibitor ................................................................................40 
1.4.1. 
Pharmacology .............................................................................................................41 
1.4.2. 
Toxicology ..................................................................................................................41 
1.4.3. 
Clinical Pharmacology ................................................................................................42 
1.4.4. 
Prior Clinical Experience with Tislelizumab ..............................................................42 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................43 
1.5. 
Study Rationale ...........................................................................................................44 
1.5.1. 
Rationale for Phase 1 Dose Escalation Study Design ................................................44 
1.5.2. 
Rationale for Combination of BGB-A425 and Tislelizumab in the Treatment 
of Advanced Solid Tumors .........................................................................................46 
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1.5.3. 
Rationale for Combination of BGB-A425, LBL-007, and Tislelizumab in the 
Treatment of Advanced Solid Tumors .......................................................................49 
1.5.4. 
Rationale for Selection of BGB-A425 Starting Dose .................................................51 
1.5.4.1. 
Allometric Scaling ......................................................................................................51 
1.5.4.2. 
Recommendation of the First in Human Dose of BGB-A425 ....................................52 
1.5.5. 
Rationale for BGB-A425 Recommended Phase 2 Dose ............................................53 
1.5.6. 
Rationale for Selection of LBL-007 Dose ..................................................................53 
1.5.7. 
Rationale for Selection of Tislelizumab Dose ............................................................54 
1.5.8. 
Rationale for Phase 2 Tumor Type Selection .............................................................55 
1.5.8.1. 
Head and Neck Squamous Cell Carcinoma ................................................................55 
1.5.8.2. 
Non-Small Cell Lung Cancer .....................................................................................56 
1.5.8.3. 
Renal Cell Carcinoma .................................................................................................57 
1.6. 
Benefit-Risk Assessment ............................................................................................58 
1.7. 
Study Conduct ............................................................................................................59 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................60 
2.1. 
Study Objectives for Phase 1 (Dose Escalation) ........................................................60 
2.1.1. 
Primary Objectives .....................................................................................................60 
2.1.2. 
Secondary Objectives .................................................................................................60 
2.1.3. 
Exploratory Objectives ...............................................................................................60 
2.2. 
Study Objectives for Phase 2 (Safety Lead-in) ...........................................................60 
2.2.1. 
Primary Objective .......................................................................................................60 
2.2.2. 
Secondary Objectives .................................................................................................60 
2.2.3. 
Exploratory Objectives ...............................................................................................61 
2.3. 
Study Objectives for Phase 2 (Dose Expansion) ........................................................61 
2.3.1. 
Primary Objective .......................................................................................................61 
2.3.2. 
Secondary Objectives .................................................................................................61 
2.3.3. 
Exploratory Objectives ...............................................................................................61 
2.4. 
Study Endpoints for Phase 1 (Dose Escalation) and Phase 2 (Safety Lead-in) ..........61 
2.4.1. 
Primary Endpoints ......................................................................................................61 
2.4.2. 
Secondary Endpoints ..................................................................................................62 
2.4.3. 
Exploratory Endpoints ................................................................................................62 
2.5. 
Study Endpoints for Phase 2 (Dose Expansion) .........................................................62 
2.5.1. 
Primary Endpoint ........................................................................................................62 
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2.5.2. 
Secondary Endpoints ..................................................................................................62 
2.5.3. 
Exploratory Endpoints ................................................................................................63 
3. 
STUDY DESIGN .......................................................................................................64 
3.1. 
Summary of Study Design ..........................................................................................64 
3.2. 
Study Periods ..............................................................................................................69 
3.2.1. 
Prescreening Period (Phase 2 Dose Expansion Only) ................................................69 
3.2.2. 
Screening Period .........................................................................................................69 
3.2.3. 
Treatment Period ........................................................................................................69 
3.2.4. 
Safety Follow-up Period .............................................................................................69 
3.2.5. 
Efficacy Follow-up Period ..........................................................................................70 
3.2.6. 
Survival Follow Up Period (Phase 2 Dose Expansion Only) .....................................70 
3.3. 
Discontinuation from the Study Treatment or from the Study ...................................70 
3.3.1. 
Patient Discontinuation from Study Treatment ..........................................................70 
3.3.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) ...........71 
3.4. 
End of Study ...............................................................................................................72 
3.5. 
DLT Definition ...........................................................................................................72 
4. 
STUDY POPULATION .............................................................................................75 
4.1. 
Inclusion Criteria ........................................................................................................75 
4.2. 
Exclusion Criteria .......................................................................................................78 
5. 
STUDY TREATMENT ..............................................................................................82 
5.1. 
Medicinal Product Approval Status ............................................................................82 
5.2. 
Formulation, Packaging, and Handling ......................................................................82 
5.2.1. 
BGB-A425 ..................................................................................................................82 
5.2.2. 
Tislelizumab ...............................................................................................................82 
5.2.3. 
LBL-007 .....................................................................................................................83 
5.3. 
Dosage, Administration, and Compliance ..................................................................83 
5.3.1. 
Phase 1 (Dose Escalation): BGB-A425 and Tislelizumab Combination ...................83 
5.3.2. 
Phase 2 (Safety Lead-in) .............................................................................................85 
5.3.2.1. 
Cohort A (LBL-007 + Tislelizumab) ..........................................................................85 
5.3.2.2. 
Cohort B (BGB-A425 + LBL-007 + Tislelizumab) ...................................................86 
5.3.3. 
Phase 2 (Dose Expansion) ..........................................................................................88 
5.3.3.1. 
BGB-A425 + Tislelizumab (Cohorts 1, 2 and 3) ........................................................88 
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5.3.3.2. 
BGB-A425 + LBL-007 +Tislelizumab (Cohorts 4 and 5) .........................................88 
5.3.3.3. 
LBL-007 + Tislelizumab (Cohorts 6 and 7) ...............................................................89 
5.4. 
Overdose of Tislelizumab and Incorrect Administration of BGB-A425 and 
LBL-007 .....................................................................................................................89 
5.5. 
Investigational Medicinal Product Accountability .....................................................90 
5.6. 
Dose Delay and Modification .....................................................................................90 
5.6.1. 
Dose Delay for BGB-A425, LBL-007, and Tislelizumab ..........................................90 
5.6.2. 
Dose Modification for BGB-A425, LBL-007, and Tislelizumab ...............................91 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................93 
6.1. 
Concomitant Therapy .................................................................................................93 
6.1.1. 
Permitted Concomitant Medications and Therapy .....................................................93 
6.2. 
Prohibited or Restricted Concomitant Medications and Therapy ...............................94 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................94 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................95 
7.1. 
Prescreening (Phase 2 Dose Expansion) .....................................................................95 
7.1.1. 
PD-L1 Test ..................................................................................................................95 
7.2. 
Screening ....................................................................................................................97 
7.2.1. 
Demographic Data and Medical History ....................................................................98 
7.2.2. 
Female Patients of Childbearing Potential and Contraception ...................................99 
7.2.3. 
Informed Consent and Screening Log ........................................................................99 
7.2.4. 
Pulmonary Function Tests ..........................................................................................99 
7.3. 
Enrollment ..................................................................................................................99 
7.3.1. 
Confirmation of Eligibility .........................................................................................99 
7.4. 
BGB-A425, LBL-007, and Tislelizumab Dispensation ...........................................100 
7.5. 
Safety Assessments ...................................................................................................100 
7.5.1. 
Vital Signs ................................................................................................................100 
7.5.2. 
Physical Examinations ..............................................................................................100 
7.5.3. 
Ophthalmologic Examination ...................................................................................100 
7.5.4. 
Eastern Cooperative Oncology Group Performance Status ......................................100 
7.5.5. 
Laboratory Safety Test .............................................................................................101 
7.5.6. 
Electrocardiograms ...................................................................................................101 
7.5.7. 
Adverse Events .........................................................................................................102 
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7.5.8. 
Hepatitis B and C Testing .........................................................................................102 
7.5.9. 
Creatine Kinase and Creatine Kinase-Cardiac Muscle Isoenzyme ..........................102 
7.6. 
Tumor and Response Evaluations ............................................................................103 
7.7. 
Pharmacokinetic Assessment and Antidrug Antibody Testing ................................105 
7.8. 
Biomarkers ................................................................................................................106 
7.9. 
Visit Windows ..........................................................................................................108 
7.10. 
Unscheduled Visits ...................................................................................................108 
8. 
SAFETY MONITORING AND REPORTING .......................................................109 
8.1. 
Risks Associated with BGB-A425, LBL-007, and Tislelizumab .............................109 
8.2. 
General Plan to Manage Safety Concerns ................................................................109 
8.2.1. 
Eligibility Criteria .....................................................................................................109 
8.2.2. 
Safety Monitoring Plan .............................................................................................110 
8.3. 
Adverse Events .........................................................................................................110 
8.3.1. 
Definitions and Reporting .........................................................................................110 
8.3.2. 
Assessment of Severity .............................................................................................111 
8.3.3. 
Assessment of Causality ...........................................................................................112 
8.3.4. 
Following Adverse Events ........................................................................................113 
8.3.5. 
Laboratory Test Abnormalities .................................................................................113 
8.4. 
Definition of a Serious Adverse Event .....................................................................113 
8.5. 
Suspected Unexpected Serious Adverse Reaction ...................................................114 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events .........................................................................................................114 
8.6.1. 
Adverse Event Reporting Period ..............................................................................114 
8.6.2. 
Reporting Serious Adverse Events ...........................................................................115 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ..........................................................115 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ......................115 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events ...........................115 
8.6.3. 
Eliciting Adverse Events ..........................................................................................116 
8.6.4. 
Recording Disease Progression ................................................................................116 
8.6.5. 
Recording Deaths ......................................................................................................116 
8.6.6. 
Recording Pregnancies .............................................................................................116 
8.6.7. 
Recording Post Study Adverse Events .....................................................................117 
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8.6.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ..............................................117 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events .................................117 
8.7. 
Management of Adverse Events of Special Interest .................................................117 
8.7.1. 
Infusion-Related Reactions .......................................................................................118 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms ...................................119 
8.7.3. 
Immune-Mediated Adverse Events ..........................................................................119 
8.7.4. 
Management of imAEs in Patients with Pre-Existing Renal Dysfunction ...............120 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...............121 
9.1. 
Statistical Analysis ....................................................................................................121 
9.1.1. 
Randomization Methods ...........................................................................................121 
9.1.2. 
Analysis Sets .............................................................................................................121 
9.1.3. 
Patient Disposition ....................................................................................................121 
9.1.4. 
Demographic and Other Baseline Characteristics ....................................................121 
9.1.5. 
Prior and Concomitant Medications .........................................................................122 
9.2. 
Efficacy Analyses .....................................................................................................122 
9.2.1. 
Secondary Efficacy Analysis in Phase 1 and Phase 2 (Safety Lead-in) ...................122 
9.2.2. 
Primary Efficacy Analysis in Phase 2 (Dose Expansion) .........................................122 
9.2.3. 
Secondary Efficacy Analysis in Phase 2 (Dose Expansion) .....................................123 
9.2.4. 
Exploratory Efficacy Analysis ..................................................................................123 
9.3. 
Safety Analyses ........................................................................................................123 
9.3.1. 
Extent of Exposure ...................................................................................................123 
9.3.2. 
Adverse Events .........................................................................................................124 
9.3.3. 
Laboratory Analyses .................................................................................................124 
9.3.4. 
Vital Signs ................................................................................................................124 
9.3.5. 
Ophthalmologic Examination ...................................................................................125 
9.4. 
Pharmacokinetic Analysis ........................................................................................125 
9.5. 
Immunogenicity Analyses ........................................................................................125 
9.6. 
Other Exploratory Analyses .....................................................................................125 
9.7. 
Sample Size Consideration .......................................................................................126 
9.8. 
Interim Analyses .......................................................................................................127 
10. 
STUDY COMMITTEES ..........................................................................................128 
10.1. 
Safety Monitoring Committee ..................................................................................128 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................130 
11.1. 
Access to Information for Monitoring ......................................................................130 
11.2. 
Access to Information for Auditing or Inspections ..................................................130 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................131 
12.1. 
Regulatory Authority Approval ................................................................................131 
12.2. 
Quality Assurance .....................................................................................................131 
12.3. 
Study Site Inspections...............................................................................................131 
12.4. 
Drug Accountability .................................................................................................131 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................133 
13.1. 
Ethical Standard ........................................................................................................133 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................133 
13.2.1. 
Protocol Amendments ..............................................................................................133 
13.3. 
Informed Consent .....................................................................................................134 
13.4. 
Patient and Data Confidentiality ...............................................................................134 
13.5. 
Financial Disclosure .................................................................................................136 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................137 
14.1. 
Data Collection and Management Responsibilities ..................................................137 
14.1.1. 
Data Collection .........................................................................................................137 
14.1.2. 
Data Management/Coding ........................................................................................137 
14.2. 
Data Integrity and In-house Blinding .......................................................................137 
14.3. 
Study Records Retention ..........................................................................................138 
14.4. 
Protocol Deviations ..................................................................................................139 
14.5. 
Publication and Data Sharing Policy ........................................................................139 
14.6. 
Study and Study Center Closure ...............................................................................140 
15. 
REFERENCES .........................................................................................................142 
16. 
APPENDICES ..........................................................................................................150 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................150 
APPENDIX 1A. PHASE 1 SCHEDULE OF ASSESSMENTS ...............................................150 
APPENDIX 1B.  PHASE 2 SAFETY LEAD-IN SCHEDULE OF ASSESSMENTS .............155 
APPENDIX 1C. PHASE 2 DOSE EXPANSION SCHEDULE OF ASSESSMENTS ............160 
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APPENDIX 1D. PHASE 1 AND PHASE 2 SAFETY LEAD-IN 
PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING 
SCHEDULE WITH SERIAL SAMPLE COLLECTION ........................................166 
APPENDIX 1E. PHASE 1 AND PHASE 2 SAFETY LEAD-IN 
PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING WITH 
SPARSE PK SAMPLE COLLECTION ...................................................................168 
APPENDIX 1F. PHASE 2 DOSE EXPANSION PHARMACOKINETIC AND 
IMMUNOGENICITY SAMPLING FOR BGB-A425, LBL-007, AND 
TISLELIZUMAB IN PATIENTS WITH SPARSE SAMPLE 
COLLECTION .........................................................................................................169 
APPENDIX 1G. PHASE 2 DOSE EXPANSION PHARMACOKINETIC AND 
IMMUNOGENICITY SAMPLING FOR BGB-A425 IN PATIENTS WITH 
SERIAL SAMPLE COLLECTION .........................................................................170 
APPENDIX 1H. PHASE 1 BLOOD AND TUMOR TISSUE BIOMARKER 
ANALYSIS...............................................................................................................171 
APPENDIX 1I. PHASE 2 (SAFETY LEAD-IN) BLOOD AND TUMOR TISSUE 
BIOMARKER ANALYSIS......................................................................................173 
APPENDIX 1J. PHASE 2 (DOSE EXPANSION) BLOOD AND TISSUE 
BIOMARKER ANALYSIS......................................................................................174 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................176 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................177 
APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES ORAUTOIMMUNE 
DISEASES ................................................................................................................178 
APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................179 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................181 
APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................182 
APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................183 
APPENDIX 9. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................194 
APPENDIX 10. CHILD-PUGH CLASSIFICATION SCORING SYSTEM ...........................204 
APPENDIX 11. LIST OF HERBAL MEDICINE OR CHINESE PATENT 
MEDICINES WHICH HAVE EFFECT OF CONTROL CANCER OR 
BOOST IMMUNITY ...............................................................................................205 
 
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LIST OF TABLES  
Table 1: 
Population PK Parameters Estimate for Monkey and Projected PK 
Parameters in Humans ................................................................................................52 
Table 2: 
Projected Safety Margins at Steady State at the Proposed Doses in Humans ............53 
Table 3: 
Investigational Medicinal Products Used in Study BGB-900-102 and Their 
Regulatory Approval Status ........................................................................................82 
Table 4: 
Phase 1 Dose Levels for BGB-A425 and/or Tislelizumab .........................................84 
Table 5: 
Phase 1 Administration of BGB-A425 and Tislelizumab and Monitoring 
Time ............................................................................................................................85 
Table 6: 
Phase 2 Safety Lead-in Dose Levels for Cohort A: LBL-007 and 
Tislelizumab ...............................................................................................................85 
Table 7: 
Phase 2 Safety Lead-in Administration of Cohort A: LBL-007 and 
Tislelizumab and Monitoring Time ............................................................................86 
Table 8: 
Phase 2 Safety Lead-in Dose Levels for Cohort B: BGB-A425, LBL-007, 
and Tislelizumab .........................................................................................................87 
Table 9: 
Phase 2 Safety Lead-in Administration of Cohort B: BGB-A425, LBL-007, 
and Tislelizumab and Monitoring Time .....................................................................88 
Table 10: Phase 2 Dose Expansion Administration of BGB-A425 and Tislelizumab 
and Monitoring Time ..................................................................................................88 
Table 11: Phase 2 Dose Expansion Administration of BGB-A425, LBL-007, and 
Tislelizumab and Monitoring Time ............................................................................89 
Table 12: Phase 2 Dose Expansion Administration of LBL-007 and Tislelizumab and 
Monitoring Time .........................................................................................................89 
Table 13: Types of PK and Immunogenetic Samplings for BGB-A425, LBL-007, and 
Tislelizumab in Phase 1 and Phase 2 ........................................................................106 
Table 14: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee ...........................................................................115 
Table 15: Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ............................................................................................................118 
 
LIST OF FIGURES  
Figure 1: 
Combined Blockade of TIM-3 and PD-1 with BGB-A425 and tislelizumab 
(BGB-A317) Enhances IFN-γ secretion in Mixed Lymphocyte Reaction .................47 
Figure 2: 
The Combination of Anti-TIM-3 and Anti-PD-1 Treatment Is More 
Effective Than Anti-PD-1 Inhibitors Alone ...............................................................48 
Figure 3: 
Sequential Anti-TIM-3 and Anti-PD-1 Treatment Increases Survival and 
Suppresses Tumor Growth Compared to Anti-PD-1 Treatment Alone ......................49 
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Figure 4: 
Tumor growth curve after treatment with LBL-007, anti-mouse PD-1 and the 
combination in MC38-OVA model ............................................................................50 
Figure 5: 
Synergy efficacy in the combination of anti-PD-1, anti-TIM-3, and 
anti-LAG-3 on tumor growth inhibition in the MC38 syngeneic model in 
human LAG-3 knock-in mice .....................................................................................51 
Figure 6: 
Simulated Serum Concentration-Time Profiles in Humans .......................................53 
Figure 7: 
Study Schema .............................................................................................................68 
Figure 8: 
PD-L1 Positivity Confirmation Flowchart .................................................................97 
 
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STUDY SYNOPSIS  
Title of Study: 
Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Various Combinations of BGB-A425 and 
LBL-007 with Tislelizumab in Patients with Advanced Solid Tumors 
Sponsor: 
BeiGene, Ltd. 
Amendment Date: 
14 December 2022 
Study Phase: 
1-2 
Regulatory Agency 
Identifier 
Number(s): 
EU CT Number: 2022-500694-14-00 
NCT03744468 
IND: 139200 
Rationale: 
Immune surveillance plays a critical role in preventing cancer cell proliferation 
and tumor metastasis. However, tumors have developed resistance 
mechanisms to suppress and/or escape the host immune system, thereby 
enabling tumorigenesis to proceed unchecked. One such resistance mechanism 
involves upregulation of immune checkpoint receptors expressed on immune 
cells (eg, effector T-cells), such as programmed cell death protein-1 (PD-1), 
T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and 
lymphocyte activation gene-3 (LAG-3). 
BGB-A425 is a humanized immunoglobulin G1 (IgG1)-variant monoclonal 
antibody (mAb) against TIM-3 that 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. LBL-007 is a fully human anti-
LAG-3 monoclonal IgG4/κ isotype antibody that is being developed for the 
treatment of advanced solid tumors. 
There is clinical evidence supporting TIM-3’s role in tumorigenesis as well as 
emerging clinical data suggesting that the TIM-3 and PD-1 often overexpress 
in various cancers and drive immune escape pathways to promote tumor 
growth. Both LAG-3 and TIM-3 when co-expressed with PD-1 on tumor 
infiltrating T cells upregulated anti-PD-1 resistance, suggesting co-blockade of 
PD-1 with LAG-3 or TIM-3 could further enhance antitumor immunity. Thus, 
clinical efficacy demonstrated by PD-1 blockade via tislelizumab could 
significantly further improve and/or extend therapeutic benefits when 
combined with anti-TIM-3 antibody (BGB-A425) and/or anti-LAG-3 antibody 
(LBL-007). 
This study will assess the safety and tolerability of BGB-A425 in combination 
with tislelizumab and LBL-007 and the efficacy of the combined treatment as 
measured in the objective criteria for tumor response in patients with advanced 
solid tumors. 
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Objectives and Endpoints: 
Objective 
Endpoint 
Phase 1 (Dose Escalation) 
Primary: 
To assess the safety and tolerability of 
BGB-A425 in combination with 
tislelizumab in patients with advanced solid 
tumors 
 
Adverse events (AE) and serious AEs (SAEs) as 
characterized by type, frequency, severity (as graded 
by National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE 
Version 5.0), timing, seriousness, and relationship to 
study therapy; laboratory abnormalities as 
characterized by type, frequency, severity (as graded 
by NCI-CTCAE v5.0), and timing; AEs meeting 
protocol defined dose limiting toxicity (DLT) criteria 
Primary: 
To determine the maximum tolerated dose 
(MTD) or maximum administered dose 
(MAD) and recommended Phase 2 dose 
(RP2D) of BGB-A425 in combination with 
tislelizumab 
The MTD or MAD, defined as the highest dose at 
which < 33% of the patients experience a DLT  
 
The RP2D of BGB-A425 in combination with 
tislelizumab will be determined based upon the MTD 
or MAD, and will also take into consideration the 
long-term tolerability, PK, efficacy, and any other 
relevant data as available 
Secondary: 
To assess the preliminary antitumor activity 
of BGB-A425 in combination with 
tislelizumab 
Objective response rate (ORR), duration of response 
(DOR), and disease control rate (DCR) will be 
determined from investigator derived tumor 
assessments per RECIST v1.1 
Secondary: 
To characterize the pharmacokinetics (PK) 
of BGB-A425 in combination with 
tislelizumab 
Maximum observed plasma concentration (Cmax), 
minimum observed plasma concentration (Cmin), time 
to maximum plasma concentration (Tmax), half-life 
(t1/2), area under the concentration-time curve from 
zero to 21 days (AUC0-21d), clearance (CL), and 
apparent volume of distribution (Vz) for BGB-A425 
and Cmax, Cmin for tislelizumab 
Secondary: 
To assess host immunogenicity to BGB-
A425 in combination with tislelizumab 
Immunogenic responses to BGB-A425 and 
tislelizumab will be assessed by summarizing the 
number and percentage of patients who develop 
detectable antidrug antibodies 
Exploratory: 
To explore drug exposure and response 
(safety and efficacy) correlations 
Assessments of the correlations between drug 
exposure and response (efficacy and safety endpoints) 
Exploratory: 
To assess predictive, prognostic, and 
pharmacodynamic biomarkers including 
any association with response to study 
treatment and mechanism(s) of resistance 
Evaluation of biomarkers from patient derived tumor 
tissue(s) and blood (or blood derivatives) samples 
obtained before, during and/or after the combination 
treatment. Candidate biomarkers may include, but are 
not limited to PD-1, TIM-3 receptor occupancy (RO) 
and immune cell subpopulation in peripheral blood 
cells, concentrations of cytokine and soluble proteins 
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in plasma or serum, circulating tumor DNA (ctDNA) 
analysis in peripheral blood, programmed cell death 
ligand-1 (PD-L1), TIM-3 expression, tumor 
infiltrating lymphocytes (TILs), gene expression 
profiling and tumor mutation analysis in tumor tissue. 
Phase 2 (Safety Lead-in) 
Primary:  
To assess the safety and tolerability 
BGB-A425 in combination with LBL-007 
and tislelizumab or LBL-007 in 
combination with tislelizumab in patients 
with advanced solid tumors 
Adverse events (AEs) and SAEs as characterized by 
type, frequency, severity (as graded by NCI-CTCAE 
v5.0, timing, seriousness, and relationship to study 
therapy; laboratory abnormalities as characterized by 
type, frequency, severity (as graded by NCI-CTCAE 
v5.0), and timing; AEs meeting protocol defined DLT 
criteria 
Primary: 
To determine the MTD or MAD and 
RP2D/recommended dose for expansion of 
LBL-007 in the combination with 
BGB-A425 and tislelizumab, and LBL-007 
in combination with tislelizumab 
The MTD or MAD, defined as the highest dose at 
which < 33% of the patients experience a DLT.  
 
The RP2D/ recommended dose for expansion of the 
combination treatments will be determined based 
upon the MTD or MAD, and will also take into 
consideration the long-term tolerability, PK, efficacy, 
and any other relevant data as available 
Secondary: 
To assess the preliminary antitumor activity 
of BGB-A425 in combination with 
LBL-007 and tislelizumab or the 
combination of LBL-007 with tislelizumab 
in patients with advanced tumors 
ORR, duration of response (DOR), and disease 
control rate (DCR) will be determined from 
investigator derived tumor assessments per RECIST 
v1.1 
Secondary: 
To characterize the PK of BGB-A425, 
LBL-007, and tislelizumab in the 
combination treatments 
Maximum observed plasma concentration (Cmax), 
minimum observed plasma concentration (Cmin), time 
to maximum plasma concentration (Tmax), half-life 
(t1/2), area under the concentration-time curve from 
zero to 21 days (AUC0-21d), clearance (CL), and 
apparent volume of distribution (Vz) for BGB-A425 
and LBL-007; Cmax and Cmin for tislelizumab 
Secondary: 
To assess host immunogenicity to 
BGB-A425, LBL-007, and tislelizumab in 
the combination treatments 
Immunogenic responses to BGB-A425, LBL-007, 
and tislelizumab will be assessed by summarizing the 
number and percentage of patients who develop 
detectable antidrug antibodies. 
Exploratory: 
To explore drug exposure and response 
(safety and efficacy) correlations 
Assessments of the correlations between drug 
exposure and response (efficacy and safety endpoints) 
Exploratory: 
To assess predictive, prognostic, and 
pharmacodynamic biomarkers including 
Evaluation of biomarkers from patient derived tumor 
tissue(s) and blood (or blood derivatives) samples 
obtained before, during and/or after the combination 
treatment. Candidate biomarkers may include, but are 
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any association with response to study 
treatment and mechanism(s) of resistance 
not limited to PD-1, TIM-3, and LAG-3 RO and 
immune cell subpopulation in peripheral blood cells, 
concentrations of cytokine and soluble proteins in 
plasma or serum, circulating tumor DNA (ctDNA) 
analysis in peripheral blood, programmed cell death 
ligand-1 (PD-L1), TIM-3, LAG-3, and ligands 
expression, TILs, gene expression profiling and 
tumor mutation analysis in tumor tissue 
Phase 2 (Dose Expansion) 
Primary: 
To evaluate antitumor activity based on 
objective response rate (ORR) of various 
combinations of BGB-A425 and LBL-007 
with tislelizumab in selected tumor types   
ORR as determined from investigator derived tumor 
assessments per RECIST v1.1 
Secondary: 
To evaluate the antitumor activity using 
other secondary efficacy endpoints of the 
combination treatments of BGB-A425 and 
LBL-007 with tislelizumab  
Progression-free survival (PFS), DOR, and DCR will 
be determined from investigator derived tumor 
assessments as per RECIST v1.1 
Secondary: 
To further characterize the safety and 
tolerability of various combinations of 
BGB-A425 and LBL-007 with tislelizumab 
The safety of various combinations of BGB-A425 
and LBL-007 with tislelizumab will be assessed 
throughout the study by monitoring AEs and SAEs 
per NCI-CTCAE v5.0, physical examinations, 
electrocardiograms (ECGs), and laboratory 
assessments as needed 
Secondary: 
To further characterize the PK of 
BGB-A425 and LBL-007 in combination 
with tislelizumab 
PK parameters such as Cmax, Cmin, Tmax, t1/2 and 
AUC0-21d for BGB-A425and LBL-007; Cmax and Cmin 
for tislelizumab 
Secondary: 
To further assess host immunogenicity to 
BGB-A425 and LBL-007 in combination 
with tislelizumab 
Immunogenic responses to BGB-A425, LBL-007, 
and tislelizumab will be assessed by summarizing the 
number and percentage of patients who develop 
detectable antidrug antibodies (ADAs) 
Exploratory: 
To assess overall survival (OS) 
OS is defined as the date of the first dose of study 
drug to the date of death due to any cause 
Exploratory: 
To explore drug exposure and responses 
(safety and efficacy) correlations 
Assessments of the correlations between drug 
exposure and response (efficacy and safety endpoints) 
Exploratory: 
To assess predictive, prognostic, and 
pharmacodynamic biomarkers including 
any association with response to study 
treatment and mechanism(s) of resistance 
Evaluation of biomarkers from patient derived tumor 
tissue(s) and blood (or blood derivatives) samples 
obtained before, during and/or after treatment. 
Candidate biomarkers may include, but are not 
limited to, LAG-3 RO in peripheral blood cells, 
concentrations of cytokine and soluble proteins in 
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plasma or serum, ctDNA analysis in peripheral blood, 
PDL1, TIM-3, LAG-3, and ligands expression, TILs, 
gene expression profiling and tumor mutation 
analysis in tumor tissue 
Study Design: 
This is an open-label, multicenter, nonrandomized Phase 1 and 2 clinical 
study evaluating various combinations of BGB-A425 and LBL-007 with 
tislelizumab. 
Priority enrollment for Phase 1 (dose escalation) and Phase 2 (safety lead-
in) will be granted to patients with non-small cell lung cancer (NSCLC), 
head and neck squamous cell cancer (HNSCC), hepatocellular carcinoma 
(HCC), gastric or gastroesophageal junction carcinoma, nasopharyngeal 
carcinoma, renal cell carcinoma (RCC), cervical cancer, triple-negative 
breast cancer, and urothelial carcinoma. Prioritization of additional tumor 
types will also be considered based upon emerging data and after 
consultation with the medical monitor. Enrollment for Phase 2 dose 
expansion will be granted to patients with HNSCC, NSCLC and RCC, and 
details are described as follows. 
• 
Phase 1 (dose escalation): Sequential cohorts of approximately 8 
increasing dose levels of BGB-A425 will be evaluated in 
combination with tislelizumab 200 mg in patients with advanced 
solid tumors to determine the RP2D safety, PK, and other key 
endpoints for BGB-A425 in combination with tislelizumab.  
• 
Phase 2 (safety lead-in): For the safety lead-in, there are two 
combination cohorts planned to be evaluated: 
− 
Cohort A: LBL-007 + Tislelizumab 
− 
Cohort B: BGB-A425 + LBL-007 + Tislelizumab 
For Cohort A, the dose escalation of LBL-007 starts with 
LBL-007 300 mg intravenously in combination with tislelizumab 
200 mg intravenously every 21 days (Cohort A1, n = 3 to 6); the 
sequential escalating dose is planned to be LBL-007 600 mg 
intravenously in combination with tislelizumab 200 mg 
intravenously every 21 days (Cohort A2, n = 3 to 6).   
For Cohort B, the dose escalation of LBL-007 starts with LBL-007 
300 mg intravenously in combination with BGB-A425 600 mg 
and tislelizumab 200 mg intravenously every 21 days (Cohort B1, 
n = 3 to 6), which will be initiated after the evaluation in 
Cohort A1; the sequential escalating dose is planned to be 
LBL-007 600 mg intravenously in combination with BGB-A425 
600 mg and tislelizumab intravenously every 21 days (Cohort B2, 
n = 3 to 6). 
After the evaluation of Cohort A1, which is initiated first, 
allocation of patients to the respective cohorts (ie, Cohort A2 and 
Cohort B1) will be carried out through a sequential order of 
treatment assignment. At least 6 patients will be evaluated in 
Cohort A2 and Cohort B2 in the dose escalation part of Phase 2 
safety lead-in. 
During safety lead-in dose escalation, if the combination of 
BGB-A425 600 mg, LBL-007 600 mg, and tislelizumab 200 mg 
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once every 21 days is deemed safe in Cohort B2, dose expansion 
will be evaluated in HNSCC and NSCLC cohorts following 
discussion and in agreement with the Safety Monitoring 
Committee (SMC). However, in addition to the above mentioned 
dose, lower or higher dose levels of LBL-007 may be evaluated in 
the safety lead-in cohorts based on the analysis of emerging safety, 
tolerability, PK, biomarker, and other clinical data, if 
recommended by the SMC. If a dose level higher than 600 mg of 
LBL-007 for dose expansion cohorts is recommended by the 
SMC, a protocol amendment will be implemented. 
Enrollment will be open to all eligible patients with advanced solid 
tumors as described in Phase 1 (dose escalation).  
• 
Phase 2 (dose expansion): Three combination treatments will be 
evaluated in patients with various tumor types including HNSCC, 
NSCLC and RCC. A total of 7 cohorts are planned to be 
conducted as below 
− 
Cohort 1: HNSCC - BGB-A425 + Tislelizumab 
− 
Cohort 2: NSCLC - BGB-A425 + Tislelizumab 
− 
Cohort 3: RCC - BGB-A425 + Tislelizumab 
− 
Cohort 4: HNSCC - BGB-A425 + LBL-007 + Tislelizumab 
− 
Cohort 5: NSCLC - BGB-A425 + LBL-007 + Tislelizumab 
− 
Cohort 6: HNSCC - LBL-007 + Tislelizumab  
− 
Cohort 7: NSCLC - LBL-007 + Tislelizumab  
An interim analysis will be conducted based on approximately the 
first 20 evaluable patients in each dose expansion cohort (Sections 
Section 9.1.2 and 9.7). Based upon the interim analysis for a given 
tumor type cohort, up to approximately 40 evaluable patients for 
each cohort may be enrolled in that cohort as described in Section 
9.7. As of the date of finalization of this protocol amendment v7.0, 
enrollment of Cohorts 1 and 2 is ongoing. 
In Phase 2 dose expansion, the enrollment of Cohorts 4 and 5 will 
be initiated first, followed by the enrollment of Cohorts 6 and 7. 
The enrollment of Cohorts 6 and 7 will be initiated per the 
emerging clinical data from the ongoing evaluation in Cohorts 4 
and 5. 
All patients enrolled in Phase 2 dose expansion must have disease 
progression that occurred ≥ 10 weeks from the initiation of anti-
PD-1/PD-L1 treatment for locally advanced or metastatic disease. 
All eligible patients will receive the respective combination(s) 
every 21 days starting on Cycle 1 Day 1. Positive PD-L1 
expression from either local or central testing will be required for 
enrollment of patients with HNSCC and NSCLC (refer to Section 
7.1 for additional details).  
Patients will receive study drug until 1) they are no longer considered to 
receive clinical benefit, 2) unacceptable toxicity, or 3) withdrawal of 
informed consent.  
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Except for the Phase 1 DLT period, a 21-day treatment cycle is planned for 
the remainder of Phase 1 and all of Phase 2 including Phase 2 safety lead-
in. 
For Phase 1 dose escalation, a 28-day DLT observation period will be 
utilized for initial dose finding recommendations. 
Trial Population: 
Phase 1: Patients with histologically or cytologically confirmed advanced, 
metastatic, unresectable solid tumors who have previously received 
standard systemic therapy as per respective local guidelines, unless 
standard systemic therapy is not available, not tolerated, or determined not 
appropriate based on investigator’s judgement, and who have not received 
prior therapy targeting TIM-3. 
Phase 2 (Safety lead-in): Patients with histologically or cytologically 
confirmed advanced, metastatic, unresectable solid tumors who have 
previously received standard systemic therapy as per respective local 
guidelines, unless standard systemic therapy is not available, not tolerated, 
or determined not appropriate based on investigator’s judgement, and who 
have not received prior therapy targeting TIM-3 and LAG-3. 
Phase 2 (Dose Expansion): Patients with one of the following 
histologically or cytologically confirmed solid tumors: 
HNSCC patients (Cohorts 1, 4 and 6) whose disease progressed while 
receiving up to 3 lines of systemic therapy that includes anti-PD-1/PD-L1 
antibody and available standard of care as per respective local guidelines 
and who are PD-L1 positive (Refer to Section 7.1 for additional details).  
Squamous or non-squamous NSCLC patients (Cohorts 2, 5 and 7) whose 
disease progressed while receiving up to 3 lines of systemic therapy that 
includes anti-PD-1/PD-L1 antibody and available standard of care as per 
respective local guidelines, and who are PD-L1 positive (Refer to Section 
7.1 for additional details). 
RCC patients (Cohort 3) while receiving up to 3 lines of systemic therapy 
that includes anti-PD-1/PD-L1 antibody and available standard of care as 
per respective local guidelines. 
Interventions: 
Phase 1 (Dose Escalation) : 
A BGB-A425 dose recommended for the respective cohort will be 
administered intravenously as a single agent on Day 1 of each cycle. In the 
first cycle, tislelizumab will be administered intravenously on Day 8 
(+2 days) at a fixed dose of 200 mg. Patients will be monitored for DLTs 
for 28 days after the first administration of BGB-A425. If tolerated, 
patients will receive BGB-A425 + tislelizumab sequentially on Day 29 and 
every 21 days (ie, once every 21 days) thereafter until they meet a 
discontinuation criterion. The doses of BGB-A425 to be tested are 2 mg, 
6 mg, 20 mg, 60 mg, 200 mg, 400 mg, 800 mg, and 1600 mg. However, 
lower, intermediate and/or higher dose(s) and/or alternative dosing 
schedule(s) of BGB-A425 may be evaluated based upon emerging clinical 
data as appropriate. 
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Phase 2: Safety Lead-in 
For safety lead-in, the respective study drugs of Cohort A and Cohort B 
will be administered sequentially once every 21 days starting on Cycle 1 
Day 1.  
For Cohort A, the dose escalation of LBL-007 starts with LBL-007 
300 mg in combination with tislelizumab 200 mg intravenously every 
21 days (Cohort A1); the sequential escalating dose is planned to be 
LBL-007 600 mg in combination with tislelizumab 200 mg intravenously 
every 21 days (Cohort A2). 
For Cohort B, the dose escalation of LBL-007 starts with LBL-007 300 mg 
in combination with BGB-A425 600 mg and tislelizumab 200 mg 
intravenously every 21 days (Cohort B1), which will be initiated after the 
evaluation of Cohort A1; the sequential escalating dose is planned to be 
LBL-007 600 mg in combination with BGB-A425 600 mg and 
tislelizumab 200 mg intravenously every 21 days (Cohort B2).  
However, in addition to the above mentioned dose, lower or higher dose 
levels of LBL-007 may be evaluated based on the analysis of emerging 
safety, tolerability, PK, biomarker, and other clinical data, if recommended 
by the SMC. 
Phase 2 Dose Expansion:  
Three different combinations will be administered. For Cohorts 1, 2, and 3, 
the recommended dose level of BGB-A425 is 600 mg in combination with 
tislelizumab 200 mg administered intravenously once every 21 days. It is 
planned that BGB-A425 and tislelizumab will be administered sequentially 
once every 21 days starting on Cycle 1 Day 1. For Cohorts 4 to 7, the 
recommended dose(s) will be determined based on safety, tolerability, PK 
data, pharmacodynamic biomarker, and preliminary antitumor activity, in 
Phase 2 safety lead-in. 
Ethical Considerations 
The BGB-A425 animal toxicology data showed no toxicity at the maximal 
allowed dose. There is limited human experience with BGB-A425. 
Preliminary data from the Phase 1 dose escalation of the study 
BGB-900-102 shows that increasing dose levels of BGB-A425 of up to 
1600 mg in combination with tislelizumab 200 mg has been well tolerated 
in patients with advanced solid tumors and would support continued 
evaluation in clinical studies.  
Tislelizumab is being developed for the treatment of several types of 
human malignancies in multiple regions as monotherapy or in combination 
with other therapies. Tislelizumab has also been approved and is currently 
being marketed in China for indications including classical Hodgkin’s 
lymphoma, urothelial carcinoma, squamous NSCLC, non-squamous 
NSCLC, esophageal squamous cell carcinoma (ESCC), HCC and 
advanced unresectable or metastatic microsatellite instability-high 
(MSI-H) or mismatch repair deficient (dMMR) solid tumors. Based on 
data from clinical studies, tislelizumab has been safe and well tolerated 
when used as a monotherapy or in combination with other therapeutics. 
LBL-007 is well tolerated as single dose in malignant tumors and 
advanced lymphoma in Study WLZB-LBL-007-AST-001b, and in 
combination with anti-PD-1 antibody, toripalimab, in the treatment of 
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advanced malignant tumors LBL-007-CN-003 study. These data from 
ongoing studies support the development of BGB-A425 in combination 
with LBL-007 and tislelizumab.   
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
BOR 
best overall response 
CK 
creatine kinase 
CK-MB 
creatine kinase-cardiac muscle isoenzyme 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CPS 
combined positive score 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End of Treatment 
Fc 
fragment crystallizable region 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
GFR 
glomerular filtration rate 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HNSCC 
head and neck squamous cell carcinoma 
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Abbreviation 
Definition 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
LAG-3 
Lymphocyte activation gene-3 
mAb 
monoclonal antibody 
MAD 
maximum administered dose 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCC 
renal cell carcinoma 
R/M 
recurrent and metastatic 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
t1/2 
half-life  
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocytes 
TIM-3 
T-cell immunoglobulin and mucin-domain containing-3 
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Abbreviation 
Definition 
TPS 
tumor proportion score 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
Vss 
volume in steady state 
Vz 
apparent volume of distribution during the terminal phase 
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1. 
INTRODUCTION AND RATIONALES  
1.1. 
Introduction  
Immune surveillance plays a critical role in preventing cancer cell proliferation and tumor 
metastasis. However, tumors have developed resistance mechanisms to suppress and/or escape 
the host immune system, thereby enabling tumorigenesis to proceed unchecked 
(Schreiber et al 2011; Swann and Smyth 2007). One such resistance mechanism involves 
upregulation of immune checkpoint receptors expressed on immune cells (eg, effector T-cells), 
such as programmed cell death protein-1 (PD-1), T-cell immunoglobulin and mucin-domain 
containing-3 (TIM-3) (Koyama et al 2016; Sharma et al 2017) and Lymphocyte Activation 
Gene-3 (LAG-3 or CD233) (Panda et al 2020). 
BGB-A425 is a humanized immunoglobulin G1 (IgG1)-variant monoclonal antibody (mAb) 
against TIM-3. It is being developed for the treatment of human malignancies. BGB-A425 
competitively blocks the binding of phosphatidylserine to TIM-3 while concomitantly inducing 
TIM-3 internalization. The in vivo studies showed that BGB-A425 elicited potent antitumor 
effects in combination with anti-PD-1 antibody. The preliminary safety profile of BGB-A425 
showed that BGB-A425 is well tolerated in patients with advanced solid tumors (refer to 
Section 1.2). 
LBL-007 is a fully human anti-LAG-3 monoclonal IgG4/κ antibody for the treatment of 
advanced solid tumors. LBL-007 effectively blocks the binding of LAG-3 to its ligand major 
histocompatibility complex (MHC) II molecules and prevents the inhibitory signaling by LAG-3 
on T cells. The in vivo antitumor efficacy studies showed that the combination of LBL-007 and 
an anti-mouse PD-1 monoclonal antibody demonstrated a stronger antitumor effect than either 
monotherapy. LBL-007 has a favorable pharmacokinetics (PK) profile and sufficient safety 
margins based on toxicity studies and the predicted human efficacious dose (refer to Section 1.3). 
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. Tislelizumab has been 
approved and is currently being marketed in China that include the following indications: 
classical Hodgkin’s lymphoma, urothelial carcinoma, esophageal squamous cell carcinoma 
(ESCC), squamous NSCLC, non-squamous NSCLC, hepatocellular carcinoma, recurrent or 
metastatic nasopharyngeal cancer, and advanced unresectable or metastatic microsatellite 
instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors.  
Several anti-PD-1 and anti-PD-L1 agents have been approved for the treatment of histologically 
distinct tumors whereas there are several anti-TIM-3 agents and anti-LAG-3 agents in the stage 
of clinical development. Evidence has shown that both TIM-3 and LAG-3 are co-expressed with 
PD-1 on tumor infiltrating T cells and upregulated in anti-PD-1 resistant patients, suggesting 
these two immune checkpoint receptors are potential resistant mechanisms for anti-PD-1 therapy. 
Co-blockade of TIM-3, LAG-3, and PD-1 has the potential to further boost antitumor immunity 
and improve clinical response.  
 
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1.2. 
BGB-A425 as a TIM-3 Inhibitor  
TIM-3 (also known as hepatitis A virus cellular receptor 2 or CD366) is a type I transmembrane 
glycoprotein receptor that plays an important role in promoting T-cell exhaustion and tumor 
escape from immune surveillance (Anderson and Anderson 2006; Sabatos et al 2003; 
Sanchez-Fueyo et al 2003). 
TIM-3 is primarily expressed on immune cells, such as T-cells, natural killer cells, dendritic 
cells, and monocyte/macrophages (Anderson et al 2016). To date, four TIM-3 ligands have been 
identified, which include phosphatidylserine, Galectin-9, carcinoembryonic antigen-related cell 
adhesion molecule 1, and high mobility group box 1 (Das et al 2017). As demonstrated from the 
tumor infiltrating lymphocytes (TILs) of patient samples or animal models, when expressed on 
effector T-cells (cluster of differentiation [CD]4+ and CD8+), activation of TIM-3 via ligand 
binding has been shown to reduce cytokine (interferon-gamma, tumor necrosis factor-alpha and 
interleukin-2) production, T-cell proliferation, and cytotoxicity, all of which could be rescued 
with TIM-3 blocking antibodies (Fourcade et al 2010; Sakuishi et al 2010). Interestingly, 
TIM-3’s expression is minimal on peripheral effector cells while being significantly upregulated 
on TILs, which strongly suggest that the tumor microenvironment utilizes TIM-3 signaling to 
further suppress/evade immune mediated tumor cytotoxicity (Anderson 2014; Das et al 2017; 
Du et al 2017). A similar repression of natural killer cell proliferation and cytotoxicity was also 
shown for TIM-3+ peripheral natural killer cells from patients with non-small cell lung cancer 
(NSCLC) (da Silva et al 2014). However, when expressed on FoxP3+ regulatory T-cells, which 
has been reported for a variety of human tumor types (Gao et al 2012; Yan et al 2013), the TIM-
3+ regulatory T-cells demonstrated greater suppressive functions when compared to TIM-3-
negative regulatory T-cells (Sakuishi et al 2013). 
In support of TIM-3’s role in promoting tumorigenesis, a number of studies analyzing clinical 
biopsy samples have shown that TIM-3 expression is significantly greater in tumor tissue and/or 
specifically on TILs relative to nontumor tissue/lymphocytes for various malignancies including 
non-small cell lung cancer (NSCLC) (Gao et al 2012), head and neck squamous cell carcinoma 
(HNSCC) (Liu et al 2017), hepatocellular cancer (Li et al 2012), renal cell carcinoma (RCC) (Hu 
et al 2020) and gastric cancer (Cheng et al 2015; Naghavi et al 2017). Such studies have also 
demonstrated a robust correlation between TIM-3 expression from clinical biopsy samples and 
clinicopathological status, response to treatment, acquired resistance and/or survival for a 
number of different tumor types, including NSCLC (Thommen et al 2015; Zhuang et al 2012), 
HNSCC (Liu et al 2017; Jie et al 2017), hepatocellular carcinoma (Li et al 2016; Li et al 2012), 
RCC (Granier et al 2017) and gastric cancer (Cheng et al 2015; Wang et al 2015). 
Despite accumulating evidence supporting TIM-3’s role in promoting tumor immune escape, the 
published data clearly shows that the immuno-regulatory functions of TIM-3 overlap and 
cooperate with the PD-1 checkpoint pathway, although this is not always the case for PD-1 
pathway function (Anderson 2014; Das et al 2017; Du et al 2017; Alsaab et al 2017; 
Sharpe and Pauken 2018). Accordingly, TIM-3 is typically expressed on TILs only when PD-1 is 
co-expressed but the reverse does not hold true for PD-1 expression. Dual blockade of the PD-1 
and TIM-3 pathways is also required to fully reverse TIL exhaustion, and the majority of animal 
models across tumor types as well as one clinical study (Section 1.2.3) confirm that TIM-3 
blockade alone results in minimal tumor stasis but does however significantly increase the 
antitumor effect (animal models only) when combined with PD-1 blockade. Undoubtedly more 
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complex than described, but based upon the nonclinical and clinical data, it is believed that 
TIM-3 blockade by itself is unlikely to result in an efficacious antitumor immune response 
(Section 1.5.2) but has the potential to significantly improve and/or expand the therapeutic 
potential derived from PD-1 blockade. Accordingly, the clinical development of BGB-A425 will 
focus on data driven combination strategies. Therefore, the characterization of BGB-A425 
monotherapy is not a clinical objective of this study (see Section 2). 
Blocking antibodies targeting the PD-1/PD-L1 pathway have achieved remarkable results in the 
treatment of many different tumor types. However, based upon the rate of primary and secondary 
resistance to PD-1 blockade, it is apparent that additional immuno-regulatory mechanism(s) 
underlie tumor immune escape. Indeed, research shows that the TIM-3 pathway cooperates with 
PD-1 to maximize the suppression of effector TILs as well as promote resistance to anti-PD-1 
therapy. Therefore, TIM-3 represents an ideal target with the potential to significantly improve 
and/or extend the therapeutic benefit of anti-PD-1 therapy to a greater number of patients. 
1.2.1. 
Pharmacology  
BGB-A425 binds to the extracellular domain of human TIM-3 with high specificity and affinity 
(Kd = 0.22 nM) as demonstrated by target-binding assays and surface plasmon resonance 
characterization. BGB-A425 competitively blocks the binding of phosphatidylserine to TIM-3 
while concomitantly inducing TIM-3 internalization. In in vitro cell-based assays, BGB-A425 
consistently and dose-dependently enhances the functional activities of activated human 
peripheral blood mononuclear cells (PBMCs). Further, BGB-A425 displayed antitumor activity 
in both the A431 allogenic xenograft tumor model and the MC38 mouse colon cancer model in 
TIM-3 humanized mice. In the GL261 mouse glioma model in TIM-3-humanized mice, 
BGB-A425 in combination with radiation therapy significantly improved the survival of 
tumor-bearing mice compared to radiation therapy alone. 
BGB-A425 has been engineered in the heavy chain constant region to eliminate the fragment 
crystallizable region (Fc)-mediated effector functions. BGB-A425 has demonstrated no or 
minimal binding to complement 1q (C1q) or all gamma Fc receptors (FcγRs), including FcγRI, 
FcγRIIA, FcγRIIB, and FcγRIIIA, in in vitro binding assays, and does not induce 
antibody-dependent cellular toxicity or complement-dependent cytotoxicity in the cell-based 
assays. 
Refer to the BGB-A425 Investigator’s Brochure for detailed information regarding 
pharmacology studies of BGB-A425. 
1.2.2. 
Toxicology  
BGB-A425 binds to the cynomolgus monkey TIM-3 with 16-fold weaker affinity compared to 
human TIM-3 and does not bind to mouse TIM-3 because of the significant sequence divergence 
between human and mouse TIM-3. Therefore, cynomolgus monkey is considered to be the 
relevant species for nonclinical safety evaluation based upon the target sequence homology and 
cross-species TIM-3 binding activities of BGB-A425. 
The toxicity and safety profile of BGB-A425 was characterized in single dose toxicology studies 
in mice and in a 13-week repeat dose toxicology study in monkeys. These toxicity studies were 
conducted following Good Laboratory Practice regulations. Furthermore, BGB-A425 was 
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evaluated in a 6-week repeat dose study in humanized TIM-3 knock-in mice with subcutaneous 
MC38 tumors (humanized mice). The dose levels in the 13-week monkey study spanned from 
the intended human therapeutic dose to 10-fold higher. The cynomolgus monkey was considered 
the only relevant species for toxicity studies based upon the target sequence homology and 
cross-species TIM-3 binding activities of BGB-A425. The tissue cross reactivity was evaluated 
in the normal frozen tissues from both humans and monkeys. Cytokine release responses were 
also evaluated using fresh human PBMCs. 
No apparent toxicity was noted in either mice or monkeys after a single dose of BGB-A425 
ranging from 30 to 300 mg/kg nor in monkeys following a repeat dose ranging from 20 to 
200 mg/kg biweekly for 13 weeks. The toxicokinetic profile was characterized in monkey studies 
and the systemic exposure appeared to be dose proportional with no gender difference or 
accumulation observed over the dosing period. No apparent immunotoxicity was observed as no 
changes in clinical pathology or histopathology were observed in these studies. Immunogenicity 
with positive antidrug antibodies (ADAs) against BGB-A425 was noted in 6/12, 6/12, and 
0/12 animals at the repeated dose of 20, 60, and 200 mg/kg, respectively. The anti-BGB-A425 
antibody had shown a rapid clearance (CL) of BGB-A425 in serum in a few individual animals 
but did not appear to have an effect on the overall systemic exposure (area under the 
concentration-time curve [AUC]) or toxicity assessment. 
The tissue cross reactivity of BGB-A425 was evaluated in normal human and cynomolgus 
monkey frozen tissues using an immunohistochemistry method, with appropriate positive and 
negative controls. For normal human tissues, specific staining was observed on the membrane of 
T-cells, dendritic cells, and/or macrophages in lymph nodes, lung, and thymus, consistent with 
published data. In addition, the staining was also observed in the cytoplasm of interstitial 
fibroblast cells, which was not considered physiologically meaningful as the monoclonal 
antibody typically cannot access the cytoplasm of interstitial fibroblast cells in vivo. For normal 
monkey tissues, no specific staining was observed. This could be attributed to a variety of 
reasons, including weaker binding affinity, the low target expression in the animals, and the 
sensitivity of the immunohistochemistry method. 
No apparent increase in cytokine release was observed from an in vitro cytokine release assay 
following treatment of non-activated PBMCs with BGB-A425. 
Overall, no apparent toxicity was observed in the monkey or transgenic mice toxicity studies. No 
unexpected tissue cross reactivity was found in human or monkey tissues. The toxicokinetic 
profile was well characterized with dose proportional increases in systemic exposure without 
apparent accumulation or sex difference. Immunogenicity was observed without apparent 
immunotoxicity and effect on the systemic exposure. The no observed adverse effect level 
(NOAEL) of BGB-A425 in the 13-week monkey toxicity study was considered to be 200 mg/kg. 
The safety profile of BGB-A425 is considered adequate to support first in human dosing. 
Refer to the BGB-A425 Investigator’s Brochure for more detailed information regarding 
toxicology studies of BGB-A425. 
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1.2.3. 
Current Treatment Landscape of TIM-3 Inhibitors  
To date, no anti-TIM-3 therapy has been approved. Currently, 9 other anti-TIM-3 therapies are 
being evaluated in clinical oncology studies in combination with PD-1 checkpoint blockade: 
Sabatomimab (MGB453) (Novartis), TSR-022 (Tesaro/GSK), BMS-986258 (Bristol-Myers 
Squibb), LY3321367 (Eli Lilly) (Harding et al 2019), Sym023 (Symphogen), INCAGN2390 
(Incyte/Agenus), SHR-1702 (Jiangsu HengRui Medicine Co.), KL-A293 (Kelun-Biotech), and 
WBP3425 (Zhikang Hongyi). Of these 9 TIM-3 antagonists, clinical data on TSR-022 and 
sabatolimab has been reported.  
TSR-022 monotherapy was reported to be well tolerated with only one dose limiting toxicity 
(DLT) of asymptomatic Grade 3 lipase elevation observed at the highest dose level of 10 mg/kg 
(Weiss et al 2017). Adverse events (AEs) of TSR-022 were manageable and consistent with the 
safety profiles of other checkpoint inhibitors but only one unconfirmed partial response (PR) 
(n = 25; 4%) was observed. Published data of TSR-022 in combination with anti-PD-1 therapy 
(TSR-042; 500 mg once every 21 days) showed good tolerability with no DLT observed up to 
the TSR-022 900 mg dose level. Clinical activity of the combination was demonstrated in 
patients with NSCLC who had progressed on prior anti-PD-1 treatment with 4 confirmed PRs 
observed across TSR-022 100 mg and 300 mg cohorts (n = 31; 13%) (Davar et al 2018). Based 
on the tolerability and clinical activity of the combination, Tesaro/GSK decided to further 
evaluate the efficacy of their anti-TIM-3 therapy only in combination with anti-PD-1 in dose 
expansion cohorts (Tesaro Inc. 2018). 
Sabatolimab (800 mg every 4 weeks) in combination with spartalizumab (400 mg every 4 weeks) 
was determined as the RP2D through dose escalation and was reported to be well tolerated. AEs 
were manageable and consistent with the safety profiles of other anti-PD-1/PD-L1 and anti-
TIM-3 agents. Novartis is performing further evaluation of sabatolimab in multiple indications 
and in combinations including solid tumors as well as hematological malignancies.  
Bispecific monovalent dual checkpoint inhibitory PD-1 antibodies co-targeting TIM-3 are 
currently being developed. Two PD-1/TIM-3 bispecific antibody, RO7121661/RG7769 
(Hoffmann- La Roche) and AZD7789 (AstraZeneca), are being evaluated in Phase 1/2 clinical 
study in patients with advanced and/or metastatic solid tumors. RO7121661/RG7769 
demonstrated superior antitumor TIL activity, IFN-γ secretion, and tumor growth control 
compared to the monospeciﬁc PD-1 antibody in mouse models (Deak et al 2020). 
1.2.4. 
Prior Clinical Experience with BGB-A425  
The Phase 1 (Dose Escalation) part of this study is completed. Overall, no dose-dependent 
toxicities were observed and maximum tolerated dose (MTD) was not reached, with 1 DLT 
(Grade 3 autoimmune myocarditis) observed at 200 mg dose level of BGB-A425. No treatment-
related TEAEs leading to death. The combination of BGB-A425 and tislelizumab showed 
tolerable safety profile. 
As of 15 February 2022, thirty three patients received BGB-A425, either as monotherapy or in 
combination with 200 mg of tislelizumab. Monotherapy doses were 60 mg (n = 1) and 1600 mg 
(n = 1). BGB-A425 combination dose regimens with tislelizumab include 2 mg (n = 1), 6 mg 
(n = 1), 20 mg (n = 3), 60 mg (n = 5), 200 mg (n = 7), 400 mg (n = 4), 800 mg (n = 7), and 
1600 mg (n = 3). The median age for the overall group was 59.0 years; 63.6% were female and 
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87.9% were White. The median prior anticancer therapy regimens was 2.0 (range: 0 to 12). One 
patient (3.0%) did not have any prior systemic therapy; 6 patients (18.2%) had 1 prior systemic 
therapy; 10 patients (30.3%) had 2 prior systemic therapies; and 16 patients (48.5%) had > 3 
prior systemic therapies. The median treatment exposure duration for BGB-A425 was 
2.96 months (range: 0.92 to 26.51 months). The overall median study follow-up duration was 
5.29 months (range: 0.46 to 32.95) in the overall Phase 1 Safety Analysis Set. 
The Phase 2 (Dose Expansion) part of this study is ongoing, preliminary safety data obtained 
from a limited number of patients received BGB-A425 600 mg with tislelizumab 200 mg.   
As of the 15 February 2022 data cutoff date, 12 evaluable patients (6 patients with HNSCC and 6 
patients with NSCLC) received the combination of BGB-A425 600 mg with tislelizumab 200 mg 
every 21 days starting on Cycle 1 Day 1. The median age for the overall group was 60.5 years 
(60.0 years in HNSCC and 66.0 years in NSCLC). Among the 12 evaluable patients, 9 patients 
(75.0%) were male (6 patients [100.0%] in HNSCC and 3 patients [50.0%] in NSCLC) and 
50.0% (4 patients [66.7%] in HNSCC and 2 patients [33.3%] in NSCLC) were White.  The 
median prior anticancer therapy regimens were 1.5 (range: 1 to 4), with 2.0 (range: 1 to 4) in 
HNSCC and 1.0 (range: 1 to 2) in NSCLC. All patients had ≥ 1 prior systemic therapy; 6 patients 
(50.0%) had 1 prior systemic therapy (2 patients [33.3%] in HNSCC and 4 patients [66.7%] in 
NSCLC); 4 patients (33.3%) had 2 prior systemic therapies (2 patients [33.3%] for each 
indication group); and 2 patients (16.7%) in HNSCC group had > 3 prior systemic therapies. The 
overall Phase 2 Safety Analysis Set median treatment exposure duration for BGB-A425 was 2.89 
months (range: 0.07 to 4.63), with 3.385 months (range: 0.69 to 4.21) in HNSCC group and 1.53 
months (range: 0.07 to 4.63) in NSCLC. The overall median study follow-up duration was 3.105 
months (range: 0.07 to 6.21) with 3.385 months (range: 2.17 to 6.21) in HNSCC group and 2.09 
months (range: 0.07 to 4.63) in NSCLC.  
Refer to the BGB-A425 Investigator’s Brochure for more detailed information regarding 
preliminary safety results. 
1.2.4.1. 
Preliminary Safety  
1.2.4.1.1. Dose-Escalation DLTs  
As of 15 February 2022, MTD was not 
 One DLT was reported in Study BGB-900-102. 
This occurred in a 
-year-old
patient of 
 ethnicity who 
initiated BGB-A425 200 mg treatment on 
 2019 and tislelizumab 200 mg treatment 
on 
 2019. This patient had concurrent
 Prior to the Cycle 2 Day 1 Visit on 
 2019, the patient experienced a Grade 3 
autoimmune myocarditis event and was hospitalized. The diagnosis was based on increased 
creatine kinase-cardiac muscle isoenzyme (CK-MB) and troponin I as well as probable anterior 
infarct indicated by electrocardiogram (ECG). The patient was asymptomatic, and 
echocardiogram showed normal cardiac structure and function. Both investigational agents were 
temporarily held and the patient initiated corticosteroids. The patient was discharged on 
 
2019 and both BGB-A425 and tislelizumab treatment was permanently discontinued. 
The event of autoimmune myocarditis was reported as recovered/resolved with sequelae on
 2019. The investigator assessed the autoimmune myocarditis event as serious due to 
hospitalization. The investigator assessed the event as related to BGB-A425 and tislelizumab. 
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1.2.4.1.2. Safety Results in Phase 1 Dose Escalation  
As of 15 February 2022, of the 33 patients in the Safety Analysis Set, 33 (100.0%) experienced 
at least 1 treatment-emergent adverse event (TEAE). Nineteen patients (57.6%) had TEAEs 
which were assessed as related to treatment. Nineteen patients (57.6%) had a Grade 3 or above 
TEAE, three of which was considered related to treatment. Fifteen patients (45.5%) had serious 
TEAEs, three of which was considered related to treatment. Eight patients (24.2%) experienced 
TEAEs leading to treatment discontinuation, 3 of which were assessed as related to treatment. 
Two patients experienced fatal adverse events which are not related to study drugs. 
Most TEAEs occurred in the gastrointestinal disorders (23 patients, 69.7%), followed by 
musculoskeletal and connective tissue disorders (18 patients, 54.5%), general disorders and 
administration site conditions (17 patients, 51.5%) and investigations (9 patients, 27.3%). The 
most commonly occurring TEAEs were nausea and arthralgia (10 patients [30.3%] each) 
followed by fatigue (8 patients, 24.2%), abdominal pain and oedema peripheral (7 patients 
[21.2%] each). 
Treatment-related TEAEs occurred in a total of 19 (57.6%) patients. Most events occurred as 
musculoskeletal and connective tissue disorders (9 patients, 27.3%), followed by gastrointestinal 
disorders SOC and general disorders and administration site conditions SOC (5 patients [15.2%] 
each). The most commonly occurring treatment-related TEAE was arthralgia (6 patients, 18.2%), 
followed by fatigue (4 patients, 12.1%), nausea (3 patients, 9.1%), and myalgia, oedema 
peripheral, hyperthyroidism, hypothyroidism and dry eye (2 patients [6.1%] each). 
In total, 15 patients (45.5%) experienced a treatment-emergent SAEs. Most commonly occurring 
treatment-emergent SAEs presented as gastrointestinal disorders (8 patients, 24.2%), followed by 
respiratory, thoracic and mediastinal disorders (4 patients, 12.1%), general disorders and 
administration site conditions, and investigations (2 patients [6.1%] each). All other treatment-
emergent SAEs occurred in single instance. Three patients experienced treatment-emergent 
SAEs assessed as related to study treatments (BGB-A425 or tislelizumab or both). Among these 
3 patients, one patient who received 200 mg of BGB-A425 in combination with 200 mg of 
tislelizumab experienced a SAE of Grade 3 autoimmune myocarditis that was assessed as related 
to both BGB-A425 and tislelizumab and considered a DLT. One patient who received 20 mg of 
BGB-A425 in combination with 200 mg of tislelizumab experienced 2 SAEs of Grade 3 diarrhea 
and Grade 3 immune-mediated enterocolitis assessed as related to both BGB-A425 and 
tislelizumab. One patient who received 800 mg of BGB-A425 in combination with 200 mg of 
tislelizumab experienced a SAE of Grade 3 pneumonitis assessed as related to tislelizumab. 
Grade 3 or above TEAEs occurred in a total of 19 (57.6%) patients. Most commonly occurring 
Grade 3 or above TEAEs presented as gastrointestinal disorders (7 patients, 21.2%), followed by 
investigations (5 patients, 15.2%), and respiratory, thoracic and mediastinal disorders (3 patients, 
9.1%). The most commonly occurring Grade 3 or above TEAEs were ALT increased (3 patients, 
9.1%), AST increased (3 patients, 9.1%), and anemia (2 patients, 6.1%). Three patients (9.1%) 
had a Grade 3 or above TEAEs assessed to be related to treatment, which presented as 
autoimmune myocarditis (1 patient, 3.0%), diarrhea (1 patient, 3.0%), hypoxia and pneumonitis 
(1 patient had both hypoxia and pneumonitis). 
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A single occurrence of Grade 4 TEAE of depression (1 patient, 3.3%) in a patient receiving 20 
mg of BGB-A425 in combination with 200 mg of tislelizumab was assessed as not related to 
study treatment.  
Two patients experienced fatal adverse events. One patient administered with 60 mg of BGB-
A425 in combination with 200 mg of tislelizumab experienced a fatal TEAE of multiple organ 
dysfunction syndrome. The other patient administered with 400 mg of BGB-A425 in 
combination with 200 mg of tislelizumab experienced a fatal TEAE of aspiration. Both fatal 
events were assessed as not related to study treatment. 
1.2.4.1.3. Safety Results in Phase 2 Dose Expansion  
As of 15 February 2022, among 12 treated patients, 9 patients (75.0%) experienced at least 1 
TEAE. Five patients (41.7%) had TEAEs which were assessed as related to treatment, with 4 
patients (66.7%) with HNSCC and 1 patient (16.7%) with NSCLC. Four patients (33.3%) had a 
Grade 3 or above TEAEs. Among them, one patient with HNSCC was considered related to 
treatment. Four patients (33.3%) had serious TEAEs, one of which was considered related to 
treatment and this patient was in HNSCC indication group. No patient experienced TEAEs 
leading to treatment discontinuation. No patient experienced fatal adverse events. 
Most TEAEs occurred in the gastrointestinal disorders and general disorders and administration 
site conditions SOCs (5 patients [41.7%] each), followed by musculoskeletal and connective 
tissue disorders, metabolism and nutrition disorders, and investigations SOC (4 patients [33.3%] 
each). The most commonly occurring TEAEs were fatigue (3 patients, 25.0%) followed by 
constipation, diarrhoea, hypercalcaemia, muscular weakness, pain in extremity, and dyspnoea (2 
patients [16.7%] each). 
The treatment related TEAEs occurred in a total of 5 patients (41.7%). Treatment-related TEAEs 
occurred as gastrointestinal disorders, general disorders and administration site conditions, and 
investigations (2 patients [16.7%] each). The most commonly occurring treatment-related TEAE 
was diarrhoea (2 patients, 16.7%), followed by fatigue, non-cardiac chest pain, ALT increased, 
blood creatine phosphokinase increased, blood creatinine increased, blood urea increased, 
neutrophil count decreased, white blood cell count decreased, hypercalcaemia, peripheral 
sensory neuropathy, immune-mediated lung disease, and uncoded event (reported verbatim: 
immune related pneumonia) (1 patient [8.3%] each). One patient (1 patient, 8.3%) with HNSCC 
had a Grade 3 or above TEAE of immune-mediated lung disease assessed as related to study 
treatment. 
The treatment-emergent SAE occurred in a total of 4 patients (33.3%); two patients (16.7%) with 
NSCLC experienced musculoskeletal and connective tissue disorders. The treatment-emergent 
SAEs presented as pain in extremity (2 patients, 16.7%) and musculoskeletal chest pain (1 
patient, 8.3%) by PT. Other treatment-emergent SAEs occurred in single instance include 
nervous system disorders (spinal cord compression in Grade 3), respiratory, thoracic and 
mediastinal disorders (Immune-mediated lung disease in Grade 3), and uncoded event (reported 
verbatim: immune related pneumonia) in Grade 2.  
Grade 3 or above TEAEs occurred in 4 patients (33.3%). Most commonly occurring Grade 3 or 
above TEAEs presented as musculoskeletal and connective tissue disorders (2 patients, 16.7%), 
followed by nervous system disorders (1 patient, 8.3%) and respiratory, thoracic and mediastinal 
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disorders (1 patient, 8.3%).  The most commonly occurring Grade 3 or above TEAE was pain in 
extremity (2 patients, 16.7%). All the other TEAEs occurred in single instances (1 patient, 8.3%).  
The TEAE of Grade 3 immune-mediated lung disease in one patient with HNSCC was assessed 
as related to study treatment. As of 15 February 2022, no patients in Phase 2 developed fatal 
adverse events.  
1.2.4.2. 
Pharmacokinetics in Humans  
As of the data cutoff date of 15 February 2022, serial PK data were collected from 25 patients 
from across the first 7 dose cohorts in dose escalation. BGB-A425 exhibited rapid CL and short 
half-life (t1/2) at doses of 6 mg and below which is consistent with target-mediated drug 
disposition for mAbs at lower dose levels. At 200 mg dose and above, the CL of BGB-A425 
appears linear with similar terminal t1/2 between 9 and 16 days and near proportional increase in 
AUC0-inf. However due to the limitation associated with non-compartmental analysis, the reported 
t1/2 is likely an underestimate of true elimination t1/2. In a preliminary population PK analysis 
with PK data from 20 mg and above, the estimated t1/2 of BGB-A425 is approximately 26 days. 
Refer to the BGB-A425 Investigator’s Brochure for more detailed information regarding 
Preliminary PK parameters. 
1.3. 
LBL-007 as a LAG-3 Inhibitor  
Lymphocyte Activation Gene-3 (LAG-3 or CD223) is an immune checkpoint protein 
predominantly expressed on the surface of activated T cells (Huard et al 1995), and natural killer 
(NK) cells (Triebel et al 1990). LAG-3 expression in B cells (Kisielow et al 2005) and 
plasmacytoid dendritic cells (pDCs) (Workman et al 2009) also have been reported. MHC 
Class II is the main ligand for LAG-3 (Huard et al 1995), engagement of LAG-3 by MHC II 
ligand leads to a state of T cell exhaustion, characterized by attenuation of T-cell activation, 
inability to proliferate in response to antigen and reduced cytokine production (Workman and 
Vignali 2003, Huang et al 2004, Workman et al 2004). LSECtin (Xu et al 2014), galectin-3 
(Kouo et al 2015), and FGL1 (Wang et al 2019) are other immune-inhibitory ligands that have 
been identified to interact with LAG-3 and mediate its inhibitory function in T cells. Consistent 
with its inhibitory function, LAG-3 expression is high in chronically exhausted or dysfunctional 
T cells in cancer, particularly in tumor infiltrated T cells (Matsuzaki et al 2010). In addition, 
LAG-3 is also expressed on regulatory T (Treg) cells and LAG-3 + Treg cells are highly 
suppressive compared to LAG-3- Treg cells (Huang et al 2004, Camisaschi et al 2010). LAG-3 
blockade is shown to promote T cell proliferation and enhance the function of cytotoxic T cells 
(Lichtenegger et al 2018). LAG-3 inhibition can also reduce the immunosuppressive activity of 
LAG-3+ Treg cells, resulting in enhanced activation of effector T cells (Huang et al 2004).  
LAG-3 is frequently co-expressed with PD-1 on tumor infiltrating T cells, LAG-3, and PD-1 
double positive T cells are in a more severe dysfunction state than T cells expressing PD-1 or 
LAG-3 alone. Moreover, LAG-3 expression is upregulated following anti-PD-1 treatment, and 
the frequency of LAG-3+ T cells is significantly higher in anti-PD-L1 resistant or non-
responsive patients with solid tumors, including NSCLC, HNSCC, melanoma and bladder cancer 
(Gettinger et al 2017, Datar et al 2017, Hanna et al 2018, Johnson et al 2018, Kates et al 2021). 
Co-blockade of PD-1 and LAG-3 synergize to restore the function of exhausted T cells and 
inhibit tumor growth by enhance antitumor immunity in mouse models (Yang et al 2017, Ghosh 
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et al 2019, Mimura et al 2021). Those results suggest that the combination of anti-LAG-3 and 
anti-PD-1 could further improve the clinical outcome of anti-PD-1, and the combination therapy 
may provide clinical benefit for those patients who are resistant or do not response to anti-PD-1 
therapy. Indeed, the combination has been proved to be effective in clinic, in patients with 
previously untreated metastatic or unresectable melanoma, co-blockade of LAG-3 and PD-1 
provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone 
(Tawbi et al 2022). 
1.3.1. 
Pharmacology  
LBL-007 is a fully human anti-LAG-3 monoclonal IgG4/κ isotype antibody co-developed by 
Nanjing Leads Biolabs Co., Ltd. and BeiGene, Ltd. for the treatment of advanced solid tumors.  
LBL-007 binds to the human LAG-3 extracellular domain with high specificity and affinity 
(Kd = 0.439 x 10-10 M). LBL-007 effectively blocks the binding of LAG-3 to MHC II 
molecules, and thereby activates the immune system. In vitro binding assay showed that 
LBL-007 also blocks the binding of LAG-3 with other ligands, including fibrinogen like-1 
(FGL-1), liver sinusoidal endothelial cell lectin (LSECtin) and galectin 3. In addition, in vivo 
studies in human LAG-3 knock-in mice showed LBL-007 significantly inhibiting the tumor 
growth when used alone or in combination with an anti-PD-1 monoclonal antibody. 
In vitro studies showed that LBL-007 did not bind to either FcγRIIIA or C1q, indicating weak or 
no antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent 
cytotoxicity (CDC) effect in humans. Additionally, in vitro experiments showed that LBL-007 
with an S228P modification in the hinge region was more stable than wild-type LBL-007, and 
did not exchange Fab arms with a wild-type human IgG4 antibody. Therefore, it was predicted 
that the LBL-007 antibody would be stable in vivo. 
Refer to the LBL-007 Investigator’s Brochure for detailed information regarding pharmacology 
studies of LBL-007.  
1.3.2. 
Toxicology  
Cynomolgus monkey is considered to be the relevant species for nonclinical safety evaluation 
because it is the pharmacologically relevant species based on sequence homology of LAG-3 and 
binding affinity activity; and it is a commonly used species for biologic products with a 
substantial historical toxicology database. 
The nonclinical toxicity and toxicokinetic profile of LBL-007 was characterized in a single dose 
study in cynomolgus monkeys and in repeat dose studies in rats and cynomolgus monkeys. 
These toxicity studies were conducted following Good Laboratory Practice regulations.  
At the single dose of 150 or 300 mg/kg (3 animals per group), the MTD was 300 mg/kg; no 
mortality or moribundity was observed in cynomolgus monkeys. 
In the 3-week repeat dose study in rats, no LBL-007-related abnormal changes were observed in 
body weight, food consumption, ophthalmological examination, urinalysis, lymphocyte subsets, 
complement counts, immunoglobulin counts (IgA, IgG, IgM, IgE) following intravenous 
infusion of LBL-007 at 20 mg/kg, 60 mg/kg, and 150 mg/kg once a week for 3 consecutive 
weeks (4 doses). Other abnormalities in hematology and blood chemistry recovered after 
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4 weeks of dose interruption. The weight coefficient of the liver was increased in female rats in 
the 150 mg/kg group, and slight to mild hepatocellular necrosis or inflammatory cell infiltration 
was observed in the histopathological examination. Considering the lack of binding activity of 
LBL-007 to the LAG-3 in rats, the effects of LBL-007 on the liver were considered to be mostly 
off-target toxicities. Given that in vitro data indicated cellular and tissue binding with LBL-007 
were highly specific to monkey and human, and the absence of LBL-007 pharmacological 
activity in the rat, the findings in the 3-week repeat dose study are of uncertain clinical relevance.  
The 4-week repeat dose study in cynomolgus monkeys indicated that LBL-007 was well 
tolerated. Five consecutive weekly doses of LBL-007 at 10, 30, and 100 mg/kg in monkeys 
between 3 to 5 years old were not associated with any adverse effects. The no-observed-adverse-
effect-level (NOAEL) was 100 mg/kg. LAG-3 receptor occupancy (RO) was increased in female 
and male cynomolgus monkeys at 1 to 2, 24 to 25, and 168 to 169 hours after the first dose as 
well as at 24 to 25 and 168 to 169 hours after the last dose. No significant dosage-related 
increase of LAG-3 RO was observed at all dose levels. At the dose level of 10, 30, and 
100 mg/kg, after the first dose, the increased exposure of LBL-007 in the serum of monkeys in 
each LBL-007 group was correlated with increase of the infusion dose. No gender differences in 
exposure were observed. After 5 consecutive doses, the accumulation factors of LBL-007 ranged 
from 2.02 to 0.61, indicating a slight accumulation. 
The in vitro studies to assess hemolytic potential were conducted in erythrocytes from Japanese 
white rabbits. There was no evidence of hemolysis or agglutination observed in vitro in rabbit 
erythrocytes with LBL-007 at a concentration of 5 mg/mL. 
The tissue cross-reactivity of LBL-007 was evaluated in healthy cynomolgus monkeys and 
healthy human frozen tissues using immunohistochemistry. LBL-007 specifically bound to 
human tissues of colon, ileum, pituitary gland, skeletal muscle, testis, lymph nodes, duodenum, 
and parathyroid gland, while LBL-007 specifically bound to cynomolgus monkey tissue of the 
cerebellum. 
The in vitro cytokine release study indicated that LBL-007 did not evoke cytokine release in 
human peripheral blood mononuclear cells. 
Refer to the LBL-007 Investigator’s Brochure for more details on the toxicology of LBL-007. 
1.3.3. 
Current Landscape of LAG-3 Inhibitors  
In 2022, BMS announced that Relatlimab (in combination with nivolumab, OpdualagTM) has 
been approved by the U.S. Food and Drug Administration (FDA) and European Commission 
(EC) for marketing, thus becoming the first LAG-3 antibody approved in the US and EU, while 
multiple LAG-3 antibody drugs have entered clinical studies worldwide.  
MK4280/Favezelimab (LAG-3 antibody) and pembrolizumab (PD-1 antibody) developed by 
Merck is currently being evaluated in combination in Phase 3 clinical study. Likewise, bispecific 
antibody, MGD013/Tebotelimab (MacroGenics Inc and Zai Lab), targeting PD-1 and LAG-3 is 
being tested in various unresectable or metastatic tumors. Furthermore, Sym-022 (Symphogen 
A/S) and Encelimab (GlaxoSmithKline/GSK) are studied in combination with anti-TIM-3 
monoclonal antibody and anti-PD-1 monoclonal antibody in Phase 1. Besides, more than 
10 antibodies against LAG-3 are explored in the various clinical studies as monotherapy or 
combined with other checkpoint inhibitors. 
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In a Phase 2/3 trial of Relatlimab in combination with nivolumab versus nivolumab monotherapy 
in previously untreated metastatic or unresectable melanoma (registration number 
NCT03470922, Study RELATIVITY-047), a total of 714 patients were included in clinical 
studies randomized 1: 1, 355 patients received BMS-986016 (160 mg) in combination with 
nivolumab 480 mg (Q4W) and 359 patients received nivolumab 480 mg monotherapy (Q4W). 
The primary endpoint was progression-free survival (PFS) according to RECIST v1.1 and the 
secondary endpoints were overall survival and objective response rate. The results showed that 
with a median follow-up time of 13.2 months, the median PFS was significantly longer in the 
combination group (10.1 months) than in the monotherapy group (4.6 months), and the 12-month 
PFS rates were 47.7% and 36.0% in the combination group and the monotherapy group, 
respectively. Overall, the combination regimen of relatlimab and nivolumab has a manageable 
safety profile, with no new safety signals compared to nivolumab monotherapy (Tawbi et al 
2022). Numerically higher incidence of immune-mediated adverse events such as 
hypothyroidism or thyroiditis, diarrhea or colitis, hepatitis, adrenal insufficiency, pneumonitis 
and myocarditis was observed in the combination group than nivolumab monotherapy. 
1.3.4. 
Clinical Pharmacology  
Study WLZB-LBL-007-AST-001: 
After single intravenous infusion of LBL-007 in patients at 0.05 mg/kg, 0.25 mg/kg, 1 mg/kg, 
3 mg/kg, 6 mg/kg or 10 mg/kg, the mean t1/2 values were determined, 49.54 hours, 105 hours, 
196 hours, 184 hours, and 182 hours, respectively; the mean Cmax values were 0.37 μg/mL, 
3.10 μg/mL, 13.03 μg/mL, 43.77 μg/mL, 80.23 μg/mL, 99.5 μg/mL, respectively; and the mean 
AUC0-t values were 6.19 h•μg/mL, 258 h•μg/mL, 1810 h•μg/mL, 6790 h•μg/mL, 
14,800 h•μg/mL, 192,00 h•μg/mL, respectively, indicating that both Cmax and AUC0-t increased 
with increasing dose, and the in vivo drug exposure increased in a dose-proportional manner. 
The mean time to peak (Tmax) was 1 to 9 h in each dose level of LBL-007. Most subjects reached 
the peak Tmax at the end of administration. For each dose group of LBL-007, when the dosage 
was increased from 0.05 mg/kg to 1 mg/kg, the t1/2 of LBL-007 tended to increase with 
increasing dose, and the clearance rate (CL) tended to decrease with increasing dose; however, 
when the dosage reached 3 mg/kg, CL did not change with the increase of dosage. There was no 
dose-dependent trend for Tmax, volume of distribution during terminal phase (Vz), or volume of 
distribution at steady state (Vss). 
The PK characteristics of multiple doses were similar to those of single dose, with Tmax values of 
1 to 9 hours in most patients in each dose group. After multiple intravenous infusion (every 2 
weeks) of LBL-007 in patients 0.05 mg/kg, 0.25 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg and 
10 mg/kg, Cmax and AUC0-t were observed to increase with increasing dose. No obvious 
accumulation was observed after multiple consecutive doses of 0.05 to 3 mg/kg, but the serum 
level increased slightly at doses between 6 and 10 mg/kg dose groups, suggesting that there may 
be limited accumulation 
Study LBL-007-CN-002: 
After a single intravenous infusion of 0.25 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg LBL-007 in 
combination with toripalimab (3 mg/kg), the mean time to maximum LBL-007 concentration 
ranged from 1.0 to 2.0 h; t1/2 was 43.63 h, 108.40 h, 165.89 h, 192.30 h, respectively, with a 
dose-dependent trend; the mean Cmax values were 3.350 μg/mL, 9.927 μg/mL, 36.707 μg/mL, 
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and 73.050 μg/mL, respectively; the mean AUC0-336 values were 266.264 h•μg/mL, 
1486.522 h•μg/mL, 5011.602 h•μg/mL, and 11175.155 h•μg/mL, respectively. The exposure 
parameter Cmax increased dose proportionally and increased slightly more compared with the 
increase of dosage. Mean changes in Vss ranged from 4.785 to 6.829 L, and mean changes in CL 
ranged from 0.024 to 0.074 L/h, indicating that the drug was mainly distributed in plasma. 
The PK profile of LBL-007 after multiple doses was similar to that after a single dose. 
The accumulation ratios for Cmax and AUC after multiple doses of LBL-007 ranged from 1.018 
to 1.553 and 1.019 to 1.543, respectively, suggesting a slight accumulation of LBL-007 in vivo. 
Refer to the LBL-007 Investigator’s Brochure for more details on the clinical pharmacology 
studies of LBL-007. 
1.3.5. 
Prior Clinical Experience With LBL-007  
As of January 30, 2022, a total of 3 clinical studies (sponsored by Nanjing Leads Biolabs Co., 
Ltd.), one completed and two ongoing, have been initiated with LBL-007:  
WLZB-LBL-007-AST-001 is a Phase 1a study to evaluate the safety, tolerability, 
pharmacokinetics and efficacy of anti-LAG-3 monoclonal antibody injection (LBL-007) in 
patients with malignant tumors and advanced lymphoma. The study has been completed.   
LBL-007-CN-007-CN-002 is a multicenter Phase 1 clinical trial to evaluate the safety, 
tolerability and efficacy of LBL-007 in combination with toripalimab or LBL-007 in 
combination with toripalimab and axitinib in the treatment of unresectable or metastatic 
melanoma. The study is ongoing (in the enrollment phase).   
LBL-007-CN-003 is a multicenter Phase 1b/2 clinical study of LBL-007 in combination with 
toripalimab in the treatment of advanced malignant tumors (eg, esophageal squamous cell 
carcinoma, head and neck squamous cell carcinoma, cervical cancer, nasopharyngeal cancer, 
small cell lung cancer, diffuse large B lymphoma). The study is ongoing (in the enrollment 
phase). 
Study WLZB-LBL-007-AST-001: 
As of 15 January 2022, a total of 22 patients were enrolled and received LBL-007 every two 
weeks at 0.05 mg/kg (n = 2), 0.25 mg/kg (n = 4), 1 mg/kg (n = 3), 3 mg/kg (n = 3), 6 mg/kg 
(n = 3), or 10 mg/kg (n = 7), 20 of whom completed the tolerability evaluation. The median age 
of the 22 patients was 58.5 (range: 19 to 70) years, and included 18 (81.8%) male patients and 
4 (18.2%) female patients. 
Preliminary safety results showed that the doses were well tolerated with no DLTs in any dose 
group. MTD was not reached with the maximum-administrated dose of 10 mg/kg in this study. 
Of the 22 patients, 21 (95.5%) experienced a total of 224 treatment-emergent adverse events 
(TEAEs), and TEAEs occurred in ≥ 10% of the patients were anemia (59.1%), hyperglycemia 
(27.3%), neutrophil count increased, hypocalcemia, upper respiratory tract infection, 
hyponatremia, and pyrexia (22.7% each), gamma-glutamyltransferase increased (18.2%), white 
blood cell count increased (18.2%), weight decreased, platelet count decreased, 
hypoalbuminemia, hypercalcemia, decreased appetite, asthenia, and sinus tachycardia (13.6% 
each). 
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Two patients (9.1%) had TEAE leading to permanent discontinuation of study treatment, 
including hypocalcemia (0.25 mg/kg dose group, possibly related to study drug) and 
gastrointestinal hemorrhage (3 mg/kg dose group, unlikely related to study drug) each in 
1 patient, with the outcomes of ongoing and unknown, respectively. No TEAE leading to death 
was reported each. 
During the treatment period, 8 patients (36.4%) experienced 13 serious adverse events (SAEs). 
Of them, 9 SAEs occurred in 5 patients (22.7%) were considered to be related to the study drug. 
The 9 SAEs occurred that happened in 1 patient each with an incidence of 4.5% each and 
included upper gastrointestinal hemorrhage (Grade 2, resolved without sequelae), gastrointestinal 
hemorrhage (Grade 3, ongoing), hypoalbuminemia (Grade 2, resolving to Grade 1), 
hypocalcemia (Grade 4, outcome unknown), bronchitis and bronchiectasis (reported by 
investigator as one AE term, Grade 3, ongoing), deep vein thrombosis (Grade 3, outcome other: 
resolving to Grade 2), and anemia (2 events of Grade 3, resolving to Grade 2 and Grade 1, 
respectively; 1 event of Grade 2, upgraded to Grade 3). The remaining 4 SAEs were considered 
not to be related to the study drug. The events included enteritis (Grade 2, resolved without 
sequelae), abdominal pain upper (Grade 3, ongoing), hyponatremia (Grade 3, outcome other: 
downgraded), and blindness unilateral (Grade 3, outcome unknown) and all occurred in 1 patient 
with an incidence of 4.5%. 
Efficacy results showed that of the 18 evaluable patients (2 patients in the 0.05 mg/kg group, 
1 patient in the 0.25 mg/kg group, 3 patients in the 1 mg/kg group, 3 patients in the 3 mg/kg 
group, 3 patients in the 6 mg/kg group, and 6 patients in the 10 mg/kg group), the objective 
response rate (ORR) was 5.6% (1 patient with esophageal cancer in 10 mg/kg group had PR) and 
the disease control rate (DCR) was 55.6% (1 patient of PR and 9 patients of stable disease ).  
Study LBL-007-CN-002:  
As of January 15, 2022, a total of 37 patients were enrolled and treated with LBL-007 at 
different dose (0.25, 1, 3, and 6 mg/kg, every 2 weeks) in combination with toripalimab 
(3 mg/kg, every 2 weeks). Four patients enrolled in the 0.25 mg/kg dose group, 3 patients in the 
1 mg/kg dose group, 16 patients in the 3 mg/kg dose group, and 11 patients in the 6 mg/kg dose 
group. Seventeen patients completed the DLT assessment, and no DLT events were observed. 
Of the 37 patients, 35 (94.6%) experienced a total of 344 TEAEs. Frequently reported TEAEs 
(incidence ≥ 10%) were blood lactate dehydrogenase increased (35.1%), blood creatine 
phosphokinase increased (24.3%), anemia (24.3%), aspartate aminotransferase increased 
(21.6%), hypothyroidism (21.6%), blood glucose increased (18.9%), pyrexia (18.9%), asthenia 
(18.9%), blood bilirubin increased (16.2%), hypokalemia (16.2%), alanine aminotransferase 
increased (13.5%), bilirubin conjugated increased (13.5%), and gamma-glutamyltransferase 
increased, blood cholesterol increased, blood pressure increased, hypoalbuminemia, 
hyponatremia, hypertriglyceridemia, nausea, vomiting, hyperthyroidism, proteinuria, and back 
pain (10.8% for each). 
The incidence of TEAEs leading to dose delay and permanent discontinuation were 16.2% and 
2.7%, respectively. 
Nine SAEs were reported in 6 patients: obstructive jaundice (3.0 mg/kg, Grade 3, unlikely 
related), T2 bone destruction: melanoma metastasis (suspected; 3.0 mg/kg, Grade 3, definitely 
not related), hypopituitarism (0.25 mg/kg, Grade 3, possibly related), disease progression 
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(6.0 mg/kg, Grade 5, unlikely related), nausea (3.0 mg/kg, Grade 2, unlikely related), vomiting 
(3.0 mg/kg, Grade 2, unlikely related), myocarditis (6.0 mg/kg, Grade 2, probably related), 
severe anemia (6.0 mg/kg, Grade 3, possibly related), unknown death (3.0 mg/kg, Grade 5, to be 
evaluated). 
A total of 32 patients with melanoma were evaluable for response assessment, 21 had not 
received anti-PD-L1 antibody therapy (abbreviated as immunotherapy naive), 11 had previously 
received prior anti-PD-L1 antibody therapy (abbreviated as immunotherapy treated), of whom 
4 patients achieved PR (3 acral cutaneous melanoma and 1 non-acral cutaneous melanoma, with 
all were immunotherapy naive patients), 13 patients achieved stable disease, of whom 11 were 
immunotherapy naive patients and 2 were immunotherapy-treated patients (1 mucosal melanoma 
and 1 non-acral cutaneous melanoma). 
Study LBL-007-CN-003: 
As of 30 January 2022, a total of 10 patients received LBL-007 in combination with toripalimab 
(3 mg/kg, every 3 weeks), including 4 patients in the dose group of LBL-007 200 mg (every 
3 weeks) and 6 patients in the dose group of LBL-007 400 mg (every 3 weeks). The tolerability 
evaluation for 400 mg was completed with no DLT cases, and the MTD for this study was not 
reached with the maximum-administrated dose of 400 mg. A total of 12 TEAEs were reported in 
7 patients, including pain in the left lower extremity and anemia (2 patients each), and 
constipation, vomiting, oropharyngeal pain, rash, peripheral neuralgia, back pain, hyperuricemia, 
and lymphocyte count decreased in 1patient each. There were no SAEs of any grade.  
Response assessment was performed in 4 patients, all of which were stable disease (2 patients 
with lung adenocarcinoma, 1 patient each with nonkeratinizing pleomorphic nasopharyngeal 
carcinoma and small cell lung cancer). 
Refer to the LBL-007 Investigator’s Brochure for more details on the clinical studies of 
LBL-007. 
1.4. 
Tislelizumab as a PD-1 Inhibitor  
Immune checkpoint-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 the T-cell receptor and attenuates T-cell proliferation and functional activities, leading 
to T-cell exhaustion. PD-1 expression is markedly upregulated in TILs, 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 interferon-gamma (IFN-γ) and interferon-alpha 
(IFN-α) in the tumor microenvironment. Furthermore, the increased PD-1 expression in TILs 
and/or PD-L1 expression in tumor and tumor-associated stromal cells is observed in many types 
of solid human tumors including, but not limited to, melanoma, squamous cell carcinoma, uveal 
melanoma, NSCLC, HNSCC, triple-negative breast cancer, renal cell carcinoma, bladder cancer, 
and ovarian cancer. Several anti-PD-1 agents have been approved for the treatment of several 
cancers. Thus, PD-1 is an established target for cancer immunotherapy. 
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1.4.1. 
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 (dissociation constant = 0.15 nM). It competitively blocks binding efforts by 
both PD-L1 and PD-L2, thus inhibiting PD-1-mediated negative signaling in T-cells in in vitro 
cell-based assays. In addition, tislelizumab has demonstrated antitumor activity in human PD-1 
transgenic mice in vivo. 
The IgG4 variant antibody has very low binding affinity to FcγRI, FcγRIIIA, and complement 
1q, a subunit of complement 1, by in vitro assays, suggesting either low or no antibody-
dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity or complement-
dependent cytotoxicity effects in humans. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
pharmacology of tislelizumab. 
1.4.2. 
Toxicology  
In single dose toxicity studies in both mice and cynomolgus monkeys, no mortality or apparent 
toxicity was noted at a single dose up to 100 mg/kg. 
In the repeat dose study in cynomolgus monkeys, no apparent toxicity, including inflammation, 
was noted following intravenous infusion of tislelizumab at 3, 10, or 30 mg/kg once every 
2 weeks for 13 weeks (7 doses). No test-article-related histopathologic changes were noted in 
any tissues. No specific concerns were identified for the vital organ system functions, including 
the cardiovascular system, the central nervous system, and the respiratory system. Antidrug 
antibodies with neutralization activity were noted but appeared to have no impact on systemic 
exposure except at the low dose of 3 mg/kg; thus, with sustained systemic drug exposure, the 
efficacy of the drug would not be impacted. The NOAEL was considered to be 30 mg/kg in this 
study.  
The systemic exposure appeared to increase dose proportionally without apparent sex difference 
or accumulation. The systemic exposure of tislelizumab at 30 mg/kg (NOAEL) appears to be 
significantly higher in cynomolgus monkeys (approximately 5- to 8-fold) than in humans at all 
dose levels tested based on clinical human PK data. 
The tissue cross-reactivity of tislelizumab was evaluated in healthy cynomolgus monkey and 
healthy human frozen tissues using immunohistochemistry. No specific tissue cross-reactivity 
with tislelizumab was noted in cynomolgus monkey or human tissues. No apparent cytokine 
release was detected in a human PBMCs assay. The potential of enhanced immune recall 
responses was observed in an in vitro human PBMC-based cell assay but not in human PD-1 
transgenic mice in vivo. 
Overall, the available toxicological data are considered adequate in the clinical development of 
tislelizumab in patients with advanced cancer. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
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1.4.3. 
Clinical Pharmacology  
A population PK analysis was performed based on the pooled data (PK, dosing information, 
demographics, and patient or disease characteristics) from 2596 patients across 12 clinical 
studies. The PK of tislelizumab was best characterized using a 3-compartmental model with 
linear clearance mechanism. No time-varying clearance was observed in tislelizumab PK. The 
typical estimates of clearance (CL), central volume of distribution (Vc), and peripheral 
volumes 2 and 3 (V2 and V3, respectively), were 0.153 L/day, 3.05 L, 1.27 L, and 2.10 L, 
respectively, with interindividual variability in CL (26.3%), Vc (16.7%), V2 (74.7%), and V3 
(99.9%). The terminal t1/2 was estimated to be approximately 23.8 days. The accumulation ratios 
were estimated to be 2.14 and 2.49 for AUC at steady state (AUCss) and minimum serum 
concentration at steady state (Cmin,ss), respectively. Steady state is expected to be reached in 
approximately 12 weeks. 
The population PK analyses demonstrated that race, baseline alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin, lactate dehydrogenase, estimated glomerular 
filtration rate, Eastern Cooperative Oncology Group (ECOG) Performance Status score, and sum 
of products of perpendicular diameters of classical Hodgkin Lymphoma had no statistically 
significant influences on tislelizumab PK. Baseline body weight, tumor size of solid tumors, 
albumin, age, sex, immunogenicity, and tumor type were found to be statistically significant 
covariates on the PK of tislelizumab; however, the exposure changes by these covariates were 
small compared to the overall estimated PK exposures range and thus are not considered 
clinically meaningful. 
1.4.4. 
Prior Clinical Experience with Tislelizumab  
Tislelizumab is being developed for the treatment of several types of human malignancies in 
multiple regions as monotherapy or in combination with other therapies. Tislelizumab has also 
been approved and is currently being marketed in China for indications including classical 
Hodgkin’s lymphoma, urothelial carcinoma, ESCC, squamous NSCLC, non-squamous NSCLC, 
hepatocellular carcinoma, and advanced unresectable or MSI-H or dMMR solid tumors.  
The overall safety experience with tislelizumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in 3498 patients (2150 patients treated with monotherapy 
and 1348 patients treated with combination therapy) as of the cutoff date 20 May 2021. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AE to tislelizumab dose level. The safety profile for 
single-agent tislelizumab is similar to those observed in other PD-1 inhibitors. The initial data 
collected in these studies suggest that tislelizumab can result in antitumor activity across a 
variety of tumor types. Antitumor activity has been observed across the dose ranges evaluated in 
patients.  
For combination studies, the safety profile of tislelizumab is generally consistent with use as a 
single agent and appears to be safe and well tolerated when used in combination with other 
agents and in multiple different chemotherapy backbones. Preliminary antitumor activities of 
tislelizumab in combination with chemotherapy and other agents have been observed in multiple 
tumor types.  
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As of 20 May 2021, there are currently 33 studies with tislelizumab ongoing and 9 studies have 
been completed. Of the 33 ongoing studies, 15 have preliminary data available for presentation 
in the Investigator’s Brochure, Edition 9.0 (effective 20 October 2021): 6 monotherapy studies 
(BGB-A317-207, BGB-A317-208, BGB-A317-209, BGB-A317-210, BGB-A317-302, and 
BGB-A317-303); 2 chemotherapy combination therapy studies (BGB-A317-304 and BGB-
A317-307); and 7 targeted therapy combination studies (BGB-900-102 [tislelizumab in 
combination with BGB-A425 (anti-TIM-3 mAb)], BGB-900-103 [tislelizumab in combination 
with sitravatinib (also known as MGCD516, a receptor tyrosine kinase inhibitor)], BGB-900-104 
(sitravatinib alone and in combination with tislelizumab), BGB-900-105 [tislelizumab in 
combination with ociperlimab (also known as BGB-A1217, an anti-TIGIT mAb)], BGB-A317-
211 [tislelizumab in combination with lenvatinib], BGB-A317-A445-101 [tislelizumab in 
combination with BGB-A445 (anti-OX40 agonist mAb)], BGB-A317-ZW25-101 [zanidatamab 
(also known as ZW25) in combination with chemotherapy with and without tislelizumab].  
Additionally, there are 18 ongoing studies that do not have clinical data presented in the 
Investigator’s Brochure, Edition 9.0 (effective 20 October 2021): 10 studies that are blinded or 
have a data integrity plan in place (BGB-A317-301, BGB-A317-305, BGB-A317-306, 
BGB-A317-309, BGB-A317-310, BGB-A317-311, BGB-A317-312, BGB-A317-314, and BGB-
A317-315, and BGB-A317-A1217-203; 7 studies with ≤ 10 patients enrolled (BGB-A317-
15025-101, BGB-A317-212, BGB-A317-213, BGB-A317-214, BGB-A317-3111-10188-101, 
BGB-A317-A1217-202, and BGB-fruquintinib-201); 1 study focused on drug supply where 
safety data collection is limited (BGB-A317-290-LTE1). 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on 
efficacy and safety of tislelizumab. 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
A pooled analysis of monotherapy studies in total of 2150 patients was conducted to provide a 
comprehensive safety assessment presented based either as solid tumors (1992 patients) or 
hematologic malignancies (158 patients).  
The patients in the solid tumor group of pooled monotherapy studies had a median treatment 
exposure duration of 4.07 months (range: 0.10 to 41.46) and median study follow-up duration of 
11.53 months (range: 0.07 to 58.91). The median age of the patients was 60 years and 72.1% 
were male. These patients had a median of 1.0 prior systemic anticancer therapy regimens 
(range: 0 to 12). 
The patients in the hematologic malignancy group of pooled monotherapy studies had a median 
treatment exposure duration of 6.99 months (range: 0.33 to 38.60) and median study follow-up 
duration of 18.37 months (range: 0.33 to 38.64). The median age of the patients was 43 years and 
61.4% were male. These patients had a median of 3.0 prior systemic anticancer therapy regimens 
(range: 1 to 11). 
Of the 1992 patients in the solid tumor group of monotherapy studies, 1922 (96.5%) of patients 
experienced ≥ 1 TEAE, while 69.8% of patients (n = 1391) experienced ≥ 1 TEAE considered 
treatment related TEAEs ≥ Grade 3 in severity were experienced by 847 of 1992 patients 
(42.5%) and 269 patients (13.5%) experienced a ≥ Grade 3 TEAE considered treatment related. 
Serious TEAEs were reported in 706 patients (35.4%) and 209 patients (10.5%) experienced 
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≥ 1 serious TEAE considered treatment related. A total of 141 patients (7.1%) experienced a 
TEAE leading to death. 
The most commonly occurring TEAEs in the solid tumor group of pooled monotherapy studies 
were anemia (502 of 1992 patients, 25.2%), AST increased (359 patients, 18.0%), ALT 
increased (333 patients, 16.7%), decreased appetite (329 patients, 16.5%), and cough (301 
patients, 15.1%).  
Of the 158 patients in the hematologic malignancy group of monotherapy studies, 149 (94.3%) 
of patients experienced ≥ 1 TEAE and 129 patients (81.6%) experienced ≥ 1 TEAE considered 
treatment related. TEAEs ≥ Grade 3 in severity were experienced by 82 of 158 patients (51.9%) 
and 33 patients (20.9%) experienced a ≥ Grade 3 TEAE considered treatment related. Serious 
TEAEs were reported in 59 patients (37.3%) and 31 patients (19.6%) experienced ≥ 1 serious 
TEAE considered treatment related. A total of 15 patients (9.5%) died as a result of a TEAE in 
this group. 
The most commonly occurring TEAEs in the hematologic malignancy group of pooled 
monotherapy studies were pyrexia (66 of 158 patients, 41.8%), upper respiratory tract infection 
(37 patients, 23.4%), hypothyroidism (37 patients, 23.4%), weight increased (29 patients, 
18.4%), and anemia (28 patients, 17.7%). 
1.5. 
Study Rationale  
1.5.1. 
Rationale for Phase 1 Dose Escalation Study Design  
As described earlier, despite the wealth of evidence supporting TIM-3’s role in promoting tumor 
immune tolerance, TIM-3 blockade alone (ie, BGB-A425 monotherapy) is unlikely to result in 
an efficacious antitumor response (see Section 1.2). Therefore, the clinical development of 
BGB-A425 focuses on rationale combinations, such as with tislelizumab. Taking this into 
account, the dose escalation study was designed to minimize a patient’s exposure to BGB-A425 
monotherapy and therefore maximize the patient’s potential therapeutic benefit while 
simultaneously achieving the clinical objective of characterizing the safety and efficacy of 
BGB-A425 in combination with tislelizumab. 
The appropriateness of the study design is also based upon the following data, which suggest the 
combination of BGB-A425 + tislelizumab will be safe and tolerable with a manageable safety 
profile: 
1. Based upon the BGB-A425 animal toxicology data, which showed no toxicity at the 
maximal allowed dose (Section 1.2.2), and confirmed clinically by another anti-TIM-3 
therapy (Weiss et al 2017), BGB-A425/TIM-3 blockade is expected to be safe and well 
tolerated; 
2. Tislelizumab and/or other anti-PD-1 therapies have shown to be safe and tolerable, both 
as a monotherapy and in combination with other effector T-cell stimulating 
immuno-oncology agents (Section 1.3, Wang et al 2017; Esin et al 2017; Boutros et al 
2016; Naing et al 2018); 
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3. The combination of anti-TIM-3 and anti-PD-1 was publicly reported to be well tolerated 
in patients and showed preliminary efficacy, resulting in further evaluation of the 
combination in dose expansion (Davar et al 2018); 
4. The starting dose of BGB-A425 encompasses a 3950-fold safety margin 
(Section 1.5.4.2); 
5. An extensive clinical, laboratory and ECG monitoring plan has been established to 
closely monitor patient safety so as to identify and address immune-mediated toxicities as 
early as possible (Appendix 1); 
6. A comprehensive and effective algorithm based upon guidelines from the European 
Society for Medical Oncology or American Society for Clinical Oncology has been 
established to monitor, diagnose and manage immune-mediated toxicities (Appendix 8). 
7. For reasons described in Section 1.2, there is currently no intention to clinically evaluate, 
characterize and/or develop BGB-A425 for use as a monotherapy 
It is important to emphasize the safety experience gained from prior clinical studies whereby 
anti-PD-1 has been evaluated in combination with other effector T-cell stimulating 
immune-oncology agents. In general, the combinations lead to similar AEs compared to 
anti-PD-1 alone, although in some cases with greater frequency, severity and/or earlier onset but 
ultimately shown to be safe, tolerable and if necessary, manageable with standard of care 
(Section 1.3, Wang et al 2017; Esin et al 2017; Boutros et al 2016; Naing et al 2018). However, 
TIM-3 and PD-1 have overlapping immuno-regulatory functions and in the absence of 
activation, peripheral effector T-cells typically do not express TIM-3, thereby limiting the 
potential for peripheral immune autoreactivity (Anderson 2014; Das et al 2017; Du et al 2017). 
Therefore, there is a distinct possibility that the combination of BGB-A425 and tislelizumab will 
result in a safety profile (type, frequency, severity, timing etc.) that is similar to tislelizumab 
alone. Regardless, an effective diagnostic and treatment algorithm is available to address 
immune mediated toxicities related to PD-1 blockade alone or the combined blockade of 
multiple immuno-regulatory pathways. 
The DLT dosing schema was designed based upon the following rationale: 1) allows for the 
evaluation of acute toxicities related to BGB-A425 alone (eg, immediate and/or non-immediate 
hypersensitivity reactions, cytokine release syndrome, delayed infusion reactions etc. 
[Baldo 2013 Picard and Galvao 2017]) as well as early onset immune mediated toxicities related 
to the combination of BGB-A425 and tislelizumab; 2) based upon the projected t1/2 and trough 
levels of BGB-A425, the DLT dosing schema also provides sufficient exposure throughout the 
DLT period that is estimated to achieve 90% TIM-3 RO in PBMCs, which is necessary to fully 
and consistently evaluate the safety of BGB-A425 alone or in combination with tislelizumab; 3) 
based upon the time to event profile of immune mediated toxicities related to checkpoint 
therapies, it is unlikely that the toxicity profile of BGB-A425 monotherapy will differ 
significantly for a 3-week versus 1-week observation period thereby negating the benefit of 
evaluating BGB-A425 alone for the first cycle while only serving to delay optimal treatment of 
cancer patients with advanced disease; 4) all toxicities regardless of when they occur will be 
taken into consideration regarding dosing decisions; 5) if unexpected toxicity is observed, the 
protocol does allow for immediate implementation of additional dose escalation criteria (eg, 
extension of the DLT period) as described in Section 3.5. 
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Another important consideration is that the safety profile of tislelizumab has been characterized 
in over 1,705 patients (Tislelizumab Investigator’s Brochure), thereby serving as a safety 
reference when evaluating and/or characterizing the safety of BGB-A425 in combination with 
tislelizumab. Finally, BeiGene has in place a multi-layered process for ensuring patient safety in 
part through close collaboration between study investigators and the BeiGene study team. The 
study will also utilize BeiGene’s established processes for the continual collection, review, and 
aggregate analyses of all safety data. 
In summary, the current dose escalation study design allows patients, most of whom have failed 
multiple prior lines of therapy and/or experiencing rapid disease progression typical for a Phase 1 
study, the opportunity to obtain maximal therapeutic benefit without compromising patient safety 
nor clinical objectives. 
1.5.2. 
Rationale for Combination of BGB-A425 and Tislelizumab in the Treatment of 
Advanced Solid Tumors  
Blocking antibodies targeting PD-1 have achieved remarkable results in the treatment of many 
types of tumors. However, it is also worth noting that this therapeutic strategy typically achieves 
a < 30% ORR as a monotherapy in patients whose tumors exhibit low positive PD-L1 expression 
and/or are microsatellite stable (Chen and Han 2015). 
TIM-3 and PD-1 function as immune checkpoint receptors in the overlapping regulation of 
immune tolerance. As noted above, TIM-3 and PD-1 have been shown to be overexpressed on 
the TILs from patient samples of various solid tumors including, but not limited to HNSCC, 
NSCLC and RCC. Subsequently, the activation of TIM-3 and PD-1 represent TILs from both 
patients or animals across solid tumor types with the most exhausted immunophenotype (ie, 
cytokine expression, proliferation etc.), which can be reversed with combined blockade of TIM-3 
and PD-1. Interestingly, TIM-3 is typically only expressed on effector T-cells when PD-1 is 
co-expressed (Du et al 2017; Thommen et al 2015) and the expression both of which is 
upregulated following effector activation (Gao et al 2012). As such, immune escape via PD-1 
will be sustained in patients with PD-L1 positive tumors thereby negating TIM-3 blockade alone. 
The overlap in expression and function indicates that TIM-3 and PD-1 cooperate to promote 
effector cell exhaustion which may impede an effective antitumor immune response. Indeed, the 
combined blockade of TIM-3 and PD-1 significantly increased IFN-  production in vitro 
relative to the increase seen for TIM-3 or PD-1 blockade alone, thus demonstrating that the 
combined blockade of TIM-3 and PD-1 can mitigate effector cell exhaustion following activation 
and chronic antigen stimulation (Figure 1). 
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Figure 1: 
Combined Blockade of TIM-3 and PD-1 with BGB-A425 and tislelizumab 
(BGB-A317) Enhances IFN-γ secretion in Mixed Lymphocyte Reaction 
 
Abbreviations: IFN-γ, interferon-gamma; PBMC, peripheral blood mononuclear cell; PD-1, programmed cell death 
protein-1; TIM-3, T-cell immunoglobulin and mucin-domain containing-3 
A conventional mixed lymphocyte reaction assay was performed. In brief, "stimulator PBMCs" from a healthy 
donor were pre-treated with mitomycin-c (100 μg/ml, Sigma) and co-cultured with "responder PBMCs" of a 
different donor in the complete RPMI1640 media with 10% AB serum (Sigma) plus BGB-A425 and/or 
tislelizumab/BGB-A317 (50 ng/ml) in a 96-well flat-bottom plates for 4 days. The secretion of IFN-γ into the cell 
culture was analyzed as a readout of T-cell function. All conditions were performed in triplicates and results are 
shown as mean ± SD. The EC50 for BGB-A425 alone is 6.1 μg/mL, and the EC50 for combination of BGB-A425 and 
tislelizumab/BGB-A317 is 0.89 μg/mL. 
Further, combined blockade of TIM-3 and PD-1 resulted in a greater antitumor effect in vivo 
compared to PD-1 blockade alone as observed for various solid tumor models (Figure 2) 
(Ngiow et al 2011; Fourcade et al 2010; Kim et al 2017; Sakuishi et al 2010). Importantly, 
following treatment with anti-PD-1, the expression of TIM-3 was shown to be upregulated on 
TILs in both patient samples and animal models of NSCLC and HNSCC, which was temporally 
correlated with the development of resistance to anti-PD-1 treatment (Koyama et al 2016; 
Shayan et al 2016; Oweida et al 2018). Subsequently, following this “adaptive resistance” to 
anti-PD-1 monotherapy, sequential treatment with anti-TIM-3 significantly improved the 
antitumor effects in both NSCLC and HNSCC mouse models (Figure 3). 
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Figure 2: 
The Combination of Anti-TIM-3 and Anti-PD-1 Treatment Is More Effective 
Than Anti-PD-1 Inhibitors Alone 
 
Abbreviations: cIg, control immunoglobulin; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; 
MCA, methylcholanthrene; PD-1, programmed cell death protein-1; TIM-3, T-cell immunoglobulin and mucin-
domain containing-3 
Figure 2A: MCA (induced sarcoma model) mice were treated prophylactically with control (cIg), anti- TIM-3, 
anti-PD-1, or anti-PD-1 + anti-TIM-3 (100 mg administered intraperitoneally) on Days -1, 0, and weekly for 
8 weeks. Statistical differences determined by a Log Rank Mantel–Cox test (*, monotherapy compared with cIg; 
**, anti-PD-1 + anti-TIM-3 compared with either anti-PD-1 or anti-TIM-3 alone) (Ngiow et al 2011). 
Figure 2B: Groups of B6 mice (n = 5) were inoculated subcutaneously with CT26. On Days 3, 7, 11, and 15, mice 
were treated intraperitoneally with either control (cIg), anti-TIM-3, anti-CTLA-4, anti-PD-1, or their combination 
(100 mg) as indicated. Tumor sizes are represented as the mean standard error of the mean. Statistical differences in 
tumor sizes between mice treated with cIg and single monoclonal antibody therapy were determined by a 
Mann-Whitney test (*, p < 0.05). Statistical differences between mice treated with single monoclonal antibody 
therapy or a dual combination were determined by a Mann–Whitney test (**, p < 0.05). (Ngiow et al 2011). 
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Figure 3: 
Sequential Anti-TIM-3 and Anti-PD-1 Treatment Increases Survival and 
Suppresses Tumor Growth Compared to Anti-PD-1 Treatment Alone 
 
Abbreviations: Ab, antibody; PD-1, programmed cell death protein-1; TIM-3, T-cell immunoglobulin and 
mucin-domain containing-3 
Figure 3A: Non-small cell lung cancer mouse survival model. Survival following PD-1 blockade alone (anti-PD-1 
resistant) or PD-1 and sequential TIM-3 blockade combination treatment (PD-1 alone: n = 16 and sequential 
combination treatment: n = 11) (p = 0.0008) after documented tumor burden. Treatment with anti-PD-1 started at 
week 0. Median survival with anti-PD-1 = 5 weeks versus anti-PD-1 + anti-TIM-3 sequential treatment = 11.9 
weeks (Koyama et al 2016). 
Figure 3B: Metastatic human papilloma virus + oropharyngeal squamous cell carcinoma mouse model. Mice were 
treated with anti-mouse PD-1monoclonal antibody given at 5 doses every 2 days, and sequential anti-TIM-3 
monoclonal antibody treatments were given to one group of mice starting from Day 22 for 4 doses every 2 days. 
Tumor volume was measured every 2 days (*, p < 0.05) (Shayan et al 2016). 
Based upon the overlapping expression profiles and immuno-regulatory functions, the improved 
in vivo antitumor effects, as well as the potential for TIM-3 mediated adaptive resistance, there is 
strong scientific rationale to evaluate the antitumor effects derived from the combined blockade 
of TIM-3 and PD-1 in advanced solid tumors. 
1.5.3. 
Rationale for Combination of BGB-A425, LBL-007, and Tislelizumab in the 
Treatment of Advanced Solid Tumors  
Co-expression of multiple immune checkpoint proteins occurs frequently on tumor infiltrating T 
cells and is associated with their dysfunction state. Both LAG-3 and TIM-3 were shown to be co-
expressed with PD-1 on tumor infiltrating T cells and were upregulated in anti-PD-1 resistant 
and non-responder patients, suggesting co-blockade of PD-1 with LAG-3 or TIM-3 could further 
enhance antitumor immunity (Gettinger et al 2017, Hanna et al 2018, Johnson et al 2018, Kates 
et al 2021). 
In preclinical mouse study, LBL-007 in combination with anti-PD-1 significantly improved 
antitumor effect with a tumor growth inhibition (TGI) of 77.63%, superior to LBL-007 
(TGI=56.10%) or anti-PD-1(TGI=58.99%) monotherapy in MC38-OVA (mouse colorectal 
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cancer cell line stably expressing OVA protein) xenograft model in a human LAG-3 transgenic 
mouse (Figure 4). There were no significant differences in body weight between groups.  
Figure 4: 
Tumor growth curve after treatment with LBL-007, anti-mouse PD-1 and 
the combination in MC38-OVA model  
 
The synergic antitumor efficacy for anti-LAG-3 antibody in combination with anti-PD-1 
antibody has been preliminarily validated in clinical study. The first anti-LAG-3 antibody was 
recently approved by FDA based on the significant clinical benefit of LAG-3/PD-1 
combinational therapy compared to anti-PD-1 alone in unresectable metastatic melanoma (Tawbi 
et al 2022). The combination of LBL-007 with anti-PD-1 (toripalimab) is now under clinical 
evaluation in melanoma (LBL-007-CN-002). A total of 32 evaluable patients had an ORR of 
12.5% (4 patients experiencing partial response) and a DCR of 53.1% (4 patients experiencing 
partial response and 13 patients experiencing stable disease). Of the 11 evaluable patients with 
cutaneous acral melanoma who did not receive anti-PD-L1 antibody treatment before, the ORR 
was 27.3% and the DCR was 81.8%. Moreover, in the study of LBL-007 in combination with 
toripalimab in the treatment of advanced malignancies (Study LBL-007-CN003), the antitumor 
efficacy was assessed in 4 patients, all of whom experienced stable disease. 
Furthermore, LAG-3 was shown to confer resistance to anti-TIM-3/PD-1 combination therapy. 
LAG-3 expression on tumor infiltrating T cells was increased following the combinational 
treatment of anti-PD-1 and anti-TIM-3 in preclinical settings (Yang et al 2020). In an in-vivo 
efficacy study in MC38 syngeneic tumor model, anti-mouse PD-1 antibody Ch15mt, anti-human 
LAG-3 antibody LBL-007, and anti-mouse TIM-3 antibody RMT3-23 combination 
demonstrated a greater antitumor effect than either anti-TIM-3/anti-PD-1 or anti-LAG-3/anti-
PD-1 combinations (data on file; see Figure 5).  
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Taken together, those data suggest a combination targeting TIM-3, LAG-3, and PD-1 could 
synergistically improve the responses of antitumor immunotherapy, and thus providing a strong 
scientific rationale for testing the triple combination in clinical studies. 
Figure 5: 
Synergy efficacy in the combination of anti-PD-1, anti-TIM-3, and 
anti-LAG-3 on tumor growth inhibition in the MC38 syngeneic model in 
human LAG-3 knock-in mice  
 
  
Abbreviations: biw, twice a week; ip, intraperitoneal; LAG-3, lymphocyte activation gene-3; qw, once a week. 
MC38 xenograft tumor growth curve in B6-hLAG-3 mice under different treatments. On Day 8 after cell 
inoculation, the mice were randomized into 6 groups according to tumor volume. The mice were treated with 
Ch15mt, LBL-007, and RMT3-23 and tumor volumes were plotted to Day 26 after tumor inoculation. Data were 
presented as mean tumor volume ± standard error of the mean of 15 animals. One-way ANOVA was used to analyze 
logarithmic transformed tumor volume data, * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. 
1.5.4. 
Rationale for Selection of BGB-A425 Starting Dose  
1.5.4.1. 
Allometric Scaling  
Serum concentration-time profiles from 6 monkeys receiving single doses of BGB-A425 at 12, 
40, and 120 mg/kg, respectively, and 6 monkeys receiving 5 weekly doses of 40 mg/kg 
(BGB-A425 Investigator’s Brochure) were used in a population PK analysis with NONMEM 
version 7.3. 
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A 2-compartment model with first order elimination described the data well. Inter-subject 
variability was estimated for the CL and central volume of distribution. Human PK parameters 
were obtained by scaling respective monkey PK parameters multiplied by the ratio of body 
weight (human/monkey) and taken to the power of 0.75 for CL and inter-compartmental CL and 
1.0 for the volume for the central compartment and the peripheral compartment. 
Table 1: 
Population PK Parameters Estimate for Monkey and Projected PK 
Parameters in Humans 
Parameter 
Monkey 
Human 
Estimate 
%RSV 
Projection 
CL (L/h) 
0.000785 
7.4 
0.00892 
Vc (L) 
0.159 
6.2 
4.06 
Vp (L) 
0.0465 
29 
1.19 
Q (L/h) 
0.00226 
34 
0.0257 
IIV CL (%) 
28 
34 
NA 
IIV Vc (%) 
22 
33 
NA 
Residual error 
59 
10 
NA 
Abbreviations: CL, clearance; h, hour; IIV, inter-subject variability; L, liter; NA, not applicable; PK, 
pharmacokinetics; Q, inter-compartmental clearance; RSV, relative standard error; Vc, volume of central 
compartment; Vp, volume of peripheral compartment 
The simulation of serum BGB-A425 concentration-time profiles in humans was conducted in 
Berkeley Madonna version 8.3. 
1.5.4.2. 
Recommendation of the First in Human Dose of BGB-A425  
Similar to anti-PD-1, anti-TIM-3 is a checkpoint inhibitor. Therefore, both the minimally 
anticipated biologic effect level (MABEL) and NOAEL approaches were used to determine the 
starting dose in humans.  
To define MABEL, the mixed lymphocyte reaction (MLR) assay was performed to evaluate the 
effect of BGB-A425 alone or in combination with BGB-A317 on effector cell exhaustion 
(Section 1.5.2). In the presence of 50 ng/mL of BGB-A317, the EC90 value of BGB-A425 was 
0.89 µg/mL. A starting dose of 2 mg was selected because its Cmax after a single dose is projected 
to be 0.5 µg/mL, which is below the EC90 value for the combination of BGB-A425 and 
BGB-A317 in the MLR assay. The projected t1/2 of approximately 17 days in humans supports a 
flat dosing regimen given every 21 days. 
Figure 6 presents the simulated human doses of 2, 6, 20, 60, 200, 400, and 800 mg of BGB-A425 
given once every 4 weeks in Cycle 1 and every 21 days starting from Cycle 2. The step size in 
dose was approximately tripled for the first 3 doses and doubled thereafter. 
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Figure 6: 
Simulated Serum Concentration-Time Profiles in Humans 
 
Abbreviations: EC90, concentration corresponding to 90% receptor occupancy of TIM-3 
Based on the steady state AUC at 200 mg/kg in the 3-month toxicity study in monkeys 
(BGB-A425 Investigator’s Brochure), the projected safety margins at the proposed human dose 
are provided in Table 2. At the proposed starting dose of 2 mg, the projected safety margins 
based on AUC and Cmax are 3950 and 6960, respectively, which reflects favorably on the safety 
profile of BGB-A425. 
Table 2: 
Projected Safety Margins at Steady State at the Proposed Doses in Humans 
Doses (mg) 
2 
6 
20 
60 
200 
400 
800 
AUC Safety Margin 
3950 
1320 
395 
132 
39 
20 
13 
Cmax Safety Margin 
6960 
2320 
696 
232 
70 
35 
17 
Abbreviations: AUC, area under the concentration-time curve; Cmax, maximum observed concentration. 
1.5.5. 
Rationale for BGB-A425 Recommended Phase 2 Dose  
The combination RP2D was determined primarily from the Phase 1 safety, tolerability, 
preliminary antitumor activity, pharmacodynamic biomarker and PK data. The RP2D is 
determined as BGB-A425 600 mg in combination with tislelizumab 200 mg administered every 
21 days, which will be evaluated in the Phase 2 dose expansion phase. 
1.5.6. 
Rationale for Selection of LBL-007 Dose  
In the single-agent dose escalation trial of WLZB-LBL-007-AST-001b (as mentioned in 
Section 1.3.5), the highest dose of 10 mg/kg (every 2 weeks) was tested in 7 patients with no 
DLT and generally well tolerated. Little accumulation was observed at steady-state due to its 
short half-life. The dose of 10 mg/kg (every 2 weeks) provides exposure coverage up to 
LBL-007 600 mg dosed every 3 weeks, and LBL-007 600 mg (every 3 weeks) could be chosen 
as the highest dose as in the range of the LBL-007 starting dose in combination with tislelizumab 
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200 mg administered every 21 days or BGB-A425 600 mg and tislelizumab 200 mg administered 
every 21 days for Phase 2 safety lead-in.  
Additionally, in LBL-007-CN-003 study, doses ranging up through 400 mg of LBL-007 (every 3 
weeks) was evaluated with toripalimab (anti-PD-1 antibody) with no DLT (n = 6). Similarly, in 
LBL-007-CN-002, the combination of LBL-007 (doses ranging up through 6 mg/kg; every 2 
weeks) with toripalimab was well tolerated with no DLT observed in 14 patients at this dose.  
Since this is the first-in-human study where BGB-A425 will be combined with LBL-007 and 
tislelizumab, considering the safety and tolerability of this combination, we plan to evaluate 
LBL-007 at 300 mg as the starting dose of LBL-007, which is one dose level below the highest 
LBL-007 dose (ie, 600 mg; every 21 days) as mentioned above, for combining with tislelizumab 
200 mg or with BGB-A425 600 mg and tislelizumab 200 mg. Then the dose level of LBL-007 
will be escalated to 600 mg in the combination treatment cohorts. If LBL-007 600 mg in 
combination with tislelizumab or BGB-A425 and tislelizumab are well tolerated, a higher dose 
of LBL-007 (eg, 900 mg every 21 days) may be explored based on emerging safety, tolerability, 
PK, and other clinical data. 
1.5.7. 
Rationale for Selection of Tislelizumab Dose  
The PK, safety, and efficacy data obtained from the first in human study BGB-A317_Study_001, 
as well as other clinical study data, were analyzed in aggregate to determine the recommended 
dose for pivotal studies of tislelizumab. The flat dose of tislelizumab 200 mg intravenously once 
every 21 days was selected for further evaluation. 
Rates of treatment-related AEs and serious AEs (SAEs) observed in patients receiving 2 mg/kg 
and 5 mg/kg once every 2 weeks and once every 21 days were comparable, suggesting no clear 
dose-dependence across these regimens. Similarly, confirmed ORRs in patients treated with 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared 
to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once every 21 days. 
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 PR, 
4 patients (31%) had a BOR of stable disease, 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 every 21 days. 
In conclusion, tislelizumab 200 mg once every 21 days is the recommended dose for pivotal 
studies. 
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1.5.8. 
Rationale for Phase 2 Tumor Type Selection  
1.5.8.1. 
Head and Neck Squamous Cell Carcinoma  
HNSCC, the ninth most common cancer globally, represents nearly 700,000 new cases and 
380,000 deaths worldwide (Cohen et al 2019). Traditional treatment for HNSCC is associated 
with substantial morbidity and toxicity. Recurrent and metastatic (R/M) disease is usually 
incurable.  
However, analysis of tissue samples from patients with HNSCC shows a highly immunogenic 
tumor microenvironment (Mandal et al 2016). Indeed, it has been shown that over 40 to 80% of 
patients with R/M disease have a combined positive score (CPS) for PD-L1 expression ≥ 1 to 20. 
An analysis of 280 different tumors also showed that HNSCC are among the most highly 
immune-infiltrated cancer types among other phenotypes indicative of an inflamed tumor. In 
2016, the United States Food and Drug Administration (FDA) approved two immunotherapeutic 
agents, the anti-PD-1 monoclonal antibodies, nivolumab (Opdivo®, Bristol-Myers Squibb 
Company) and pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp.), for the treatment of 
patients with R/M HNSCC refractory to platinum-based therapy. Subsequently in 2019, the FDA 
approved pembrolizumab for the first-line treatment of patients with unresectable R/M HNSCC. 
For frontline therapy, pembrolizumab was approved for use in combination with platinum and 
fluorouracil for all patients with R/M HNSCC and as a single agent for patients whose tumors 
express PD-L1 with CPS ≥ 1 as determined by an FDA-approved test (Cohen et al 2019). As 
anti-PD-1 therapy becomes the standard of care for first and second-line patients with 
unresectable R/M disease, patients who develop resistance to anti PD-1 therapy have limited 
therapeutic options thereby creating a significant unmet need to address anti-PD-1 resistance.  
Accumulating data strongly supports TIM-3’s role in the immunosuppression of TILs in 
HNSCC. Analysis of patient biopsy samples showed TIM-3’s expression was significantly 
increased relative to paired non-tumor, non-diseased tissue as well as nonpaired dysplastic tissue 
(Liu et al 2017; Liu Z et al 2018; Liu JF et al 2018; Partlova et al 2015). Expression of TIM-3 
was correlated with recurrence and lymph node metastases (Liu et al 2017; Liu Z et al 2018; 
Partlova et al 2015). TILs isolated from patient biopsy samples also showed the co-expression of 
TIM-3 and PD-1 CD8 TILs resulted in the greatest reduction in proinflammatory cytokines, 
compared with TIM-3+/PD-1- or TIM-3-/PD-1+ CD8 TILs, as well as in the proliferation of 
TILs (Shayan et al 2016). Nonclinical studies showed from two different groups showed anti-
PD-1 treatment significantly increased TIM-3 expression on CD4+ and CD8+ T effector cells 
from both patient samples and murine models (in vitro, ex vivo, and in vivo) of HNSCC. 
Induction of TIM-3 expression was further associated with resistance to anti-PD-1 therapy such 
that combined blockade of TIM-3 and PD-1 pathways significantly increased in vivo tumor 
growth inhibition in mouse models of HNSCC. 
LAG-3 also plays an important role in the immunosuppression of TILs in HNSCC. Analysis 
from TCGA database showed LAG-3 expression ranked high in HNSCC, compared with all the 
indications. Expression frequency of LAG-3 was also high in HNSCC (Chen et al 2020). 
Meanwhile, expression of LAG-3 was correlated with clinical state, including pathological 
grades and larger tumor size (Deng et al 2016). Importantly, a 3-year observational study 
followed with HNSCC patients who treated with anti-PD-L1 therapy, showed that both 
TIM-3+/PD-1+ and LAG-3+/PD-1+ co-expressed CD8+T cells was increased among 
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nonresponders, compared with anti-PD-L1 responders (12.4% vs. 4.4%, P= 0.03; 23.1% vs. 
1.2%, P = 0.02, respectively); whereas the expression of CTLA4 was not significantly changed, 
which could be a driven mechanism of anti-PD-L1 resistance (Hanna et al 2018). 
Taken as a whole, there is significant scientific rationale that blockade of the TIM-3 and/or 
LAG-3 pathway in patients with HNSCC may overcome resistance to anti-PD-1 therapy. The 
Cohorts 1, 4, 6 of Phase 2 dose expansion will evaluate the preliminary antitumor activity of 
BGB-A425 + tislelizumab, BGB-A425 + LBL-007 + tislelizumab, and LBL-007 + tislelizumab 
in patients with R/M HNSCC who developed resistance to prior anti-PD-1/PD-L1 therapy, 
respectively. 
1.5.8.2. 
Non-Small Cell Lung Cancer  
Lung cancer is the most common type of cancer occurring in both men and women in the past 
decade and is the leading cause of cancer deaths worldwide. With 2.1 million new lung cancer 
cases and 1.8 million deaths predicted in 2018, lung cancer represents close to 1 in 5 (18.4%) 
cancer deaths. NSCLC accounts for 80% to 85% of all lung cancers (American Cancer Society 
2020).  
The success of immune checkpoint therapy in recent years has revolutionized traditional cancer 
treatment. The biggest breakthrough of NSCLC treatment with immunotherapy has been 
demonstrating clinical practice change of durable efficacy from a late-line to a first-line setting. 
The FDA has approved 4 different monoclonal antibodies targeting the PD-1/PD-L1 pathway in 
NSCLC, covering stage III chemoradiation treatment to late-line in metastatic setting: 
pembrolizumab (PD-1 inhibitor) (KEYTRUDA® prescribing information), nivolumab (PD-1 
inhibitor) (OPDIVO® prescribing information), atezolizumab (PD-L1 inhibitor) 
(TECENTRIQ® prescribing information), durvalumab (PD-L1 inhibitor) (IMFINZI™ 
prescribing information). Mounting evidence suggests that PD-L1 expression is useful 
biomarkers in NSCLC and widely used in clinical practice. The expression of PD-L1 in the 
tumor tissue is the most widely used biomarker and considered a companion diagnostic for the 
immunotherapy monotherapy for the first-line treatment of NSCLC after the results of 
KEYNOTE-024 (Garon et al 2015; Garon et al 2019). The KEYNOTE-024 study demonstrated a 
significant progression-free survival (PFS) (10.3 versus 6 months) and overall survival (OS) 
benefit with pembrolizumab alone compared with chemotherapy as the first-line treatment in 
patients with PD-L1 expression ≥ 50% (Reck et al 2016). In addition, KEYNOTE-042 study 
demonstrated a survival benefit with pembrolizumab in the first-line setting in patients with 
PD-L1 expression > 1% tumors (Mok et al 2019). Similar efficacy trend in correlation with 
PD-L1 status has also been observed in other PD-L1 clinical studies (Borghaei et al 2015; 
Gandhi et al 2018; Ancevski et al 2018).  
Despite this stream of new life-extending treatments involving anti-PD-1/PD-L1 therapy, 
advanced or metastatic NSCLC remains an incurable disease for most patients. The interactions 
between the human immune system and tumor cells are continuous, dynamic, and evolving. 
Acquired resistance is described as the lack of response to immunotherapy after the patient 
initially responds to anti-PD-L1 treatment then relapses or progresses (Sharma et al 2017). The 
frequencies of primary resistance in advanced NSCLC patients whose best responses were 
progressive disease in first-line immune checkpoint inhibitors with or without chemotherapy 
varied from 7% to 27%; whilst in a pretreated setting with immune checkpoint monotherapy, the 
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reported rates ranged from 20% to 44% (Walsh and Soo 2020). For patients who experienced 
complete response, partial response, or stable disease from immunotherapy but tumor eventually 
relapsed or progressed, more effective treatment options with combating resistance and 
expanding the duration of response are needed.  
Accumulating data also support TIM-3’s role in the immunosuppression environment in NSCLC. 
Flow cytometry data of patient-derived TILs obtained at baseline showed that both squamous 
and adenocarcinoma patients had higher TIM-3 positive CD4+ and CD8+ T-cell percentage than 
the normal healthy people (Koyama et al 2016). By comparing the immune cells isolated from 
PD-1 native control effusions, PD-1 resistant effusions and primary tumor, it showed that the 
PD-1 resistant patients had higher TIM-3 positive CD4+ and CD8+ T-cell percentage than PD-1-
naive patients. The RNA-seq data from 2 NSCLC mouse models also suggested upregulation of 
TIM-3 (HAVCR2) in PD-1 resistant mice than the untreated group (Lizotte et al 2016). 
In addition, preliminary clinical efficacy signals were observed in anti-TIM-3 treatment, though 
the sample size was very limited. TSR-022 in combination with TSR-042, both developed by 
Tesaro, demonstrated 4 confirmed PRs observed across TSR-022 100 mg and 300 mg cohorts 
(n = 31; 13%) (Davar et al 2018) in patients with non-small cell lung cancer whose disease had 
progressed on prior anti-PD-1 treatment. 
Similar as in HNSCC, LAG-3 also plays an important role in the immunosuppression of TILs in 
NSCLC. Analysis from TCGA database showed LAG-3 expression also ranked high in NSCLC, 
compared with all the indications. Multiplex quantitative immunofluorescence data from 730 
clinically annotated NSCLC tissue analysis showed LAG-3 and TIM-3 were detected in TILs 
from 41.5% and 25.3% of NSCLC cases, respectively (Datar et al 2019, indicated high LAG-3 
and TIM-3 expression frequency in NSCLC. Besides, elevated LAG-3 ligands (FGL1 or 
Galectin3) are found associated with worse response to anti-PD-L1 therapy (Wang et al 2019).  
Taken together, the increasingly huge unmet medical needs, the pre-clinical research evidence, 
and the preliminary efficacy signals in TIM-3 clinical studies support the rationale to explore the 
hypothesis that anti-TIM-3 and/or anti-LAG-3 in combination with anti-PD-1 treatment has the 
potential to overcome the resistance from prior checkpoint inhibitor treatment. The Cohort 2, 5, 7 
of Phase 2 dose expansion will evaluate the preliminary antitumor activity of BGB-A425 + 
tislelizumab, BGB-A425 + LBL-007 + tislelizumab, and LBL-007 + tislelizumab in patients 
with NSCLC who have been previously treated with checkpoint inhibitors, respectively.  
1.5.8.3. 
Renal Cell Carcinoma  
RCC represents 2% to 3% of all cancers, corresponding to 338,000 new cases diagnosed each 
year worldwide. Around 30% of patients will present metastatic disease at the time of diagnosis 
and metastases are found in 30% to 40% of those initially treated in curative intent. Clear cell 
RCC account for about 75% of RCC (Ferlay et al 2015). The management and treatment of 
metastatic RCC have undergone major improvements over the last 20 years. The development of 
targeted therapies, including vascular endothelial growth factor pathway inhibitors, mammalian 
target of rapamycin inhibitors; and, more recently, the emergence of checkpoint inhibitors, 
including PD-1 inhibitors, PD-L1 inhibitors, and anti-CTLA-4 antibodies have led to a wide 
treatment landscape remodeling (Kammerer-Jacquet et al 2019). FDA-approved immunotherapy 
include nivolumab, either alone or in combination with ipilimumab, as well as pembrolizumab 
and avelumab, both in combination with axitinib. These therapies produce response rates of 40% 
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to 60%, and median OS now approaches 4 years in patients with intermediate or poor risk treated 
with ipilimumab and nivolumab (Tannir et al 2020; Rini et al 2019; Motzer et al 2019).  
Nonetheless, most patients with RCC receiving checkpoint inhibitors ultimately experience 
disease progression and require subsequent therapies. Current guideline recommendations 
regarding sequential therapy were based on data from the VEGFR-TKI era (Level of Evidence 
IV) (Albiges et al 2019; Auvray et al 2019; Escudier et al 2019). As checkpoint inhibition 
therapy becomes the standard of care in frontline setting, patients with RCC who develop 
resistance have no widely established treatment options thereby creating a significant unmet need 
to address checkpoint inhibition resistance. 
Nonclinical research has discovered some evidence of TIM-3 role in the RCC disease 
pathological features. Immunofluorescence in tissue chips showed RCC tumors had significant 
higher TIM-3 fluorescence score in tumor infiltrating CD8-positive T-cells than the normal 
tissues. Looking at the clinical data, PFS is also different between the patients expressing PD-1 
and TIM-3 above and below the median. Those above the median level of PD-1 and TIM-3 co-
expression were more likely to relapse after locoregional treatment. In comparison, there was no 
such differentiation in the TIM-3 negative population. In addition, an in vitro cytokine release 
assay was conducted using CD8+ T-cells isolated from 2 RCC patients’ tumors and then 
stimulated with CD3 and CD28. The results showed IFN-γ production significantly decreased in 
CD8+ T-cells co-expressing PD-1 and TIM-3 compared with the other 2 populations, which 
suggested impaired functions by PD-1 and TIM-3 co-expression (Hu et al 2020; Granier et al 
2017).  
In short, these research findings and the unmet medical needs in checkpoint inhibition resistant 
RCC supports the rationale to explore the hypothesis that anti-TIM-3 in combination with anti-
PD-1 treatment has the potential to overcome the resistance mechanism. Cohort 3 of Phase 2 will 
evaluate the preliminary antitumor activity of BGB-A425 in combination with tislelizumab as 
the second-line or third-line treatment in RCC patients who have been pre-exposed to prior 
checkpoint inhibition and have demonstrated disease progression.  
1.6. 
Benefit-Risk Assessment  
There is limited human experience with BGB-A425 and LBL-007; therefore, their clinical 
benefit in patients with advanced solid tumors has not been determined. However, as discussed 
above, there is extensive evidence supporting the role of immune checkpoint protein TIM-3 and 
LAG-3 in promoting tumor immune escape, the combination of anti-TIM-3 or anti-LAG-3 with 
anti-PD-1 could further improve the antitumor response (Section 1.2, Section 1.3, Section 1.5.2, 
Section 1.5.3).  
Combined with the clinical efficacy that has been demonstrated for PD-1 blockade via 
tislelizumab (Section 1.4), the data strongly suggest that BGB-A425 has the potential to 
significantly improve and/or extend the therapeutic benefits of tislelizumab. Similarly, clinical 
studies of LBL-007 or similar drugs in combination with anti-PD-1 monoclonal antibody show 
that anti-LAG-3 antibody has synergistic effects with anti-PD-1 antibody, and can greatly 
improve antitumor activity. The clinical study results of LBL-007 or same class drug in 
combination with anti-PD-1 monoclonal antibody showed favorable benefit risk profile. 
Therefore, the development of LBL-007 in combination with tislelizumab is expected to have a 
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potential favorable benefit risk ratio in patients with advanced solid tumors. As discussed 
in Section 1.4.4, PD-1 blockade by tislelizumab has been evaluated in more than 3498 patients 
with a safety and efficacy profile similar to what has been reported for other anti-PD-1 therapies. 
As discussed earlier in Section 1.2 to 1.5, based upon the mechanism(s) of action, nonclinical as 
well as clinical data, the combined blockade of TIM-3 and PD-1 by BGB-A425 and tislelizumab, 
respectively, or combined blockade of LAG-3 and PD-1 by LBL-007 and tislelizumab, 
respectively, or combined blockade of TIM-3, LAG-3 and PD-1 by BGB-A425, LBL-007 and 
tislelizumab, respectively, are expected to result in the observation of a increase in immune-
mediated toxicities compared with what has been observed with tislelizumab alone.  
Although  a increased safety risk has been shown for other anti-PD-1 based immuno-oncology 
combinations, a comprehensive algorithm derived from the European Society for Medical 
Oncology and American Society for Clinical Oncology, has been established to monitor, 
diagnose as well as manage such immune-mediated toxicities (Appendix 8). It is important to 
note that peripheral effector T-cells typically do not express TIM-3, which is in contrast to TILs 
stimulated by the antigenic tumor microenvironment. Therefore, this mechanism provides the 
combination an opportunity to specifically augment the activity of effector T-cells at the level of 
the tumor rather than periphery and/or nontumor tissue (Anderson 2014; Das et al 2017; Du et al 
2017).  
As shown in Appendix 1, a comprehensive monitoring plan will be utilized to monitor patient 
safety. The subsequent safety data will be continuously analyzed by the sponsor’s study team 
and in consultation with investigator(s) as needed. Refer to Section 1.5.1 and Section 8 for 
information regarding additional safeguards and considerations related to potential risk. 
In summary, there is strong scientific rationale that the combined blockade of the TIM-3 and 
PD-1 pathway, or combined blockade of LAG-3 and PD-1 pathway or combined blockade of 
TIM-3 and LAG-3 and PD-1 pathway may significantly enhance the antitumor properties of anti-
PD-1 monotherapy. Therefore, the potential risks associated with proposed combinations are 
justified by the potential treatment benefits to patients with advanced solid tumors. 
1.7. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice standards and the applicable regional regulatory requirements (eg, Regulation 
[EU] No. 536/2014). 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives for Phase 1 (Dose Escalation)  
2.1.1. 
Primary Objectives  
• To assess the safety and tolerability of BGB-A425 in combination with tislelizumab in 
patients with advanced solid tumors  
• To determine the maximum tolerated dose (MTD) or maximum administered dose 
(MAD) and recommended Phase 2 dose (RP2D) of BGB-A425 in combination with 
tislelizumab 
2.1.2. 
Secondary Objectives  
• To assess the preliminary antitumor activity of BGB-A425 in combination with 
tislelizumab 
• To characterize the pharmacokinetics (PK) of BGB-A425 in combination with 
tislelizumab 
• To assess host immunogenicity to BGB-A425 in combination with tislelizumab 
2.1.3. 
Exploratory Objectives  
• To explore drug exposure and response (safety and efficacy) correlations 
• To assess predictive, prognostic, and pharmacodynamic biomarkers including any 
association with response to study treatment and mechanism(s) of resistance 
2.2. 
Study Objectives for Phase 2 (Safety Lead-in)  
2.2.1. 
Primary Objective  
• To assess the safety and tolerability of BGB-A425 in combination with LBL-007 and 
tislelizumab or LBL-007 in combination with tislelizumab in patients with advanced 
solid tumors  
• To determine the MTD or MAD and RP2D/ recommended dose for expansion of 
LBL-007 in combination with BGB-A425 and tislelizumab, and LBL-007 in combination 
with tislelizumab  
2.2.2. 
Secondary Objectives  
• To assess the preliminary antitumor activity of BGB-A425 in combination with LBL-007 
and tislelizumab or the combination of LBL-007 with tislelizumab in patients with 
advanced solid tumors  
• To characterize the PK of BGB-A425, LBL-007, and tislelizumab in the combination 
treatments  
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• To assess host immunogenicity to BGB-A425, LBL-007, and tislelizumab in the 
combination treatments 
2.2.3. 
Exploratory Objectives  
• To explore drug exposure and response (safety and efficacy) correlations 
• To assess predictive, prognostic, and pharmacodynamic biomarkers including any 
association with response to study treatment and mechanism(s) of resistance 
2.3. 
Study Objectives for Phase 2 (Dose Expansion)  
2.3.1. 
Primary Objective  
• To evaluate antitumor activity based on objective response rate (ORR) of various 
combinations of BGB-A425 and LBL-007 with tislelizumab in selected tumor types  
2.3.2. 
Secondary Objectives  
• To evaluate antitumor activity using other secondary efficacy endpoints of the 
combination treatments of BGB-A425 and LBL-007 with tislelizumab  
• To further characterize the safety and tolerability of various combinations of BGB-A425 
and LBL-007 with tislelizumab   
• To further characterize the PK of BGB-A425 and LBL-007 in combination with 
tislelizumab  
• To further assess host immunogenicity to BGB-A425 and LBL-007 in combination with 
tislelizumab  
2.3.3. 
Exploratory Objectives  
• To assess overall survival (OS) 
• To explore drug exposure and responses (safety and efficacy) correlations 
• To assess predictive, prognostic, and pharmacodynamic biomarkers including any 
association with response to study treatment and mechanism(s) of resistance 
2.4. 
Study Endpoints for Phase 1 (Dose Escalation) and Phase 2 (Safety 
Lead-in)  
2.4.1. 
Primary Endpoints  
• Adverse events (AEs) and serious AE (SAEs) as characterized by type, frequency, 
severity (as graded by National Cancer Institute-Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] Version 5.0), timing, seriousness, and relationship to 
study therapy; laboratory abnormalities as characterized by type, frequency, severity (as 
graded by NCI CTCAE v5.0), and timing; AEs meeting protocol defined dose limiting 
toxicity (DLT) criteria 
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• The MTD or MAD is defined as the highest dose at which < 33% of the patients 
experience a DLT  
• The RP2D/recommended dose for expansion of the combination treatments will be 
determined based upon the MTD or MAD, and will also take into consideration the long-
term tolerability, PK, efficacy, and any other relevant data as available 
2.4.2. 
Secondary Endpoints  
• Efficacy evaluations: ORR, duration of response (DOR), and disease control rate (DCR) 
will be determined from investigator derived tumor assessments per RECIST v1.1 (as 
described in Section 9.2.1) 
• PK: Maximum observed plasma concentration (Cmax), minimum observed plasma 
concentration (Cmin), time to maximum plasma concentration (Tmax), half-life (t1/2), area 
under the concentration-time curve from zero to 21 days (AUC0-21d), CL, and apparent 
volume of distribution (Vz) for BGB-A425 and LBL-007; Cmax and Cmin for tislelizumab 
• Immunogenicity: Immunogenic responses to BGB-A425, LBL-007, and tislelizumab will 
be assessed by summarizing the number and percentage of patients who develop 
detectable antidrug antibodies 
2.4.3. 
Exploratory Endpoints  
• Assessments of the correlations between drug exposure and response (efficacy and safety 
endpoints) 
• Evaluation of biomarkers from patient derived tumor tissue(s) and blood (or blood 
derivatives) samples obtained before, during and/or after the combination treatment. 
Candidate biomarkers may include, but are not limited to, programmed cell death 
protein-1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and 
lymphocyte activating gene-3 (LAG-3) RO and immune cell subpopulation in peripheral 
blood cells, concentrations of cytokine and soluble proteins in plasma or serum, 
circulating tumor DNA (ctDNA) analysis in peripheral blood, programmed cell death 
ligand-1 (PD-L1), TIM-3, LAG-3, and ligands expression, TILs, gene expression 
profiling and tumor mutation analysis in tumor tissue. 
2.5. 
Study Endpoints for Phase 2 (Dose Expansion)  
2.5.1. 
Primary Endpoint  
• ORR as determined from investigator derived tumor assessments per RECIST v1.1 (as 
described in Section 9.2.2) 
2.5.2. 
Secondary Endpoints  
• Progression-free survival (PFS), DOR, and DCR will be determined from investigator 
derived tumor assessments as per RECIST v1.1 (as described in Section 9.2.3) 
• Safety and tolerability: The safety of various combinations of BGB-A425 and LBL-007 
with tislelizumab will be assessed throughout the study by monitoring AEs and SAEs per 
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NCI-CTCAE v5.0, physical examinations, electrocardiograms (ECGs), and laboratory 
assessments as needed 
• PK: PK parameters such as Cmax, Cmin, Tmax, t1/2, and AUC0-21d for BGB-A425 and 
LBL-007; Cmax and Cmin for tislelizumab 
• Immunogenicity: Immunogenic responses to BGB-A425, LBL-007, and tislelizumab will 
be assessed by summarizing the number and percentage of patients who develop 
detectable antidrug antibodies (ADAs). 
2.5.3. 
Exploratory Endpoints  
• OS is defined as the date of the first dose of study drug to the date of death due to any 
cause 
• Assessments of the correlations between drug exposure and response (efficacy and safety 
endpoints) 
• Evaluation of biomarkers from patient derived tumor tissue(s) and blood (or blood 
derivatives) samples obtained before, during and/or after treatment. Candidate 
biomarkers may include, but are not limited to, LAG-3 RO in peripheral blood cells, 
concentrations of cytokine and soluble proteins in plasma or serum, ctDNA analysis in 
peripheral blood, PD-L1, TIM-3, LAG-3, and ligands expression, TILs, gene expression 
profiling and tumor mutation analysis in tumor tissue. 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, multicenter, nonrandomized Phase 1 and 2 clinical study evaluating 
various combinations of BGB-A425 and LBL-007 with tislelizumab. The study design schematic 
is presented in Figure 7. For all Phase 1 and Phase 2 study assessments and procedures, see 
Section 7 and Appendix 1. 
Priority enrollment for Phase 1 (dose escalation) and Phase 2 (safety lead-in) will be granted to 
patients with NSCLC, HNSCC, hepatocellular carcinoma, gastric or gastroesophageal 
carcinoma, nasopharyngeal carcinoma, RCC, cervical cancer, triple-negative breast cancer, and 
urothelial carcinoma. Prioritization of additional tumor types will also be considered based upon 
emerging data and after consultation with BeiGene’s medical monitor. Enrollment for Phase 2 
(dose expansion) will be granted to patients with HNSCC, NSCLC and RCC, and details are 
described as follows. 
This study consists of the following phases: 
• Phase 1 (dose escalation): Sequential cohorts of approximately 8 increasing dose levels of 
BGB-A425 will be evaluated in combination with tislelizumab 200 mg in patients with 
advanced solid tumors to determine the RP2D, safety, PK, and other key endpoints for 
BGB-A425 in combination with tislelizumab.  
• Phase 2 (safety lead-in): For the safety lead-in, there are two combination cohorts 
planned to be evaluated: 
− Cohort A: LBL-007 + Tislelizumab 
− Cohort B: BGB-A425 + LBL-007 + Tislelizumab 
For Cohort A, the dose escalation of LBL-007 starts with LBL-007 300 mg intravenously 
in combination with tislelizumab 200 mg intravenously every 21 days (Cohort A1, n = 3 
to 6); the sequential escalating dose is planned to be LBL-007 600 mg intravenously in 
combination with tislelizumab 200 mg intravenously every 21 days (Cohort A2, n = 3 
to 6).  
For Cohort B, the dose escalation of LBL-007 starts with LBL-007 300 mg intravenously 
in combination with BGB-A425 600 mg and tislelizumab 200 mg intravenously every 
21 days (Cohort B1, n = 3 to 6), which will be initiated after the evaluation in Cohort A1; 
the sequential escalating dose is planned to be LBL-007 600 mg intravenously in 
combination with BGB-A425 600 mg and tislelizumab 200 mg intravenously every 
21 days (Cohort B2, n = 3 to 6). 
After the evaluation of Cohort A1, which is initiated first, allocation of patients to the 
respective cohorts (ie, Cohort A2 and Cohort B1) will be carried out through a sequential 
order of treatment assignment. At least 6 patients will be evaluated in Cohorts A2 and B2 
in the dose escalation part of Phase 2 safety lead-in. 
During safety lead-in dose escalation, if the combination of BGB-A425 600 mg, 
LBL-007 600 mg, and tislelizumab 200 mg once every 21 days is deemed safe in 
Cohort B2, dose expansion will be evaluated in HNSCC and NSCLC cohorts following 
discussion and in agreement with the Safety Monitoring Committee (SMC). However, in 
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addition to the above mentioned dose, lower or higher dose levels of LBL-007 may be 
evaluated in the safety lead-in cohorts based on the analysis of emerging safety, 
tolerability, PK, biomarker, and other clinical data, if recommended by the SMC. If a 
dose level higher than 600 mg of LBL-007 for dose expansion cohorts is recommended 
by the SMC, a protocol amendment will be implemented. 
Enrollment will be open to all eligible patients with advanced solid tumors as described 
in Phase 1 (dose escalation).  
• Phase 2 (dose expansion): Three combination treatments will be evaluated in patients 
with various tumor types including HNSCC, NSCLC and RCC. A total of 7 cohorts will 
be conducted as listed below:  
− 
Cohort 1: HNSCC - BGB A425 + Tislelizumab  
− 
Cohort 2: NSCLC - BGB-A425 + Tislelizumab 
− 
Cohort 3: RCC - BGB-A425 + Tislelizumab 
− 
Cohort 4: HNSCC - BGB-A425 + LBL-007 + Tislelizumab 
− 
Cohort 5: NSCLC - BGB-A425 + LBL-007 + Tislelizumab  
− 
Cohort 6: HNSCC - LBL-007 + Tislelizumab  
− 
Cohort 7: NSCLC - LBL-007 + Tislelizumab 
An interim analysis will be conducted based on approximately the first 20 evaluable 
patients in each dose expansion cohort (Sections 9.1.2 and 9.7). Based upon the interim 
analysis for a given tumor type cohort, up to approximately 40 evaluable patients for each 
cohort may be enrolled in that cohort as described in Section 9.7. As of the date of 
finalization of this protocol amendment v7.0, enrollment of Cohorts 1 and 2 is ongoing.  
In Phase 2 dose expansion, the enrollment of Cohorts 4 and 5 will be initiated first, 
followed by the enrollment of Cohorts 6 and 7. The enrollment of Cohorts 6 and 7 will be 
initiated per the emerging clinical data from the ongoing evaluation in Cohorts 4 and 5. 
All patients enrolled in Phase 2 dose expansion must have disease progression that 
occurred ≥ 10 weeks from the initiation of anti-PD-1/PD-L1 treatment for locally 
advanced or metastatic disease. All eligible patients will receive the respective 
combination(s) every 21 days starting on Cycle 1 Day 1. Positive PD-L1 expression from 
either local or central testing will be required in HNSCC and NSCLC patients in all dose 
expansion cohorts prior to enrollment. For baseline tumor tissue, fresh biopsy will be 
mandatory in the absence of sufficient archival tissue prior to the patient commencing 
first drug administration on Cycle 1 Day 1 (refer to Section 7.1 for additional details). 
Patients will receive study drug until 1) they are no longer considered to receive clinical benefit, 
2) unacceptable toxicity, or 3) withdrawal of informed consent. 
Except for the Phase 1 DLT period, a 21-day treatment cycle is planned for the remainder of 
Phase 1 and all of Phase 2 including Phase 2 safety lead-in. 
For Phase 1 dose escalation, a 28-day DLT observation period will be utilized for the initial 
dose-finding recommendations. To incorporate this DLT period into one cycle, only Cycle 1 will 
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have a duration of 28 days from Day 1. During this DLT period, patients must receive 
BGB-A425 alone on Cycle 1 Day 1 followed by tislelizumab alone on Cycle 1 Day 8 (+2 days) 
to be DLT evaluable. If no DLT(s) are observed thereafter and through the completion of the 
initial 28-day cycle, patients will receive both BGB-A425 and tislelizumab sequentially on 
Day 29 and every 21 days (ie, once every 21 days) until they meet a treatment discontinuation 
criterion. The occurrence of a DLT during the DLT observation period will result in expansion of 
that dose level cohort as discussed below. Refer to Section 5.6.1 and Section 5.6.2 regarding 
continued treatment of patients who are unable to receive tislelizumab on Cycle 1 Day 8 
(+2 days). 
The first BGB-A425 dose level (2 mg) will initially be evaluated in 1 patient, whereas the second 
BGB-A425 dose level (6 mg) will be evaluated in 1 or more patients. Accordingly, escalation of 
the BGB-A425 dose level will proceed if no DLT is observed in the DLT-evaluable patient(s) 
during the DLT period. However, if a DLT occurs within the DLT observation period for the 
first or second dose level, enrollment for that dose level will be expanded per the 3+3 design 
rules described below. 
Starting with the BGB-A425 20 mg dose level, escalation of the BGB-A425 dose level will 
proceed if no DLT is observed during the DLT period in a minimum of 3 DLT-evaluable 
patients. However, if a DLT occurs within the DLT observation period for a given dose level, 
enrollment for that dose level will be expanded per the 3+3 design rules as follows: 
a) BGB-A425 (Phase 1) dose escalation will advance if the first cycle DLT rate < 33%; 
b) BGB-A425 (Phase 1) dose escalation will stop if the first cycle DLT rate is ≥ 33%. A 
minimum of 6 patients will be enrolled to the current dose level of BGB-A425 
(Phase 1), if DLT rate is 33% (eg, 1/3) or the next lower dose level if DLT rate is 
> 33% (eg, 2/3 or 3/3); 
c) The MTD or MAD dose level is defined as the highest dose level at which < 33% of 
the patients experience a DLT. 
More than 3 patients may be enrolled simultaneously during the DLT period(s) for a given dose 
level. In such cases, the dose escalation decision will be made based upon the above 3+3 rules. 
Further, for dose escalation decisions, only DLTs occurring within 28 days of Cycle 1 Day 1 for 
the corresponding dose level will be evaluated. However, as noted below and in Section 3.5, 
additional considerations may be taken into account if clinically significant toxicity(ies) is 
observed regardless of when it occurred. 
Based upon emerging clinical data, lower, intermediate and/or higher dose levels and/or 
alternative dosing intervals of BGB-A425 may also be evaluated. However, the dosing regimen 
of tislelizumab will remain fixed for each different BGB-A425 dose level evaluated. 
As of the date of finalization of this protocol amendment v7.0, the Phase 1 dose escalation phase 
has been completed. The BGB-A425 + tislelizumab combination RP2D was determined 
primarily from the Phase 1 safety, tolerability, preliminary antitumor activity, pharmacodynamic 
biomarker, and PK data. The combination RP2D will be evaluated in the Phase 2 dose 
expansion.  
For the Phase 2 safety lead-in, a dose escalation of LBL-007 will be carried out in Cohort A and 
Cohort B. In Cohort A, the dose escalation will start with Cohort A1; for Cohort B, the dose 
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escalation will be initiated after the evaluation in Cohort A1 and will start with Cohort B1. 
Specifically, the starting dose of LBL-007 300 mg will be evaluated with a fixed dose of 
tislelizumab 200 mg in 3 to 6 patients in Cohort A1; likewise, LBL-007 300 mg will be 
evaluated with BGB-A425 600 mg and tislelizumab 200 mg in 3 to 6 patients in Cohort B1. 
Moreover, based on the emerging safety, tolerability, PK, and other clinical data, higher dose 
levels of LBL-007 (eg, 900 mg every 21 days) will be evaluated in the respective combination 
cohorts, as the other LBL-007 study (LBL-007-CN-003) is being conducted in combination with 
toripalimab (anti-PD-1 antibody). 
In Safety Lead-in Phase, a 21-day DLT observation period will be utilized for all LBL-007 dose 
finding cohorts. During this DLT period, patients must receive all combination treatments on 
Cycle 1 Day 1 to be DLT evaluable. Dose escalation to next dose level of LBL-007 will proceed 
if no DLT is observed in DLT-evaluable patients. However, if a DLT occurs within the DLT 
observation period for a given dose level, enrollment for that dose level and dose finding 
decisions will proceed as per the 3+3 design rules described below. All dose escalation(s) will 
continue based upon the emerging clinical data as determined by the sponsor and the SMC. 
Starting with the LBL-007 300 mg dose level, escalation of the LBL-007 dose level will proceed 
if no DLT is observed during the DLT period in a minimum of 3 DLT-evaluable patients. 
However, if a DLT occurs within the DLT observation period for a given dose level, enrollment 
for that dose level will be expanded per the 3+3 design rules as follows: 
a) LBL-007 (Phase 2 Safety lead-in) dose escalation will advance if the first cycle DLT 
rate < 33%; 
b) LBL-007 (Phase 2 Safety lead-in) dose escalation will stop if the first cycle DLT rate 
is ≥ 33%. A minimum of 6 patients will be enrolled to the current dose level of 
LBL-007, if DLT rate is 33% (eg, 1/3) or the next lower dose level if DLT rate is 
> 33% (eg, 2/3 or 3/3); 
c) The MTD or MAD dose level is defined as the highest dose level at which < 33% of 
the patients experience a DLT. 
In Phase 2 dose expansion (Cohorts 1, 2, and 3 only), the BGB-A425 and tislelizumab RP2D 
will be administered sequentially starting on Cycle 1 Day 1 and every 21 days (ie, once every 
21 days) thereafter until the patient meets a discontinuation criterion.  
The recommended dose(s) for the 2 combinations (BGB-A425 + LBL-007 + tislelizumab and 
LBL-007 + tislelizumab) in Phase 2 dose expansion (Cohorts 4 to 7) will be determined based on 
safety, tolerability, PK data , pharmacodynamic biomarker, and preliminary antitumor activity  
from the Phase 2 safety lead-in. 
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Figure 7: 
Study Schema 
Abbreviations: A317, tislelizumab (BGB-A317); A425, BGB-A425; C, Cycle; D, Day; HNSCC, head and neck squamous cell cancer; IA, interim analysis; 
NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; RP2D, recommended Phase 2 dose; TBD, to be determined  
Notes: For Phase 2 safety lead-in, the dose for BGB-A425 and tislelizumab are 600 mg and 200 mg, respectively; Cohort A1 will be initiated first (as in 
Section 3.1). For Phase 2 dose expansion, Cohort 3 will be initiated per the results in Cohort 1 and Cohort 2; the enrollment of Cohorts 6 and 7 will be initiated 
per the emerging clinical data from the ongoing evaluation in Cohorts 4 and 5. 
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3.2. 
Study Periods  
This study consists of the following periods. See Section 7 and Appendix 1 for study procedures 
to be conducted in each period. 
3.2.1. 
Prescreening Period (Phase 2 Dose Expansion Only)  
The purpose of the prescreening period in Phase 2 dose expansion is to allow time for 
confirmation of the PD-L1 test for HNSCC and NSCLC patients only. HNSCC and NSCLC 
patients with positive PD-L1 expression are eligible for enrollment.  
The prescreening period has a maximum duration of 56 days prior to the first administration of 
study drug(s) and starts with the signing of the Prescreening ICF. Extension of the 56-day period 
may be granted on a case-by-case basis after discussion and written approval from the sponsor’s 
medical monitor approval in discussion with the investigator. 
Refer to Section 7.1 for additional details. 
3.2.2. 
Screening Period  
Unless otherwise specified, patients who agree to participate in this study will sign the ICF prior 
to undergoing any screening procedure.  
The screening period has a maximum duration of 28 days prior to the first administration of 
study drug(s) and starts with the signing of the Screening ICF.  
If a patient does not meet eligibility criteria for the study, they can be rescreened once with the 
sponsor’s medical monitor approval, in discussion with the investigator. Patients who are 
planned to be rescreened (following sponsor approval) are required to be reconsented if 
assessments cannot be completed within the original 28-day screening period.   
Refer to Section 7.2 for additional details. 
3.2.3. 
Treatment Period  
After completing all screening activities, patients confirmed to be eligible by the investigator will 
be treated with combination treatments as described in Section 3.1, Section 5.3, or Appendix 1. 
All patients will receive study drug until 1) they are no longer considered to receive clinical 
benefit, 2) unacceptable toxicity, or 3) withdrawal of informed consent. Refer to Section 3.3.1 
for more details.  
The End of Treatment (EOT) Visit is conducted within 7 days from the date 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 EOT Visit, these tests need not be 
repeated. Tumor assessment is not required at the EOT Visit provided that fewer than 6 weeks 
have passed since the last assessment. 
3.2.4. 
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 (see Appendix 1 for assessments), which is to occur within 30 days 
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(± 7 days) after last dose of the study drug(s) or before initiation of a new anticancer treatment, 
whichever occurs first. The EOT Visit may also be used as the Safety Follow-up Visit, provided 
that it occurred 30 days (± 7 days) after the last study treatment.  If the EOT Visit and Safety 
Follow-up Visit are combined, all individual study assessments (for both visits per Appendix 1 ) 
will need to be completed. 
In addition, telephone contact and/or clinic visits with patients will be conducted to assess 
imAEs (serious and nonserious), anticancer therapy, and concomitant medications/procedures 
where appropriate (ie, associated with an imAE etc) 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. 
If a patient reports a suspected imAE at a telephone follow-up contact, the investigator should 
arrange an unscheduled visit if further assessment is indicated. In Phase 2, an additional 
pregnancy test must be performed for women of childbearing potential at approximately 
120 days after the last dose of study treatment. 
All AEs, including SAEs, will be collected as described in Section 8.7. 
3.2.5. 
Efficacy Follow-up Period  
Patients who discontinue study treatment for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments following the original plan (Section 7.6 or 
Appendix 1) until the patient meets one of the discontinuation criteria (Section 3.3.2). 
3.2.6. 
Survival Follow Up Period (Phase 2 Dose Expansion Only)  
In Phase 2 dose expansion, patients will be followed for survival and further anticancer therapy 
information after discontinuation of study treatment. This will occur via telephone calls, patient 
medical records, and/or clinic visits approximately every 3 months (± 14 days) after the 90 days 
Safety Follow-up phone call (at the expected date) or as directed by the sponsor until death, 
withdrawal of consent, loss to follow-up, or end of study. 
3.3. 
Discontinuation from the Study Treatment or from the Study  
3.3.1. 
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 one of the study drugs will be required to discontinue other study drugs. Rare 
exceptions may be made after approval from the medical monitor. Patients who discontinue 
study treatment must undergo follow-up as described in Section 7.5 and Section 7.6), where 
possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons which include, but are not limited to, the following: 
• Progressive disease (PD) 
Note: Patients who experience PD should be assessed to exclude pseudo-progression by 
additional tumor imaging at 4 weeks or later, but no less than 12 weeks, after the initial 
date of disease progression (as per Section 7.6). If the patient has confirmed PD on the 
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follow-up scan and the investigator believes that the patient could continue to benefit 
from the assigned study drug treatment after PD, the patient may continue their assigned 
treatment after patient re-consent using the Treatment Through Progression ICF, only 
after discussion and agreement by both investigator and sponsor’s medical monitor.  
• Adverse events 
• Patient withdrawal of consent for study treatment 
• 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 herbal medicine and 
Chinese patent medicines] for the treatment of cancer) 
• Patient noncompliance 
If patients have confirmed compete response (CR), partial response (PR), or stable disease after 
24 months, the study treatment can be paused for a period of time (at patient request) after the 
investigator’s agreement and sponsor’s written approval. The decision to pause treatment should 
be based on the investigator’s evaluation, with the patient’s clinical benefit and risk taken into 
consideration. The investigator should notify and seek written agreement from the sponsor’s 
medical monitor that treatment will be paused prior to the event. In such a case, the study 
assessments and procedures will be performed every 12 weeks (in conjunction with repeated 
radiographic imaging) as per section 7.6.  
Following a period of paused treatment, the recommencement of combination therapies will be 
determined by the investigator and sponsor following the clinical risk/benefit assessment, and 
will be contingent on the continued availability of study drug(s). 
3.3.2. 
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 for the study 
• Death 
• Lost to follow-up (at minimum, 3 contact attempts must be made and documented in 
the source documents) 
• Patients have completed all study assessments 
Once the patients decide to discontinue from the study, they will be provided with Patient’s 
Discontinuation From Study Participation ICF to sign.  If a patient is unable to sign the Patient’s 
Discontinuation From Study Participation ICF for any reason, the investigator should document 
the patient’s decision to discontinue from the study and, if possible, the reason for discontinuation 
in the patient history. The reason for discontinuation should also be entered into the relevant 
section of the eCRF.  
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3.4. 
End of Study  
The end of study is defined as whichever timepoint comes first: the last study patient dies, is lost 
to follow-up, or withdraws from study; or the sponsor decides to terminate or complete the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit and Safety Follow-up Visit. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
The sponsor also 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 
• Noncompliance with Good Clinical Practice 
• Study activity is completed (ie, all patients have completed, and all obligations have been 
fulfilled) 
Currently, the sponsor does not have any plans to provide any study drug or other treatments or 
interventions to the patients after the completion of the study or after patients withdraw informed 
consent for this study. The patients are suggested to return to their primary physician to 
determine the following standard of care. If the study is successfully completed, any patients 
who have completed the study and, in the opinion of the investigator, continue to benefit from 
study drugs at study termination may be offered the option to continue the study treatment in a 
company-sponsored clinical trial, subject to local regulatory requirements and availability of 
study drug. 
3.5. 
DLT Definition  
All toxicities or AEs will be graded according to the NCI-CTCAE v5.0. The occurrence of any 
of the following toxicities will be considered a DLT: 1) during the Phase 1 dose escalation if it 
occurs within 28 days of receiving BGB-A425 on Cycle 1 Day 1 and is deemed to be related to 
study drug; 2) during the Phase 2 safety lead-in if it occurs within 21 days of receiving LBL-007 
combination treatments on Cycle 1 Day 1 and is deemed to be related to study drug. 
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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 38.3°C or a sustained temperature of 38°C 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) 
Nonhematologic: 
1. ≥ Grade 4 toxicity 
2. Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 3 days of initiating optimal supportive care 
Note: The following AEs will not be considered as DLTs: 
1. Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
2. Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors)  
3. Grade 3 rash 
4. Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset). 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), 
will be reviewed by the sponsor’s medical monitor and study team members from 
Pharmacovigilance/Drug Safety, Clinical Pharmacology and Biostatistics with input from other 
members as appropriate. On the basis of a review of these data and in consultation with the 
investigators, a determination will be made regarding dose finding decisions and/or safety 
management. As such, clinically important or persistent toxicities that are not included above 
may also be considered a DLT following review by the sponsor in consultation with investigators 
or following review by the SMC (see Section 10.1). Additionally, any clinically significant 
toxicities that occur after the DLT observation period (eg, late immune-mediated AE) for a given 
dose level, may be taken into account regarding subsequent dose escalation and/or RP2D 
decisions. In such cases where patients have been safely dosed at the next dose level, additional 
dose escalation criteria (eg, increase minimum number of patients, expand the DLT observation 
period, etc.) for subsequent dose levels will be considered by the sponsor in consultation with 
participating investigators. 
Patients must meet one of the following during the DLT observation period to be considered 
DLT evaluable:  
1) For Phase 1 dose escalation: received ≥ 80% of the assigned doses of BGB-A425 on Cycle 1 
Day 1 and tislelizumab on Cycle 1 Day 8 (+2 days) and remained on study for 28 days following 
Cycle 1 Day 1 administration of BGB-A425; or  
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2) For Phase 2 safety lead-in: received ≥ 80% of the assigned doses of LBL-007 with the 
respective combination treatments (Cohort A and Cohort B) on Cycle 1 Day 1 and remained on 
study for 21 days following Cycle 1 Day 1 administration of combinations; or  
3) Experienced a DLT.  
Patients who fail to meet one of the above criteria may be replaced. 
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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 must meet all of the following inclusion criteria to be considered eligible for 
participation in this study: 
1. Able to provide written informed consent by the patient and can understand and comply 
with the requirements of the study and the Schedule of Assessments 
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the 
jurisdiction in which the study is taking place) 
3. Phase 1 and Phase 2 safety lead-in: Patients with histologically or cytologically 
confirmed advanced, metastatic, unresectable solid tumors who have previously received 
standard systemic therapy as per respective local guidelines, unless standard systemic 
therapy is not available, not tolerated, or determined not appropriate based on 
investigator’s judgement 
4. Patient has not received prior therapy targeting TIM-3 and/or LAG-3 
5. Phase 2 dose expansion: Patients with one of the following histologically or 
cytologically confirmed solid tumors: 
For HNSCC patients in Cohort 1, 4 and 6: 
• Recurrent/metastatic head and neck squamous cell cancer of the oral cavity, oropharynx, 
hypopharynx, and/or larynx whose tumor is not amenable to local therapy with curative 
intent (ie, surgery or radiation therapy with or without chemotherapy) 
• Have received up to 3 lines* of prior systemic therapy that includes anti-PD-1/PD-L1 
antibody and available standard of care (such as anti-PD-1 and cetuximab) as per 
respective local guidelines, unless standard systemic therapy is not available, not 
tolerated, or determined not appropriate based on investigator’s judgement 
• Anti-PD-1/PD-L1 antibody treatment for local disease will count as a line of therapy if 
disease progression occurred ≤ 6 months between the completion of treatment and date of 
recurrence 
• Disease progression occurred ≥ 10 weeks from the initiation of anti-PD-1/PD-L1 
treatment for locally advanced or metastatic disease  
• PD-L1 expression positivity defined as PD-L1 CPS ≥ 1 by PD-L1 IHC 22C3 pharmDx 
assay (preferred) or PD-L1 (CPS ≥ 1, vCPS or TAP ≥ 1%) by VENTANA PD-L1 
(SP263) in local testing, or 22C3 pharmDx assay in central testing on recently obtained 
archival tissue or fresh tumor biopsy. Refer to Section 7.1 for additional details 
Note: PD-L1 positivity determined by PD-L1 IHC 22C3 pharmDx assay will be used for 
HNSCC patients in the EU. 
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• No prior treatment with an anti-TIM-3, anti-LAG-3 or any therapies targeting T-cell 
costimulation or checkpoint pathway other than the above noted prior anti-PD-1/PD-L1 
treatment. Prior anti-CTLA-4 treatment is allowed 
• Patients’ tumor status for human papillomavirus must be known. Documentation of p16 
is sufficient to determine human papillomavirus status for tumor originating from the 
oropharynx 
For NSCLC patients in Cohort 2, 5 and 7:  
• Stage IIIB, IIIC, or Stage IV squamous or non-squamous non-small cell lung cancer  
• Have received up to 3 lines* of prior systemic therapy that includes anti-PD-1/PD-L1 
antibody and available standard of care (such as combination of anti-PD-1 and 
chemotherapy, received either as combination therapy or 2 separate lines) as per 
respective local guidelines, unless standard systemic therapy is not available, not 
tolerated, or determined not appropriate based on investigator’s judgement 
• Anti-PD-1/PD-L1 antibody treatment for local disease will count as a line of therapy if 
disease progression occurred ≤ 6 months between the completion of treatment and date of 
recurrence 
• Disease progression occurred ≥ 10 weeks from the initiation of anti-PD-1/PD-L1 
treatment for locally advanced or metastatic disease  
• PD-L1 expression positivity defined as PD-L1 TPS or TC ≥ 1% by PD-L1 IHC 22C3 or 
28-8 pharmDx or VENTANA PD-L1 (SP263) assay in local testing, or 22C3 pharmDx 
assay in central testing on recently obtained archival tissue or fresh tumor biopsy. Refer 
to Section 7.1 for additional details 
Note: If PD-L1 IHC 28-8 assay is to be used for determining PD-L1 positivity, it will be 
used for nonsquamous NSCLC patients only in the EU. 
• No prior treatment with an anti-TIM-3, anti-LAG-3, or any therapies targeting T-cell 
costimulation or checkpoint pathway other than the above noted prior anti-PD-1/PD-L1 
treatment). Prior anti-CTLA-4 treatment is allowed 
For RCC patients in Cohort 3:  
• Locally advanced unresectable or metastatic and histologically confirmed renal cell 
carcinoma with a clear cell histology 
• Have received up to 3 lines* of prior systemic therapy that includes anti-PD-1/PD-L1 
antibody and available standard of care (such as a second line of treatment based on 
tyrosine kinase inhibitor) as per respective local guidelines, unless standard systemic 
therapy is not available, not tolerated, or determined not appropriate based on 
investigator’s judgement 
• Anti-PD-1/PD-L1 antibody treatment for local disease will count as a line of therapy if 
disease progression occurred ≤ 6 months between the completion of treatment and date of 
recurrence  
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• Disease progression occurred ≥ 10 weeks from the initiation of anti-PD-1/PD-L1 
treatment for locally advanced or metastatic disease 
• No prior treatment with an anti-TIM-3 or any therapies targeting T-cell costimulation or 
checkpoint pathway other than the above noted prior anti-PD-1/PD-L1 treatment. Prior 
anti-CTLA-4 treatment is allowed  
• Able to provide recently obtained archival tumor tissue or fresh tumor biopsy 
*Note: A line of treatment includes the following 
a. At least 1 complete cycle of a single agent, a regimen consisting of a combination of 
several drugs, or a planned sequential therapy of various regimens 
b. Adjuvant and neo-adjuvant systemic therapy will count as a prior line of systemic 
therapy if the disease progressed on or within 6 months between the last dose and the 
date of recurrence 
c. In locally advanced and unresectable HNSCC and NSCLC, disease progression on or 
within 6 months of the end of prior curative intended multimodal therapy will count 
as a prior line of systemic therapy. If chemoradiation is followed by planned systemic 
therapy without documented progression between chemoradiation and systemic 
therapy, the entire treatment course counts as 1 line of therapy 
6. Complete the required tumor imaging screening evaluations ≤ 28 days before the first 
dose of study drug(s): 
a. Phase 2 safety lead-in: mandatory imaging of the head (preferably MRI), neck, chest, 
abdomen and pelvis; and other known or suspected sites of disease must be included in 
the imaging assessments. 
b. Phase 2 dose expansion: All other known or suspected sites of disease and the following 
imaging (CT or MRI as appropriate) is required:  
− for HNSCC patients: mandatory imaging of head (preferably MRI), neck, chest, and 
abdomen  
− for NSCLC and RCC patients: mandatory imaging of head (preferably MRI), chest, 
abdomen, and pelvis  
7. Phase 1 and Phase 2 safety lead-in: hepatocellular carcinoma patients must meet the 
Child-Pugh A classification for liver function as assessed within 7 days before first dose 
of study drug (Appendix 10) 
8. Phase 1 and Phase 2 safety lead-in: has at least 1 evaluable lesion per RECIST v1.1 
9. Phase 2 dose expansion: has at least 1 measurable lesion outside of the central nervous 
system per RECIST v1.1 that has not undergone prior locoregional therapy regardless of 
subsequent progression 
10. Phase 1 and Phase 2 safety lead-in: If available, patients must be able to provide an 
archived formalin fixed paraffin embedded (FFPE) tumor tissue sample (block or 
approximately 15 freshly cut unstained FFPE slides) 
Phase 2 dose expansion: Patients must be able to provide a recently obtained FFPE 
tumor tissue sample (FFPE block or approximately 15 freshly cut unstained FFPE slides). 
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If archival tissue is insufficient, a fresh tumor biopsy is mandatory prior to commencing 
treatment on Cycle 1 Day 1.  
11. Has ECOG performance status ≤ 1 
12. Has adequate organ function as indicated by the following laboratory values within 
7 days prior to the first dose of study drug(s): 
• 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 
• Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or estimated glomerular 
filtration rate (GFR) ≥ 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (Appendix 7) 
• Serum total bilirubin ≤ 1.5 X ULN (total bilirubin must be < 3 × ULN for patients 
with Gilbert’s syndrome) 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, 
or ≤ 5 × ULN for patients with liver metastases 
13. Female patients of childbearing potential must be willing to use a highly effective method 
of birth control for the duration of the study, and ≥ 6 months after the last dose of study 
drugs, and have a negative urine or serum pregnancy test ≤ 7 days of enrollment 
14. Non-sterile male patients must be willing to use a highly effective method of birth control 
for the duration of the study and for ≥ 6 months after the last dose of study drugs 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria must be excluded from this study: 
1. In Phase 2 dose expansion: NSCLC patients with known sensitizing epidermal growth 
factor receptor (EGFR) mutation, v-raf murine sarcoma viral oncogene homolog B1 
(BRAF) mutation, anaplastic lymphoma kinase (ALK) fusion, or c-ros oncogene 1 
(ROS1) fusion are excluded.  
a. For non-squamous and squamous NSCLC, patients with known EGFR mutation status, 
BRAF mutation, ALK fusion, or ROS1 fusion, who are sensitive to available targeted 
inhibitor therapy are excluded (Note: If no targeted therapy approved by local health 
authority is available for BRAF or ROS1 mutations, these patients are eligible). 
b. Patients with non-squamous histology must have been tested locally for EGFR status 
preferably using an FDA-approved or local Health Authority approved test at screening. 
Patients with sensitive EGFR mutation status will be excluded.  
c. Patients with non-squamous histology are encouraged to be tested for the mutational 
status of BRAF, ALK, and ROS1 locally using appropriate health authority 
recommended molecular test at screening. Patients with sensitive BRAF, ALK, and 
ROS1 mutation status will be excluded. If not previously tested, patients with unknown 
ALK, ROS1, or BRAF status may be enrolled. 
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d. Patients with squamous NSCLC and unknown EGFR mutation, BRAF mutation, ALK 
fusion, and ROS1 fusion status will not be required to be tested at screening 
2. Active leptomeningeal disease or uncontrolled, untreated brain metastasis.  
Patients with equivocal findings or with confirmed brain metastases are only eligible for 
enrollment if they are asymptomatic and radiologically stable without the need for central 
nervous system (CNS) disease related corticosteroid treatment for at least 4 weeks prior 
to the first dose of study drug(s) 
3. Active autoimmune diseases or history of autoimmune diseases that may relapse or 
history of life-threatening toxicity related to prior immune therapy, with the following 
exception: 
• Controlled type I diabetes 
• Hypothyroidism (provided it is managed with hormone replacement therapy only) 
• Controlled celiac disease 
• Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
• Any other disease that is not expected to recur in the absence of external triggering 
factors (requires consultation with the medical monitor prior to enrollment) 
4. 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) 
5. 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: 
• Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
• Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal 
systemic absorption 
• Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) 
6. With history of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung 
diseases, including pulmonary fibrosis, acute lung diseases, etc  
Note: Patients with significantly impaired pulmonary function, or any patient with non-small 
cell lung cancer enrolled in Phase 2, must undergo an assessment of pulmonary function at 
screening (see Section 7.2.4) 
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7. With uncontrolled diabetes, > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management, or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before the first dose of study drug 
8. With infections (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal, or antiviral therapy ≤ 14 days prior to the first dose of study drug(s), or a 
requirement for chronic prophylactic treatment with antibiotics.  
Note: antiviral therapy is permitted for eligible patients with HBV infection. 
9. A known history of HIV infection 
10. Phase 1 dose escalation and Phase 2 safety lead-in: A known history of hepatitis B 
virus (HBV) or hepatitis C virus (HCV) infection, except for patients with hepatocellular 
carcinoma.  
Note: for patients with hepatocellular carcinoma only: Patients with untreated chronic 
hepatitis B or chronic hepatitis B virus carriers with HBV DNA ≥ 500 IU/mL (or 2500 
copies/mL) or patients with detectable HCV RNA at screening  
Phase 2 dose expansion: Patients with untreated chronic hepatitis B or chronic hepatitis B 
virus carriers with HBV DNA ≥ 500 IU/mL (or 2500 copies/mL) or patients with detectable 
HCV RNA at screening  
11. Has undergone any major surgical procedure within 28 days before the first 
administration of study drug(s) 
12. Diagnosis of prior immunodeficiency or has undergone prior allogeneic stem cell 
transplantation or organ transplantation 
13. Has any of the following cardiovascular criteria: 
• 
Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, within 28 days before the first administration of study drug(s) 
• 
Pulmonary embolism or other clinically significant episode of thromboembolic 
disease within 28 days before the first administration of study drug(s) 
• 
Any history of acute myocardial infarction within 6 months before the first 
administration of study drug(s) 
• 
Any history of heart failure meeting New York Heart Association Classification III 
or IV (Appendix 6) within 6 months before the first administration of study drug(s) 
• 
Any event of ventricular arrhythmia ≥ Grade 2 in severity within 6 months before the 
first administration of study drug(s) 
• 
Any history of cerebrovascular accident within 6 months before the first 
administration of study drug(s) 
• 
Uncontrolled hypertension: systolic pressure ≥ 140 mmHg or diastolic pressure ≥ 
90 mmHg on repeated measurements that cannot be managed by standard 
antihypertension medications ≤ 28 days before the first dose of study drug(s) 
14. Has a history of severe hypersensitivity reactions to other monoclonal antibodies 
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15. Phase 1 dose escalation and Phase 2 safety lead-in: Has received any chemotherapy, 
radiotherapy, immunotherapy (eg, interleukin, interferon, thymosin, etc) or any 
investigational therapies within 28 days or 5 half-lives (whichever is shorter) of the first 
administration of study drug  
Phase 2 dose expansion: Has received any chemotherapy, radiotherapy, immunotherapy (eg, 
interleukin, interferon, thymosin, etc) or any investigational therapies within 14 days or 5 
half-lives (whichever is shorter) of the first administration of study drug(s) 
Note: Exceptions may be considered for palliative radiotherapy to a limited field following 
consultation with the medical monitor 
16. Has received any herbal medicine or Chinese patent medicines used to control cancer 
within 14 days of the first study drug(s) administration (see Appendix 11 for examples) 
17. 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) 
18. Was administered a live vaccine ≤ 28 days prior to the first dose of study drug(s) 
administration 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. For COVID-19 vaccines, non-live 
vaccines are allowed, including inactivated vaccines; live or live-attenuated vaccines ≤ 28 
days before the first dose of study treatment are not allowed. 
19. Underlying medical conditions (including psychiatric conditions and cognitive 
dysfunction) 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 AEs; or insufficient compliance during the study according to investigator’s 
judgement 
20. Concurrent participation in another therapeutic clinical trial, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an interventional 
study 
21. Women who are pregnant or nursing 
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5. 
STUDY TREATMENT  
5.1. 
Medicinal Product Approval Status  
A list of all investigational medicinal products (IMPs) that will be used in this study and their 
regulatory approval status are provided in Table 3. No auxiliary medicinal products, defined by 
Article 2(8) of Regulation (EU) 536/2014, will be used in this study. 
Table 3: 
Investigational Medicinal Products Used in Study BGB-900-102 and Their 
Regulatory Approval Status 
Country/Region 
Approved for Treatment of Advanced Solid Tumors (Yes/No) 
BGB-A425 
Tislelizumab 
LBL-007 
USA 
No 
No 
No 
Korea 
No 
No 
No 
Australia 
No 
No 
No 
European Union 
No 
No 
No 
5.2. 
Formulation, Packaging, and Handling  
5.2.1. 
BGB-A425  
BGB-A425 (20 mg/mL) is a monoclonal antibody formulated for intravenous infusion and is 
provided as a preservative-free, single-use vial, containing a minimum of 15 mL of a 20 mg/mL 
concentrated solution (300 mg) antibody in a buffered isotonic solution. BGB-A425 has been 
aseptically filled in single-use vials (20 mL; USP Type I glass) with a coated butyl rubber 
stopper and sealed with an aluminum flip-off cap. Each vial is packaged into a single carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the storage condition specified on the label. Shaking should be 
avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the BGB-A425 Investigator’s Brochure for other details 
regarding BGB-A425. 
5.2.2. 
Tislelizumab  
Tislelizumab (10 mg/mL) is a monoclonal antibody formulated for intravenous infusion and is 
provided as a preservative-free, single-use vial, containing a minimum of 10 mL of a 10 mg/mL 
concentrated solution (100 mg) of antibody in a buffered isotonic solution. Tislelizumab has 
been aseptically filled in single-use vials (20 mL; USP Type I glass) with a coated butyl rubber 
stopper and sealed with an aluminum flip-off cap. Each vial is packaged into a single carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the storage condition specified on the label. Shaking should be 
avoided. 
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Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the Tislelizumab Investigator’s Brochure for other details 
regarding tislelizumab. 
5.2.3. 
LBL-007  
LBL-007 (17 mg/mL) is a monoclonal antibody formulated for intravenous infusion and is 
provided as a preservative-free, single-use vial, containing a minimum of 5 mL of a 17 mg/mL 
concentrated solution (85 mg) of antibody in a buffered isotonic solution. LBL-007 is aseptically 
filled in single-use vials (6 mL; USP Type I glass) with a coated butyl rubber stopper and sealed 
with an aluminum flip-off cap.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the storage condition specified on the label. Do not freeze. 
Shaking should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the LBL-007 Investigator’s Brochure for additional 
information.  
5.3. 
Dosage, Administration, and Compliance  
All patients will be monitored continuously for AEs. Treatment modifications (eg, dose delay) as 
described in Section 5.6 will be based on specific laboratory and AE criteria. Guidelines for dose 
modification, treatment interruption, or discontinuation and for the management of infusion-
related reactions and imAEs are provided in detail in Section 5.6, Section 8.7, and Appendix 8. 
BGB-A425, tislelizumab and LBL-007 will be administered separately by intravenous infusion, 
through an intravenous line containing a sterile, nonpyrogenic, low-protein-binding 0.2 micron in 
line or add-on filter. As described below, BGB-A425, tislelizumab and LBL-007 must be 
prepared and administered as separate infusions and may not be administered with any other 
drug (refer to Section 6). 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3.1. 
Phase 1 (Dose Escalation): BGB-A425 and Tislelizumab Combination  
Planned and evaluated Phase 1 dose level(s) and dosing frequency for BGB-A425 and/or 
tislelizumab are provided in Table 4.
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Table 4: 
Phase 1 Dose Levels for BGB-A425 and/or Tislelizumab 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment a 
BGB-A425 
2 mg 
6 mg 
20 mg 
60 mg 
200 mg 
400 mg 
800 mg 
1600 mg 
(lower 
intermediate 
and/or higher 
dose levels may 
be explored) 
Cycle 1 Day 1, 
Cycle 2 Day 1, then 
once every 21 days  
Intravenous 
Until disease progression, 
unacceptable toxicity, or 
voluntary withdrawal of 
consent per patient decision 
Tislelizumab 
200 mg 
Cycle 1 Day 8, 
Cycle 2 Day 1, then 
once every 21 days  
Intravenous 
Until disease progression, 
unacceptable toxicity, or 
voluntary withdrawal of 
consent per patient decision 
Abbreviations: CR, complete response; PR, partial response. 
a For patients who have confirmed CR, PR, or stable disease after 24 months, the treatment can be paused for a 
period of time (at patient request) following the investigator’s agreement and sponsor’s written approval. (as in 
Section 3.3.1). 
Only Cycle 1 will be 28 days in length. Thereafter starting with Cycle 2, each cycle will be 
21 days in length (ie, once every 21 days). In the first cycle, BGB-A425 will be administered on 
Day 1, and tislelizumab will be administered on Day 8 (+2 days). Following completion of 
Cycle 1, patients will then receive tislelizumab followed by the administration of BGB-A425 on 
Day 1 of each subsequent 21-day cycle (ie, once every 21 days). Other dosing regimens of 
BGB-A425 may be explored based on safety, tolerability, PK, and antitumor activities observed 
in dose levels completed. However, the dosing regimen of tislelizumab will remain fixed as 
shown in Table 4. 
For the first 2 cycles (or first 2 administrations of study drug in case of dose delays), tislelizumab 
will be administered over 60 (± 10) minutes and BGB-A425 over 60 (± 10) minutes. For 
Cycle 2, tislelizumab will be administered first followed by the administration of BGB-A425. 
Following final infusion of study drug, patients must be monitored for at least 120 minutes in an 
area with resuscitation equipment and emergency agents (Table 5). 
If infusions of tislelizumab and BGB-A425 are well tolerated in the first 2 cycles, on Cycle 3 
Day 1 (or the third administration of study drug in case of dose delays), tislelizumab may be 
administered for no less than 30 minutes followed by the administration of BGB-A425 over 
60 (± 10) minutes. Following final infusion of study drug, patients must be monitored for at least 
120 minutes in an area with resuscitation equipment and emergency agents (Table 5). 
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If infusions of tislelizumab and BGB-A425 are well tolerated in the first 3 cycles, on Cycle 4 
Day 1 (or the fourth administration of study drug in case of dose delays) and subsequent cycles, 
tislelizumab may be administered no less than 30 minutes followed by the administration of 
BGB-A425 for no less than 30 minutes. Thereafter, patients must be monitored for at least 30 
minutes in an area with resuscitation equipment and emergency agents (Table 5). 
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 5: 
Phase 1 Administration of BGB-A425 and Tislelizumab and Monitoring 
Time 
Cycle 
BGB-A425 and Tislelizumab combination 
Cycle 1 Day 1  
BGB-A425 infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 1 Day 8 
Tislelizumab infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 2 Day 1 
Tislelizumab infusion over 60 (± 10) minutes followed by BGB-A425 infusion 
over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 3 Day 1 
Tislelizumab infusion for no less than 30 minutes followed by BGB-A425 
infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 4 Day 1 
onwards 
Tislelizumab infusion no less than 30 minutes followed by BGB-A425 infusion 
for no less than 30 minutes 
Patient monitoring for at least 30 minutes post completion of last infusion 
5.3.2. 
Phase 2 (Safety Lead-in)  
5.3.2.1. 
Cohort A (LBL-007 + Tislelizumab)  
Planned and evaluated Phase 2 safety lead-in dose level(s) and dosing frequency for LBL-007 
and tislelizumab are provided in Table 6.  
Table 6: 
Phase 2 Safety Lead-in Dose Levels for Cohort A: LBL-007 and Tislelizumab 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment a 
LBL-007 
300 mg 
600 mg 
(higher dose 
levels such as 
900 mg may be 
explored) 
Cycle 1 Day 1, then 
once every 21 days 
Intravenous 
infusion 
Until disease progression, 
unacceptable toxicity, or 
voluntary withdrawal of 
consent per patient decision 
Tislelizumab 
200 mg 
Abbreviations: CR, complete response; PR, partial response. 
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a For patients who have confirmed CR, PR, or stable disease after 24 months, the treatment can be paused for a 
period of time (at patient request) following the investigator’s agreement and sponsor’s written approval. (as in 
Section 3.3.1). 
For the first cycle (or first 2 administrations of study drug in case of dose delays), LBL-007 will 
be infused over 60 (± 10) minutes, followed by patient monitoring for 60 (± 30) minutes; then 
tislelizumab will be infused over 60 (± 10) minutes. Following final infusion of study drug, 
patients must be monitored for at least 120 minutes in an area with resuscitation equipment and 
emergency agents. 
If infusions of LBL-007 and tislelizumab are well tolerated in the first cycle, on Cycle 2 Day 1 
and Cycle 3 Day 1, LBL-007 may be infused for no less than 30 minutes followed by patient 
monitoring for 60 (± 30) minutes; then tislelizumab will be infused for no less than 30 minutes. 
Following final infusion of study drug, patients must be monitored for at least 120 minutes in an 
area with resuscitation equipment and emergency agents.  
If infusions of LBL-007 and tislelizumab are well tolerated in the first 3 cycles, on Cycle 4 
Day 1 and subsequent cycles, LBL-007 may be infused for no less than 30 minutes followed by 
patient monitoring for 60 (± 30) minutes; then tislelizumab will be infused for no less than 
30 minutes. Following final infusion of study drug, patients must be monitored for at least 
60 minutes in an area with resuscitation equipment and emergency agents (Table 7). 
Table 7: 
Phase 2 Safety Lead-in Administration of Cohort A: LBL-007 and 
Tislelizumab and Monitoring Time 
Cycle 
LBL-007 and Tislelizumab combination 
Cycle 1 Day 1 
 
LBL-007 infusion over 60 (± 10) minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 2 Day 1 
Cycle 3 Day 1 
 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion for no less than 30 minutes  
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 4 Day 1 
onwards 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion for no less than 30 minutes  
Patient monitoring for at least 60 minutes post completion of last infusion 
5.3.2.2. 
Cohort B (BGB-A425 + LBL-007 + Tislelizumab)  
Planned and evaluated Phase 2 safety lead-in dose level(s) and dosing frequency for BGB-A425, 
LBL-007, and tislelizumab are provided in Table 8.
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Table 8: 
Phase 2 Safety Lead-in Dose Levels for Cohort B: BGB-A425, LBL-007, and 
Tislelizumab 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment a 
BGB-A425 
600 mg 
Cycle 1 Day 1, then 
once every 21 days 
Intravenous 
infusion 
Until disease progression, 
unacceptable toxicity, or 
voluntary withdrawal of 
consent per patient 
decision 
LBL-007 
300 mg 
600 mg 
(higher dose 
levels such as 
900 mg may be 
explored) 
Tislelizumab 
200 mg 
Abbreviations: CR, complete response; PR, partial response. 
a For patients who have confirmed CR, PR, or stable disease after 24 months, the treatment can be paused for a 
period of time (at patient request) following the investigator’s agreement and sponsor’s written approval (as in 
Section 3.3.1). 
For the first cycle (or first 3 administrations of study drug in case of dose delays), LBL-007 will 
be infused over 60 (± 10) minutes, followed by patient monitoring for 60 (± 30) minutes; then 
tislelizumab will be infused over 60 (± 10) minutes, and BGB-A425 over 60 (± 10) minutes. 
Following final infusion of study drug, patients must be monitored for at least 120 minutes in an 
area with resuscitation equipment and emergency agents.  
If infusions of LBL-007, tislelizumab, and BGB-A425 are well tolerated in the first cycle, on 
Cycle 2 Day 1 and Cycle 3 Day 1, LBL-007 may be infused for no less than 30 minutes followed 
by patient monitoring for 60 (± 30) minutes; then tislelizumab will be infused for no less than 
30 minutes followed by the infusion of BGB-A425 for no less than 30 minutes. Following final 
infusion of study drug, patients must be monitored for at least 120 minutes in an area with 
resuscitation equipment and emergency agents.  
If infusions of LBL-007, tislelizumab, and BGB-A425 are well tolerated in the first 3 cycles, on 
Cycle 4 Day 1 and subsequent cycles, LBL-007 may be infused for no less than 30 minutes 
followed by patient monitoring for 60 (± 30) minutes; then tislelizumab will be infused for no 
less than 30 minutes followed by the infusion of BGB-A425 for no less than 30 minutes. 
Following final infusion of study drug, patients must be monitored for at least 60 minutes in an 
area with resuscitation equipment and emergency agents (Table 9).
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Table 9: 
Phase 2 Safety Lead-in Administration of Cohort B: BGB-A425, LBL-007, 
and Tislelizumab and Monitoring Time 
Cycle 
BGB-A425, LBL-007, and Tislelizumab combination 
Cycle 1 Day 1 
 
LBL-007 infusion over 60 (± 10) minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion over 60 (± 10) minutes, 
followed by BGB-A425 infusion over 60 (± 10) minutes  
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 2 Day 1 
Cycle 3 Day 1 
 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion for no less than 30 minutes, 
followed by BGB-A425 infusion for no less than 30 minutes  
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 4 Day 1 
onwards 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by tislelizumab infusion for no less than 30 minutes, 
followed by BGB-A425 infusion no less than 30 minutes  
Patient monitoring for at least 60 minutes post completion of last infusion 
5.3.3. 
Phase 2 (Dose Expansion)  
5.3.3.1. 
BGB-A425 + Tislelizumab (Cohorts 1, 2 and 3)  
The RP2D of BGB-A425 (600 mg intravenously) will be administered in combination with 
tislelizumab (200 mg intravenously). BGB-A425 and tislelizumab will be administered once 
every 21 days starting on Cycle 1 Day 1.  
Table 10: 
Phase 2 Dose Expansion Administration of BGB-A425 and Tislelizumab and 
Monitoring Time 
Cycle 
BGB-A425 and Tislelizumab combination 
Cycle 1 Day 1 
Cycle 2 Day 1 
Tislelizumab infusion over 60 (± 10) minutes, followed by BGB-A425 infusion 
over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion  
Cycle 3 Day 1 
Tislelizumab infusion for no less than 30 minutes, followed by BGB-A425 
infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 4 Day 1 
onwards 
Tislelizumab infusion for no less than 30 minutes, followed by BGB-A425 
infusion for no less than 30 minutes 
Patient monitoring for at least 30 minutes post completion of last infusion 
5.3.3.2. 
BGB-A425 + LBL-007 +Tislelizumab (Cohorts 4 and 5)  
The recommended doses for LBL-007 in the combination with BGB-A425 and tislelizumab will 
be determined by the clinical data from the Phase 2 safety lead-in Cohort A. 
Refer to Table 11 regarding infusion and monitoring times for Phase 2 dose expansion (Cohorts 
4 and 5). 
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Table 11: 
Phase 2 Dose Expansion Administration of BGB-A425, LBL-007, and 
Tislelizumab and Monitoring Time 
Cycle 
BGB-A425, LBL-007 and Tislelizumab combination 
Cycle 1 Day 1 
 
LBL-007 infusion over 60 (± 10) minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by Tislelizumab infusion over 60 (± 10) minutes, 
followed by BGB-A425 infusion over 60 (± 10) minutes  
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 2 Day 1 
onwards 
 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by Tislelizumab infusion for no less than 30 minutes, 
followed by BGB-A425 infusion no less than 30 minutes  
Patient monitoring for at least 60 minutes post completion of last infusion 
5.3.3.3. 
LBL-007 + Tislelizumab (Cohorts 6 and 7)  
The recommended doses for LBL-007 in combination with tislelizumab will be determined by 
the clinical data from the Phase 2 safety lead-in Cohort B. 
Refer to Table 12 regarding infusion and monitoring times for Phase 2 dose expansion. 
Table 12: 
Phase 2 Dose Expansion Administration of LBL-007 and Tislelizumab and 
Monitoring Time 
Cycle 
LBL-007 and Tislelizumab combination 
Cycle 1 Day 1 
 
LBL-007 infusion over 60 (± 10) minutes, followed by patient monitoring for 60 
(± 30) minutes, followed by Tislelizumab infusion over 60 (± 10) minutes 
Patient monitoring for at least 120 minutes post completion of last infusion 
Cycle 2 Day 1 
onwards 
 
LBL-007 infusion for no less than 30 minutes, followed by patient monitoring for 
60 (± 30) minutes, followed by Tislelizumab infusion for no less than 30 minutes  
Patient monitoring for at least 60 minutes post completion of last infusion 
5.4. 
Overdose of Tislelizumab and Incorrect Administration of 
BGB-A425 and LBL-007  
Any overdose of tislelizumab (defined as ≥ 600 mg in a 24-hour period) or incorrect 
administration of BGB-A425 and LBL-007 should be noted in the patient’s chart and on the 
appropriate eCRF. 
Adverse events associated with an overdose or incorrect administration of study drug will be 
recorded on the Adverse Event eCRF. If an overdose or 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 the SAE reporting process described in 
Section 8.6.2. Supportive care measures should be administered as appropriate. 
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5.5. 
Investigational Medicinal Product Accountability  
The IMPs (BGB-A425, LBL-007, and tislelizumab) required for the completion of this study 
will be provided by the sponsor. The investigational site will acknowledge receipt of the 
investigational medicinal products. Any damaged shipments will be replaced. 
Accurate records of all investigational medicinal product received, dispensed, returned, and 
disposed of need to be recorded on the site’s Drug Inventory Log. Refer to the Pharmacy Manual 
for details of investigational medicinal product management. 
5.6. 
Dose Delay and Modification  
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. 
Guidelines for treatment modification or discontinuation as well as the management of  reactions 
and -imAEs are provided in detail in Section 8.7 and Appendix 8. 
For AEs that are non-imAEs but assessed as related to tislelizumab and/or BGB-A425 and/or 
LBL-007, the following general guidance should be followed unless otherwise specified: 
• ≤ Grade 2: Maintain dose level 
• Grade 3: Delay dose until resolved to ≤ Grade 1 or baseline except for alopecia or AEs 
that, in the opinion of the investigator, are not considered a safety risk for patient 
• Grade 4: Permanent discontinuation from study. Exceptions may be considered following 
consultation with the medical monitor. 
5.6.1. 
Dose Delay for BGB-A425, LBL-007, and Tislelizumab  
Except for Cycle 1 of Phase 1, if a dose delay for any study drug is required, all the applicable 
combination treatments (ie, BGB-A425/LBL-007/Tislelizumab) are to be delayed. Exceptions 
may be considered following consultation between the investigator and the medical monitor. In 
Cycle 1 of Phase 1, if tislelizumab is delayed beyond Cycle 1 Day 8 (+2 days), tislelizumab will 
not be administered in Cycle 1 but treatment may resume in subsequent cycles as outlined in 
Section 5.6.2. 
If treatment is delayed due to treatment-emergent AE(s), treatment may resume only after the 
AE(s) have returned to baseline or ≤ Grade 1 severity except for alopecia or AEs that, in the 
opinion of the investigator, are not considered a safety risk to the patient. If a treatment delay is 
due to worsening of hematologic or biochemical parameters, the frequency of relevant blood 
tests should be increased as clinically indicated.  
If a dose/visit delay (due to the causes mentioned above) is ≤ 10 days for a planned dosing cycle 
(eg, Cycle 3 Day 1), the delayed combination treatment(s) in this cycle (eg. Cycle 3) should be 
administered, and the treatment in the next cycle (eg, Cycle 4 Day 1) will not be delayed and 
administered as scheduled. 
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If the dose/visit delay (due to the causes mentioned above) is > 10 days, then the patient should 
skip the combination treatment(s) in the delayed cycle (eg, Cycle 3 Day 1), and combination 
treatment(s) should be administered on Day 1 of the next planned cycle (eg, Cycle 4 Day 1).  
In general, dose delays for reasons other than management of AEs is prohibited as noted in 
Section 7.6. A dose delay of ≤ 12 weeks is allowed under the following guidance and at the 
discretion of the investigator after consultation with the medical monitor or designee.  
If treatment-related AEs are persistent without any improvement for more than 12 weeks, 
permanent discontinuation of the study drug should be considered. If the patient recovers from 
the treatment-related AE after 12 weeks, re-initiation of study drug is permitted only in patients 
who are deemed to be deriving clinical benefit per the opinion of the investigator following 
agreement between the investigator and the medical monitor. 
Patients who receive radiotherapy per Section 6.1.1, may resume treatment with study drug only 
after radiotherapy related AE(s) have returned to baseline or ≤ Grade 1 severity, except for AE(s) 
that in the opinion of the investigator, are not considered a safety risk to the patient. 
The tumor assessment schedule will not be altered even if the administration of study drug is 
delayed. 
Two occurrences of dose delays because of treatment-related AEs will be permitted. In the event 
of a third occurrence of a dose delay due to toxicity, permanent discontinuation of study drug 
should be considered after consultation with the medical monitor. 
For patients who have confirmed CR, PR, or stable disease after 24 months, the treatment can be 
paused for a period of time (at patient request) following investigator’s agreement and sponsor’s 
written approval. The decision to pause treatment should be based on the investigator’s 
evaluation, with the patient’s clinical benefit and risk taken into consideration. The investigator 
should notify and seek written agreement from the sponsor’s medical monitor that treatment will 
be paused prior to the event (as in Section 3.3.1). Additionally, patients need to undergo disease 
assessments (as per Section 7.6) and safety follow up if applicable, per the protocol 
recommendation (Appendix 1A, Appendix 1B, and Appendix 1C) while on study treatment 
break. 
5.6.2. 
Dose Modification for BGB-A425, LBL-007, and Tislelizumab  
No dose reductions will be allowed for tislelizumab. For Phase 2 safety lead-in, no dose 
reduction of tislelizumab and BGB-A425 will be allowed. For Phase 2 dose expansion, no dose 
reduction in any study drug will be allowed. 
For Phase 1 only, if patients are receiving a dose level of BGB-A425 that is determined to be 
beyond the MTD, the dose level of BGB-A425 may be reduced following discussion and 
agreement with the medical monitor. Further, if a patient cannot be dosed with tislelizumab on 
Cycle 1 Day 8 (+2 days), the patient will not be eligible to receive tislelizumab with the 
originally assigned dose level of BGB-A425. However, starting on Cycle 2 Day 1 and every 
21 days thereafter, the patient will be eligible, assuming any AE related delay has resolved per 
Section 5.6, to receive the combination of tislelizumab and a lower dose level of BGB-A425 that 
had previously been shown to be tolerable according to the criteria outlined in Section 3.1 and 
following discussion with the medical monitor.  
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For Phase 2 safety lead-in only, if patients are receiving a dose level of LBL-007 (eg, 300 mg or 
higher) that is determined not well tolerated, the dose level of LBL-007 may be reduced a lower 
level for further evaluation following discussion and agreement with the medical monitor. 
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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 and in keeping with local 
standards of medical care at the discretion of the investigator for supportive care (eg, antiemetics, 
antidiarrheals, granulocyte colony-stimulating factor, and other care) and in a patient’s interest 
are allowed.  
Vaccines for COVID-19 are allowed except for any live vaccine (ie, live SARS-CoV-2 virus) 
that may be developed. Attenuated (vector) COVID-19 vaccines are inactivated vaccines and as 
such, are permitted. It is recommended to avoid COVID-19 vaccination within 72 hours before 
or after study drug administration during the first 2 treatment cycles and within 24 hours before 
or after study drug administration thereafter (ie, from Cycle 3 onwards). Vaccinations are 
considered a concomitant medication and hence should be entered on the eCRF. The specific 
COVID-19 vaccine should be recorded instead of generic language, eg, mRNA-1273 vaccine 
(Moderna), BioNTech vaccine (Pfizer), etc. 
All concomitant medication will be recorded on the eCRF including all prescription, over-the-
counter, herbal supplements, and intravenous medications and fluids. 
All concomitant medication received within 30 days before the first dose of study treatment and 
30 days after the last infusion or dose of study treatment should be recorded. If changes (dose, 
stop, or start) in concomitant medication occur during the study, documentation of drug dosage, 
frequency, route, date, and reason for use will be recorded on the eCRF. 
Systemic corticosteroids given for the control of imAEs must be tapered gradually and be at 
non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the next study 
drug administration. The short-term use of steroids as prophylactic treatments (eg, patients with 
contrast allergies to diagnostic imaging contrast dyes) is permitted. 
Bisphosphonates, but not RANKL inhibitors, are allowed. 
Patients who have detectable HBsAg or HBV DNA at baseline must initiate and/or continue 
effective antiviral treatment in keeping with local standards of medical care where applicable. 
For such patients enrolled in the United States, treatment must be initiated at least 2 weeks prior 
to first dose of study drug(s) and continue until 6 months after the last dose of study drug(s). 
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline provided 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 the medical monitor, and the medical monitor agrees that the 
conditions required to receive palliative radiation are met. 
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The medical monitor should be informed of any on-study radiation therapy. Whenever possible, 
these patients should have a tumor assessment of the lesion(s) before receiving radiotherapy in 
order to rule out progression of disease. Study treatment should be withheld until any 
radiotherapy related AE(s) have returned to baseline or ≤ Grade 1 severity, except for AE(s) that 
in the opinion of the investigator, are not considered a safety risk to the patient. 
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 herbal medicine and 
Chinese patent medicines] for the treatment of cancer) is not allowed (Appendix 11) 
• Radiation therapy is not allowed, unless otherwise noted 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) 
• Immune-stimulating agents including 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. 
• Patients should not abuse alcohol or other drugs during the study 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be 
carefully monitored 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Information regarding clinical drug interactions with BGB-A425 is not available. No dedicated 
drug-drug interaction studies are planned. However, the potential for PK-based drug-drug 
interaction between BGB-A425 and small-molecule drug products is expected to be very low, 
given that BGB-A425 is a therapeutic monoclonal antibody. A PK drug-drug interaction of 
tislelizumab or LBL-007 with other therapeutics is not anticipated given that the primary 
elimination pathways are protein catabolism via the reticuloendothelial system or target-
mediated disposition. Tislelizumab and LBL-007 are not expected to induce or inhibit the major 
drug metabolizing cytochrome P450 pathways. Because BGB-A425, tislelizumab and LBL-007 
are expected to be degraded into amino acids and recycled 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 for Phase 1 and 2 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 and eCRF for each patient. 
Administration of study drug(s) must occur only after the clinical assessment and local 
laboratory test values have been reviewed and found to be acceptable per protocol guidelines. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (within the specified visit 
windows) with subsequent visits conducted according to the Schedule of Assessments 
(Appendix 1). 
7.1. 
Prescreening (Phase 2 Dose Expansion)  
Unless otherwise specified, all HNSCC and NSCLC patients who agree to participate in Phase 2 
dose expansion will sign the Prescreening informed consent form (ICF) prior to undergoing any 
prescreening procedure, this includes patients who have confirmation of local PD-L1 results (see 
Appendix 1 for details).  
HNSCC and NSCLC patients with positive PD-L1 expression are eligible for enrollment. The 
Prescreening ICF and the PD-L1 test are not required for RCC patients; therefore, all RCC 
patients are allowed to proceed directly into screening. 
The overall duration for prescreening for Phase 2 dose expansion is 56 days prior to the first dose 
of study drugs. A longer prescreening period may be granted on a case-by-case basis following 
discussion and written approval from the sponsor’s medical monitor approval in discussion with 
the principal investigator.  
Prescreening starts with the date of Prescreening ICF signature and ends with the receipt of 
PD-L1 results. Site staff should plan prescreening activities in advance to ensure that all 
subsequent screening activities (in Section 7.2) can be completed within the allowed Period with 
a maximum duration of 28 days before the first dose of study drug(s). 
Prescreening evaluations may be repeated as needed within the prescreening period; the 
investigator is to assess patient eligibility according to the latest prescreening assessment results. 
Prescreening ICFs for enrolled patients and for patients who are prescreened and/or screened but 
not enrolled will be maintained at the study site. The investigator will maintain a prescreening 
log to record details of all patients prescreened and to confirm PD-L1 test results. 
7.1.1. 
PD-L1 Test  
During the prescreening period, HNSCC and NSCLC patients in dose expansion cohorts will 
undergo PD-L1 positivity confirmation by specified PD-L1 IHC assays. 
Below are detailed requirements for confirming a patients’ PD-L1 status during prescreening. 
(1) Local documented PD-L1 result to confirm PD-L1 positivity on archival tumor tissue  
HNSCC and NSCLC patients with a local positive PD-L1 result by specified PD-L1 IHC 
assay on archival tissue can proceed directly to the screening phase. If the patient has more 
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than 1 PD-L1 test, the most recent PD-L1 result should be used for PD-L1 positivity 
confirmation. 
Local documented PD-L1 positivity result requirement: 
− PD-L1 expression must be determined using a CE-marked assay in the EU. 
− For HNSCC patients, PD-L1 (CPS ≥ 1) by IHC 22C3 pharmDx assay (preferred) or 
PD-L1 (CPS ≥ 1, vCPS or TAP ≥ 1%) by VENTANA PD-L1 (SP263) are acceptable 
for PD-L1 expression confirmation. Note: PD-L1 positivity determined by PD-L1 IHC 
22C3 pharmDx assay will be used for HNSCC patients in the EU. 
− For NSCLC patients, PD-L1 (TPS or TC ≥ 1%) by IHC 22C3 or 28-8 pharmDx or 
VENTANA PD-L1 (SP263) assay are acceptable for PD-L1 expression confirmation. 
Note: If PD-L1 IHC 28-8 assay is to be used for determining PD-L1 positivity, it will 
be used for nonsquamous NSCLC patients only in the EU. 
For all patients who provide a local documented PD-L1 result, recently obtained tissue 
within 2 years or fresh tissue biopsy is required prior to the patient commencing first drug 
administration on Cycle 1 Day 1. It is highly recommended to provide the same tissue that 
was tested for the local PD-L1 assay. Recently obtained tumor tissue or fresh biopsy will be 
sent to the central laboratory and retrospectively evaluated by VENTANA PD-L1 (SP263) 
assay and other exploratory biomarkers. 
(2) Central PD-L1 testing 
During prescreening, if HNSCC and NSCLC patients are unable to provide a local 
documented PD-L1 result, patients will be required to submit a recently obtained archival 
tumor tissue within 2 years or fresh biopsy during prescreening. IHC 22C3 pharmDx assay 
will be used for PD-L1 expression confirmation in HNSCC (PD-L1 CPS ≥ 1), or NSCLC 
(PD-L1 TPS ≥ 1%), respectively.  
The patient can only proceed to the screening period following confirmation of a positive 
PD-L1 result by either local PD-L1 positive result or following confirmation of PD-L1 
positivity from the central laboratory.  
The PD-L1 positivity confirmation flow is summarized in Figure 8 below: 
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Figure 8: 
PD-L1 Positivity Confirmation Flowchart 
 
Footnote: Option 1 refers to the scenarios in bullet (1) as mentioned above; Option 2 refers to the scenarios in bullet 
(2) as mentioned above  
PD-L1 expression positivity confirmation (in all of above situations) must be obtained before 
HNSCC and NSCLC patients are allowed to continue to screening. The PD-L1 status of patients 
will also be retrospectively evaluated by VENTANA PD-L1 (SP263) assay. 
The PD-L1 test is not required for RCC patients as part of prescreening or screening. The PD-L1 
status of patients will also be retrospectively evaluated by VENTANA PD-L1 (SP263) assay. 
7.2. 
Screening  
Unless otherwise specified, patients who agree to participate will sign the ICF prior to 
undergoing any screening procedures (see Appendix 1 for details).  
Any applicable supplementary ICFs should also be presented to the patient at the time of the 
main ICF being presented to the patient, as part of the informed consent process. 
In Phase 1 (dose escalation) and Phase 2 (safety lead-in), the signed Screening ICF and all 
screening procedures will be required within 28 days prior to the first administration of study 
drug(s). The ICF signature defines the start of the Screening Period. 
In Phase 2 (dose expansion), the signed Screening ICF and all screening procedures will be 
required within 28 days prior to the first administration of study drug(s).  
• For RCC patients, the 28-day Screening Period will start from the signatory date on the 
Screening ICF. 
• For HNSCC and NSCLC patients, the 28-day Screening Period following a local or 
central laboratory positive PD-L1 result will start from the signatory date on the 
Screening ICF. 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. 
The results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and prior to enrollment may be used for the purposes of screening rather than repeating 
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such tests unless otherwise indicated. Screening evaluations may be repeated as needed within 
the Screening Period but the investigator is to assess patient eligibility according to the latest 
screening assessment results.  
Rescreening under limited conditions may be allowed after consultation with the sponsor’s 
medical monitor (eg, when a patient narrowly misses a laboratory criterion and it is correctable 
and not because of rapidly deteriorating condition or disease progression), in discussion with the 
principal investigator. Rescreening is allowed only once. For NHSCC and NSCLC patients in 
Phase 2 dose expansion experiencing rescreening during the Screening Period, the prescreening 
procedures do not need to be repeated. 
Patients who are suspected or known to have serious/severe respiratory concurrent illness or 
exhibit significant respiratory symptoms unrelated to underlying cancer should take a pulmonary 
function test (refer to Section 7.2.4 for details). 
Procedures conducted during the Screening Visit only are described in Section 7.2.1 to 
Section 7.2.4. For the description of other assessments that are conducted at screening as well as 
throughout the study, refer to Safety Assessments (Section 7.5), Biomarker Assessments 
(Section 7.8) and Tumor and Response Evaluation (Section 7.6). 
7.2.1. 
Demographic Data and Medical History  
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
ethnicity data are collected in accordance with ICH guidance (ICH E5 1998, ICH E17 2017) 
adopted by the EMA and US FDA, to understand whether race/ethnicity could influence the PK, 
safety, and/or efficacy of the study drug. For example, population PK analysis is a well-
established, quantitative method that can quantify and explain the variability in drug 
concentrations among patients. Such variability can be attributed to intrinsic factors (eg, body 
weight, age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant medications), and 
can lead to clinically relevant changes in drug concentrations that require a change in the dose or 
dosing regimen. Results from race/ethnicity and other demographic analyses will be incorporated 
into drug product labeling to provide guidance on safety and efficacy variations (if any) linked to 
certain populations (eg, race or ethnic group) as well as any potential dose adjustment needed for 
those populations. Therefore, collecting race/ethnicity data in the study is essential to understand 
whether race/ethnicity could influence the PK, safety, and/or efficacy. 
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); and history of 
alcohol consumption and tobacco (ie, presence or absence). If appropriate, clinically significant 
disease should be graded according to NCI-CTCAE v5.0 and reported in the Medical History 
eCRF. 
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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7.2.2. 
Female Patients 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”. 
7.2.3. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures, unless otherwise specified. 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 enrollment. 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. 
7.2.4. 
Pulmonary Function Tests  
During the Screening Period, patients will undergo pulmonary function testing if they are: 
suspected or known to have serious/severe respiratory conditions, exhibit significant respiratory 
symptoms unrelated to the underlying cancer; patients with non-small cell lung cancer enrolled 
in all Phase 2 cohorts will be required to undergo pulmonary function test regardless of their 
respiratory conditions or symptoms. This may include, but is not limited to, spirometry and 
assessment of diffusion capacity. 
Pulmonary function testing includes assessment of oxygenation, spirometry and/or lung volume 
tests. The assessment of oxygenation should include at least pulse oximetry (percutaneous 
arterial oxygen saturation, SpO2) at rest and with exercise; an assessment of diffusion capacity is 
optional.  
The medical monitor needs to be consulted to confirm eligibility if test results indicate 
significantly impaired pulmonary function. Some examples are: resting pulse oximetry < 90% on 
room air and further desaturation upon exercise; forced expiratory volume in one second < 60%; 
or carbon monoxide diffusing capacity (if performed) < 60% of age and sex adjusted predicted 
performance levels (Pellegrino et al 2005). 
7.3. 
Enrollment  
7.3.1. 
Confirmation of Eligibility  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined.  No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. The sponsor’s medical 
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monitor will support the investigator and/or site staff by answering any queries or questions 
relating to protocol eligibility criteria. 
7.4. 
BGB-A425, LBL-007, and Tislelizumab Dispensation  
BGB-A425, LBL-007, and tislelizumab will be dispensed and administered as described in 
Section 5.3. 
7.5. 
Safety Assessments  
7.5.1. 
Vital Signs  
Vital signs will include measurements of temperature (˚C), pulse rate, respiratory rate, and blood 
pressure (systolic and diastolic) while the patient is in a seated position after resting for 
10 minutes.  
Vital signs will be collected at the timepoint in Phase 1 and Phase 2 as described in 
Appendix 1A, Appendix 1B and Appendix 1C. 
7.5.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including an 
evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 
4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the 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 an AE on the Adverse Event eCRF. 
Refer to Section 8.3 regarding AE definitions, reporting, and follow-up requirements. 
7.5.3. 
Ophthalmologic Examination  
The ophthalmologic examination including eye examination, visual acuity test, and optical 
coherence tomography (or equivalent diagnostic test for retinal examination) will be assessed by 
an ophthalmologist at screening. All tests mentioned above are required as per local 
ophthalmologist OCT requirements. The ophthalmologic examination captured as standard of 
care prior to obtaining written informed consent and within 28 days of enrollment 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 after the last dose of study treatment (see Appendix 1 for timepoints). 
In addition, investigators should solicit patients for information 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 1). 
7.5.4. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 3) will be assessed during the study. 
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7.5.5. 
Laboratory Safety Test  
Laboratory assessments will be conducted for serum chemistry, hematology and coagulation 
while urinalysis will be performed locally as outlined in Appendix 2 per the Schedule of 
Assessments (Appendix 1).  
For Phase 1, blood-based laboratory assessments will be performed by a central laboratory. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring 
and dosing decision(s); however, central laboratory assessments must still be collected for the 
timepoints outlined in Appendix 1. For central laboratory assessments, details regarding sample 
collection and shipment will be provided in a separate laboratory manual. For Phase 2 (safety 
lead-in and dose expansion), safety laboratory assessments will be conducted via local laboratory 
only. 
If serum chemistry, hematology, and coagulation at screening are not performed within 7 days 
prior to the administration of study drug(s) on Cycle 1 Day 1, these tests should be repeated and 
reviewed before study drug(s) administration. After Cycle 1 Day 1, results are to be reviewed 
within 72 hours before study drug administration. 
In addition, the following tests will be conducted at the central laboratory for Phase 1, and the 
local laboratory for Phase 2 (safety lead-in and dose expansion) at timepoints shown in 
Appendix 1. 
• Urine pregnancy test (local laboratory for Phase 2) (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 enrollment. Further, a negative pregnancy test (by urine or 
blood) must be completed and recorded on the same day before administration of study 
drug(s) at each cycle. A serum pregnancy test must be performed if the urine pregnancy 
test is positive or equivocal. An additional pregnancy test must be performed for women 
of childbearing potential at approximately 120 days after the last dose of study treatment. 
• Thyroid function testing: thyroid stimulating hormone, free T3, free T4 
• Hepatitis serology and viral load, refer to Section 7.5.8 
• Creatine kinase (CK) and creatine kinase-cardiac muscle isoenzyme (CK-MB), refer to 
Section 7.5.9 
7.5.6. 
Electrocardiograms  
For Phase 1, 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. However, during the course of study, sites may switch to a local ECG 
laboratory for safety monitoring purposes. Additionally, other sites will use local ECG as per the 
protocol. All ECG recordings will be performed using a standard high-quality and high-fidelity 
digital electrocardiograph. 
For Phase 2 (dose expansion and safety lead-in), ECG assessment will be performed and 
evaluated locally using a site’s internal resources. 
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For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the site. 
When coinciding with blood 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 timepoint (see Appendix 1), 3 consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine the mean QT interval corrected by Fridericia’s 
formula (QTcF) interval (QTcF = QT / [RR]1/3) (Fridericia 1920) in addition to other ECG 
parameters as needed. 
7.5.7. 
Adverse Events  
Adverse events (AEs) will be graded and recorded throughout the study according to 
NCI-CTCAE v5.0 (NCI-CTCAE 2017). Characterization of toxicities will include severity, 
duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.5.8. 
Hepatitis B and C Testing  
Testing will include HBV/HCV serology (HBsAg, hepatitis B surface antibody, hepatitis B core 
antibody, and HCV antibody) and viral load assessment (HBV DNA and HCV RNA) to be 
performed by a central laboratory for Phase 1 or local laboratory for Phase 2 (safety lead-in and 
dose expansion). 
For Phase 1, patients with hepatocellular carcinoma are required to have hepatitis serology and 
viral load tested at screening. In patients who have detectable HBV DNA at screening, the 
respective viral load test will be performed every 4 cycles. Patients with detectable HCV RNA 
will not be allowed to enroll into the study. In patients without hepatocellular carcinoma, 
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. 
For Phase 2 (safety lead-in and dose expansion), testing will be performed by the local laboratory 
at screening and will include HBV/HCV serology (HBsAg, hepatitis B surface antibody, 
hepatitis B core antibody, and HCV antibody). In case of positive HBsAg or positive HCV 
antibody results, these tests will be followed by viral load assessment (HBV DNA and HCV 
RNA). Viral load assessment (HBV DNA and HCV RNA) may be performed at the same time as 
HBV/HCV serology at investigator’s discretion in line with the clinical history of the patient. 
Patients who have detectable HBV DNA at screening but remain eligible for enrollment will 
have their respective viral load tested every 4 cycles. Testing should also be performed as needed 
for any patient during treatment where clinically indicated.  
7.5.9. 
Creatine Kinase and Creatine Kinase-Cardiac Muscle Isoenzyme  
Testing of CK and CK-MB will be performed by a central laboratory for Phase 1 or local 
laboratory for Phase 2 (safety lead-in and dose expansion) at the timepoints specified in 
Appendix 1. If your laboratory does not perform CK-MB testing, serum troponins (troponin I 
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and/or T) measurements should be performed instead; if only either troponin is assessed per local 
standards that same should be evaluated throughout. 
If significant abnormalities are detected, please evaluate the affected patients for possible 
myocarditis/myositis per institutional guidelines, including additional serum CK/CK-MB, serum 
troponin levels, ECG, etc. Please report all clinically significant abnormalities as an AE or SAE 
as described in Appendix 8. 
7.6. 
Tumor and Response Evaluations  
Tumor imaging will be performed approximately every 6 weeks (± 7 days) in the first 52 weeks 
and thereafter approximately every 12 weeks (± 7 days) as shown in Appendix 1A, Appendix 1B 
and Appendix 1C. The first tumor assessment will be performed 6 weeks (± 7 days) after the first 
administration of the study drugs. 
Screening assessments and each subsequent assessment of the tumor must include computed 
tomography (CT) scans (with oral/intravenous contrast, unless contraindicated) or magnetic 
resonance imaging (MRI). 
For Phase 1, the chest, abdomen, pelvis, and other known or suspected sites (eg, head and neck) 
of disease must be included in the imaging assessments at baseline and during the study. 
Phase 2 safety lead-in, the head (including brain, preferably MRI), neck, chest, abdomen, pelvis, 
and other known or suspected sites of disease must be included in the imaging assessments at 
baseline and during the study. 
For Phase 2 dose expansion, in addition to all other known or suspected sites of disease (eg, bone 
and extremities), the following imaging is required at baseline and during the study:  
• For HNSCC patients:  
− Imaging assessment during screening/baseline: head (including brain), neck, chest, and 
abdomen 
− Imaging assessment during the treatment: head (including brain), neck, chest, and 
abdomen 
− Pelvic imaging is not required during screening/baseline or the treatment unless 
clinically indicated.  
• For NSCLC patients: 
− Imaging assessment during screening/baseline: head (including brain), chest, 
abdomen, and pelvis.  
− Imaging assessment during the treatment: chest, abdomen, and pelvis.  
• For RCC patients:  
− Imaging assessment during screening/baseline: head (including brain), chest, 
abdomen, and pelvis.  
− Imaging assessment during the treatment: chest, abdomen, and pelvis.  
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• All measurable and evaluable lesions should be assessed and documented at the 
Screening Visit and reassessed at each subsequent tumor evaluation. The same 
radiographic procedure used to assess disease sites at screening is required to be used 
throughout the study (eg, the same contrast protocol for CT scans).  
• 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 (where required) 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 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, TC-99m or PET bone scans should be repeated when a complete response 
(CR) is suspected in target lesion or when progression in bone is suspected. 
• CT scans of extremities should also be performed at screening, only if clinically 
indicated, and should be followed throughout the study if there is evidence of metastatic 
disease in these regions at screening.  
• For NSCLC and RCC patients, imaging of the brain (preferably MRI) during the 
treatment is not required unless clinically indicated. 
• At the investigator’s discretion, other methods of assessment of target lesion and 
nontarget lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigators using RECIST v1.1 (see Appendix 9). 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 
timepoint. 
After the first documentation of PD, confirmation of PD should occur at 4 weeks or later 
(≥ 4 weeks) after the first PD or at the next scheduled assessment timepoint. 
A patient who discontinues study drugs early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments as described in Section 3.2.5 until the 
patient begins a new anticancer therapy, experiences PD per RECIST v1.1, withdraws consent, is 
lost to follow-up, dies, or until the study terminates, whichever occurs first. 
If at the investigator’s discretion a patient could continue to benefit from BGB-A425 and/or 
tislelizumab and/or LAG-3 after PD per RECIST v1.1, the patient may continue their assigned 
treatment, following sponsor’s agreement and written approval. The following criteria must be 
met: 
• Absence of clinical symptoms and signs of PD (including clinically significant worsening 
of laboratory values) 
• Stable ECOG Performance Status ≤ 1 
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• 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 drugs beyond initial investigator-assessed progression 
must be agreed with the medical monitor following confirmation of investigator-assessed 
radiological progression, and documented in the study records. In such cases, patients are 
also required to be re-consented on the Treatment Through Progression ICF (as described 
in Section 3.3.1). Patients who receive study treatment beyond disease progression will 
have tumor assessments performed according to the original schedule until study 
treatment discontinuation. 
Patients with the radiographic progression in tumor burden or the appearance of new lesions in 
the absence of significant clinical deterioration (decline in performance status and/or laboratory 
values) are permitted to continue with treatment (after re-consented) until confirmation of PD 
with follow-up imaging at least 4 weeks later or at the next scheduled imaging time point. The 
next imaging to confirm disease progression must not exceed 12 weeks from initial 
documentation of PD. Per investigator’s judgement, if a patient could draw benefit from the 
combination treatments after radiographic disease progression, the patient may continue the 
treatment as per the protocol following sponsor’s agreement and written approval. The 
subsequent disease assessment could be conducted as assigned in the protocol. 
A patient who discontinues study drug(s) early for reasons other than PD (eg, toxicity) will 
continue to undergo tumor assessments as described in Section 3.2.5 until the patient begins a 
new anticancer therapy, experiences PD, withdraws consent, is lost to follow-up, dies, or until 
the study terminates, whichever occurs first. 
Tumor assessments must be performed on schedule regardless of whether study treatment has 
been administered or withheld, ie, they should not be adjusted for delays in cycles. 
7.7. 
Pharmacokinetic Assessment and Antidrug Antibody Testing  
BGB-A425, LBL-007, 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 timepoints throughout the study (see 
Appendix 1D, Appendix 1E, Appendix 1F and Appendix 1G). 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-A425, LBL-007 
and tislelizumab in support of the clinical development program. This tiered strategy will include 
an assessment of whether ADA responses correlate with relevant clinical endpoints. 
Implementation of ADA characterization assays will depend on the safety profile and clinical 
immunogenicity data. 
The following assessments will be performed at a central laboratory: 
• ADA assays: serum samples will be tested for the presence of ADAs to BGB-A425, 
LBL-007 and tislelizumab using a validated immunoassay. 
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• PK assay: serum samples will be assayed for BGB-A425, LBL-007 and tislelizumab 
concentration with use of a validated pharmacokinetic assay. 
In Phase 1 dose escalation, serial PK and immunogenetic samples for BGB-A425 will be 
collected; sparse PK and immunogenetic samples for tislelizumab will be collected. 
In Phase 2 safety lead-in, serial PK and immunogenetic samples for LBL-007 will be collected; 
sparse PK and immunogenetic samples for BGB-A425 and tislelizumab will be collected. 
In Cohorts 1, 2, and 3 of Phase 2 dose expansion, serial PK samples and sparse immunogenetic 
samples for BGB-A425 will be collected in approximately 15 patients enrolled, 10 patients from 
South Korea, and 5 patients from Australia. In these 15 patients, sparse immunogenetic samples 
for tislelizumab will be collected. Besides, sparse PK samples and immunogenetic samples for 
BGB-A425 and tislelizumab will be collected for the rest of the patients. 
In Cohorts 4 to 7 of Phase 2 dose expansion, sparse PK and immunogenetic samples for 
LBL-007, BGB-A425, and tislelizumab will be collected. 
The table below has summarized types of PK and immunogenetic samplings of 3 study drugs in 
Phase 1 and Phase 2. The appendixes for sampling schedules are also added as reference in 
Table 13.   
Table 13: 
Types of PK and Immunogenetic Samplings for BGB-A425, LBL-007, and 
Tislelizumab in Phase 1 and Phase 2 
Compound 
Phase 1 Dose 
Escalation 
Phase 2 Safety 
Lead-in 
Phase 2 Dose Expansion 
(Cohorts 1, 2, and 3) 
Phase 2 Dose 
Expansion 
(Cohorts 4 to 7) 
BGB-A425 
Serial sampling 
(Appendix 1D) 
Sparse sampling 
(Appendix 1E) 
Serial PK sampling and 
sparse immunogenetic 
samples for the first 
15 patients 
(Appendix 1G) 
Sparse sampling for the 
rest patients  
(Appendix 1F) 
Sparse sampling 
(Appendix 1F) 
LBL-007 
NA 
Serial sampling 
(Appendix 1D) 
NA 
Sparse sampling 
(Appendix 1F) 
Tislelizumab Sparse sampling 
(Appendix 1E) 
Sparse sampling 
(Appendix 1E) 
Sparse sampling 
(Appendix 1F) 
Sparse sampling 
(Appendix 1F) 
Abbreviations: NA, not applicable. 
Shipping, storage, and handling of samples for the assessment of BGB-A425, LBL-007, 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. 
7.8. 
Biomarkers  
Shipping, storage, and handling of blood as well as archival tumor and/or fresh tumor tissue for 
the assessment of biomarkers will be managed through a central laboratory. Refer to the 
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laboratory manual for details of sample handling and the Schedule of Assessment (Appendix 1H, 
Appendix 1I, and Appendix 1J) for timepoints. 
Blood samples will be collected at specified times as described in Appendix 1H (Phase 1) or 
Appendix 1I (Phase 2-safety lead-in), or Appendix 1J (Phase 2-expansion) will be used for the 
evaluation of biomarkers including but not limited to, TIM-3, LAG-3, and PD-1 RO, 
immunophenotyping in peripheral blood cells, concentrations of cytokine and soluble proteins in 
plasma and serum, and ctDNA analysis in peripheral blood.  
In Phase 1 and Phase 2 safety lead-in, patients will provide archival tumor tissues (FFPE blocks 
or approximately 15 freshly cut unstained slides) for biomarker analysis, if available. If archival 
tissue is not available, a fresh tumor biopsy is strongly encouraged but not mandatory.  
In Phase 2 dose expansion, during the prescreening period, designated PD-L1 results are required 
for HNSCC and NSCLC patients. Either local documented results or a central analysis on 
recently obtained tissue will be acceptable. For both HNSCC and NSCLC patients, PD-L1 IHC 
22C3 pharmDx assay will be used for PD-L1 expression detection in a central lab. If local testing 
is used, PD-L1 (CPS ≥ 1) by IHC 22C3 pharmDx assay (preferred) or PD-L1 (CPS ≥ 1, vCPS or 
TAP ≥ 1%) by VENTANA PD-L1 (SP263) are acceptable for HNSCC patients (Note: PD-L1 
positivity determined by PD-L1 IHC 22C3 pharmDx assay will be used for HNSCC patients in 
the EU); PD-L1 (TPS or TC ≥ 1%) by IHC 22C3 or 28-8 pharmDx or VENTANA PD-L1 
(SP263) assay are acceptable for NSCLC patients (Note: If PD-L1 IHC 28-8 assay is to be used 
for determining PD-L1 positivity, it will be used for nonsquamous NSCLC patients only in the 
EU). This requires tissue samples obtained recently within 2 years. For patients who have known 
PD-L1 positivity, a historically documented result is acceptable for PD-L1 positivity 
confirmation by specified PD-L1 assay at the prescreening phase. Tissue obtained within 2 years 
or fresh biopsy is required prior to the patient commencing first drug administration on Cycle 1 
Day 1. It is highly recommended to provide the same tissue that was tested for the local PD-L1 
assay. If a patient has more than 1 archival tumor tissue, the most recent one is preferred. 
Positivity confirmation of PD-L1 must be obtained before HNSCC and NSCLC patients are 
allowed to continue to screening. The PD-L1 test is not required for RCC patients as part of 
prescreening or screening. For all the cohorts, PD-L1 status will also be evaluated with recently 
obtained tumor tissues or fresh biopsy, by VENTANA PD-L1 (SP263) assay.  
In Phase 2 dose expansion, patients in all cohorts must provide recent tumor tissues obtained 
within 2 years (FFPE blocks or approximately 15 freshly cut unstained slides). If recently 
obtained tumor tissue is insufficient, a fresh tumor biopsy is mandatory. If qualified tumor tissue 
samples were received in the prescreening period then a repeat tumor biopsy need not be done. 
For Phases 1 and 2, an optional biopsy after 2 cycles of treatment (approximately Cycle 3 Day 1) 
is strongly recommended to obtain tumor samples for the evaluation of pharmacodynamic 
effects. An optional biopsy will also be taken from accessible tumor sites for patients who have 
confirmed disease progression during the study in order to evaluate potential resistance 
mechanism(s). Ideally and if feasible, post-treatment biopsies should be taken from the same 
tumor lesion as the baseline biopsy/fresh tumor tissues.  
Tissue samples obtained as described above will be shipped to a BeiGene designated central 
laboratory for biomarker testing after local regulatory approval. This may occur after the start of 
study treatment if necessary. Tumor tissues will be used for immunohistochemistry analysis of 
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PD-L1, TIM-3, LAG-3, and ligands expression. In addition, other exploratory biomarkers, such 
as TIL assessment, tumor mutation burden, and gene expression profiling, that are related to 
response or clinical benefit of BGB-A425, LBL-007 and tislelizumab may also be evaluated. 
Written patient consent is required for any optional 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. Bone derived tissue samples 
should be avoided. 
7.9. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise specified (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 of each cycle should be performed before any study treatment is given unless 
otherwise noted. Laboratory results must be reviewed before dosing. For the case of dose/visit 
delay, the details for scheduling the subsequent treatment visits are described in Section 5.6.1. 
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 (within the visit window 
provided in Appendix 1). A cycle is defined as every 21 days based on the schedule of 
administration of BGB-A425. Subsequent visits should be conducted according to the planned 
schedule of assessments 21 days from Day 1 of Cycle 1. 
7.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and 
may include vital signs/focused physical examination; ECOG Performance Status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected 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. 
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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-A425, LBL-007, and Tislelizumab  
BGB-A425, LBL-007, and tislelizumab are investigational agents that are currently in clinical 
development. Limited clinical information is available for BGB-A425 and LBL-007 
(Section 1.2.4 and Section 1.3.5). Safety data is available from 33 patients treated with 
BGB-A425, 22 patients treated with LBL-007, and 2596 patients treated with tislelizumab 
(Section 1.2 and BGB-A425 Investigator’s Brochure; Section 1.3 and LBL-007 Investigator’s 
Brochure, Section 1.4 and Tislelizumab Investigator’s Brochure). The following 
recommendation is based primarily upon results from nonclinical studies of BGB-A425, clinical 
data of BGB-A425 from the dose escalation phase of this study, clinical data of LBL-007, 
nonclinical and clinical studies with tislelizumab, as well as published data on other anti-TIM-3, 
anti-LAG-3, and anti-PD-1 agents given alone or in combination with one another. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Appendix 8. BGB-A425 
mediated TIM-3 inhibition may increase the risk of immune-mediated AEs, though no apparent 
immunotoxicity, or toxicity in general, have been observed in animal models treated with 
BGB-A425 (Section 1.2.2 and BGB-A425 Investigator’s Brochure). Further, in the absence of 
activation, peripheral effector T-cells do not typically express TIM-3, thereby minimizing any 
potential negative additive affect as it relates to peripheral immune tolerance. Clinical data from 
the dose escalation phase of this study is still under review (Section 1.2.4 and BGB-A425 
Investigator’s Brochure).  
According to clinical studies for which safety results are currently available, the possible 
toxicities of LBL-007 include general reactions (fatigue), allergic reactions, infusion-related 
reactions, digestive tract toxicity (loss of appetite, diarrhea, nausea, and vomiting), 
hepatotoxicity, pulmonary toxicity (pneumonia), and cutaneous reactions (pruritis and rash).  
Although most imAEs observed with immunomodulatory agents have been mild and self-
limiting, such events should be recognized early and treated promptly to avoid potential major 
complications. To assist with this, a comprehensive algorithm to aid in the diagnostic evaluation 
and management of immune-mediated toxicities is provided in Appendix 8. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to maintain the safety of patients in this trial. Results from the 
nonclinical toxicology studies of BGB-A425, LBL-007 and tislelizumab and clinical data with 
tislelizumab, as well as the nonclinical/clinical data from other anti-TIM-3, anti-LAG-3 and 
PD-L1/PD-1 inhibitors, were taken into account. Specifically, patients at risk for study-emergent 
active autoimmune diseases or history of autoimmune diseases that may relapse and patients who 
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have received a live viral 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 AEs, defined and graded 
according to NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to 
the start of each cycle. 
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 
measurements (hematology, chemistry, etc.), and other assessments. In addition, patients will be 
closely monitored for the development of any signs or symptoms of autoimmune conditions and 
infection. 
Serum samples will be drawn for determination of ADAs to BGB-A425 and to tislelizumab in 
patients for both Phase 1 and Phase 2 portions of the study. Administration of study drug(s) will 
be performed in a setting where emergency medical equipment and staff who are trained to 
respond to medical emergencies are available (for additional information, see Section 5.3). 
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing the prescreening informed consent) and for up to 30 days after the last dose of 
study drug(s) or until the initiation of another anticancer therapy, whichever occurs first. At the 
end of treatment, ongoing AEs considered related to study treatment will be followed until the 
event has resolved to baseline or ≤ Grade 1, the event is assessed by the investigator as stable, 
the patient is lost to follow-up, the patient withdraws consent, or it has been determined that 
study treatment or participation is not the cause of the AE. 
Immune-mediated AEs will be recorded until up to 90 days after the last dose of study drug(s), 
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 AEs (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. 
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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 or 
a concurrent medication (overdose per se should not be reported as an AE or SAE). 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor. 
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 v5.0. 
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 
• Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare, 
activities of daily living 
• 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 8.4. 
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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 judgement. 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 
consult the Tislelizumab Investigator’s Brochure, BGB-A425 Investigator’s Brochure and LBL-
007 Investigator’s Brochure in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always makes an assessment of causality for every SAE prior to transmission of the 
SAE report to the sponsor, since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements. The investigator may change his/her opinion of 
causality considering follow-up information, amending the SAE report accordingly. 
2-point Causality Assessment 
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 
• An AE should be considered “related” to study drug if any of the following are met, 
otherwise the event should be assessed as not related: 
a. There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
b. There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
c. 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) 
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• 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  
Abnormal laboratory findings (eg, chemistry, hematology, coagulation) or other abnormal 
assessments (ECGs, X-rays, vital signs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs. This includes clinically significant abnormal 
laboratory findings or other abnormal assessments that are present at baseline and significantly 
worsen during the study. The definition of clinically significant is left to the judgement of the 
investigator; in general, these are the abnormalities that are associated with clinical signs or 
symptoms, require active medical intervention, or lead to dose interruption or discontinuation, or 
require close observation, or more frequent follow-up assessments, or further diagnostic 
investigation. 
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 
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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 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information) and meets the 
definition of a serious adverse drug reaction, 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 the Prescreening ICF 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. In addition, telephone contacts and/or clinic visits with patients should be 
conducted to assess imAEs (serious and nonserious), anticancer therapy, and concomitant 
medications/procedures where appropriate (ie, associated with an imAE, etc.) 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. If a patient reports a suspected imAE at a telephone follow-up contact, the 
investigator should arrange an unscheduled visit if further assessment is indicated. The 
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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 (after 
the Prescreening ICF is signed), the event must be reported immediately, without undue delay, 
but no later than within 24 hours of obtaining knowledge of the event to the sponsor or designee 
as described in Table 14. 
Table 14: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-
Up Report 
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24 hours of 
first knowledge of 
the AE 
SAE report 
As expeditiously 
as possible 
SAE report 
Email or fax 
SAE form  
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 (after the 
Prescreening ICF is signed), he/she is to report the information to the sponsor within 24 hours as 
outlined above in Section 8.6.2.1. The SAE report will always be completed as thoroughly as 
possible with all available details of the event, and forwarded to the sponsor or designee within 
the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality 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. 
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All suspected unexpected serious adverse reactions (as defined in Section 8.5), will be submitted 
to all applicable regulatory authorities and investigators for BGB-A425, LBL-007 and 
tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
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 and death because of disease progression, which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, 
the symptoms, signs or clinical sequelae that result from disease progression should be reported 
as the AE(s). 
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of disease 
progression. If a patient experienced a fatal multi-organ failure because of disease progression, 
the term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death because of disease progression.” All SAEs and 
deaths, regardless of relatedness to disease progression, should be recorded and reported. 
8.6.5. 
Recording Deaths  
Death is an outcome and not usually considered an AE. If the only information available is death 
and the cause of death is unknown, then the death is reported as an event, eg, “death”, “death of 
unknown cause”, or “death unexplained”. 
8.6.6. 
Recording Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 6 months after the last dose of tislelizumab or BGB-A425 or 
LBL-007, 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. 
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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 post study 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 discharged 
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 documents: 
• Tislelizumab Investigator’s Brochure 
• BGB-A425 Investigator’s Brochure 
• LBL-007 Investigator’s Brochure 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 (and potentially anti-TIM-3 or anti-LAG-3) therapy can cause 
autoimmune disorders, AEs considered by the investigator to be immune-mediated (see 
Section 8.7.3) should be classified as imAEs 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 imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 8. 
An extensive list of potential imAEs appears in Appendix 8. All conditions similar to those listed 
should be evaluated to determine whether they are imAEs, based upon a similar diagnostic 
process as presented in Appendix 8. 
8.7. 
Management of Adverse Events of Special Interest  
As a routine precaution, following completion of study drug(s) administration, patients must be 
monitored for a period afterwards in an area with resuscitation equipment and emergency agents. 
See Section 5.3 for additional details. 
Adverse events of special interest (AESI) do not require expedited reporting to BeiGene within 
24 hours of awareness, using the SAE report form. AESIs are only required to be entered into the 
clinical database. 
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The management for infusion-related reactions, severe hypersensitivity reactions, and imAEs 
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 or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 
Treatment modification for symptoms of infusion-related reactions because of study drug(s) is 
provided in Table 15. 
Table 15: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Study Drugs 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as needed. 
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 hrs. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described 
below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – life threatening 
Life threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs, nonsteroidal anti-inflammatory drugs 
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Once the infusion rate of the study drug(s) has been decreased by 50% or suspended because of 
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 
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 antihistamine 
(eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), and if 
considered indicated oral or intravenous glucocorticoids, epinephrine, bronchodilators, and 
oxygen. In the next cycle, patients should receive oral premedication with an antihistamine 
(eg, diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 
CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and 
oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the patient 
discontinued from study treatment. 
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 the Intensive Care Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.7.3. 
Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study. If the events listed in Appendix 8 or 
similar events occur, the investigator should exclude alternative explanations (eg, combination 
drugs, infectious disease, metabolic, toxin, disease progression, or other neoplastic causes) with 
appropriate diagnostic tests which may include but is not limited to serologic, immunologic, and 
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histologic (biopsy) data. The imAEs listed in Appendix 8 or similar conditions should be 
evaluated in patients receiving study drugs to determine whether they are immune-mediated. If 
alternative causes have been ruled out; the AE that required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy and is consistent with an immune-mediated 
mechanism of action, the imAE indicator in the eCRF AE page should be checked. However, 
these imAEs do not require expedited reporting to the sponsor within 24 hours via the SAE 
reporting method. 
Refer to Appendix 8 for a list of the most common imAEs as well as detailed recommendations 
for the diagnostic evaluation and management of imAEs according to European Society for 
Medical Oncology and American Society of Clinical Oncology guidelines (Haanen et al 2017; 
Brahmer et al 2018) as well as common immune-mediated toxicities. For any AEs not included 
in Appendix 8, please refer to the American Society of Clinical Oncology Clinical Practice 
Guideline (Brahmer et al 2018) for further guidance. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the medical monitor. Patients who experience a recurrence of any event at 
the same or higher severity grade with rechallenge should permanently discontinue treatment. 
8.7.4. 
Management of imAEs in Patients with Pre-Existing Renal Dysfunction  
Patients with renal dysfunction (estimated GFR ≥ 30 mL/min/1.73 m2 by CKD-EPI equation) 
may be enrolled into the study. Therefore, the following algorithm is proposed for the use of 
steroid treatment in the management of imAEs in patients with normal as well as pre-existing 
mild or moderate renal dysfunction: 
• If the serum creatinine (ie, estimated GFR) is normal at baseline, refer to Appendix 8 for 
diagnosis and management of patients with imAE related abnormal renal laboratory 
values. 
• If the serum creatinine is Grade 1 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with study 
drug(s), refer to Appendix 8 for diagnosis and management of patients with abnormal 
renal laboratory values. Check the estimated GFR using Appendix 7 and the estimated 
GFR calculator link. In the setting of a Grade 2 serum creatinine increase only, study 
treatment can continue unless the serum creatinine increases by at least 50% from the 
baseline value OR the estimated GFR falls below 20 mL/min/1.73 m2. 
• If the serum creatinine is Grade 2 at baseline (RCC patients only) and increase in serum 
creatinine meets criteria for serum creatinine increase ≥ Grade 3 after starting treatment 
with study drug(s), refer to Appendix 8 for diagnosis and management of patients with 
abnormal renal laboratory values. In the setting of a Grade 3 serum creatinine increase 
only, study treatment will be held until serum creatinine improves to baseline and 
treatment may resume only after discussion with the medical monitor. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released. Details of the statistical analyses will be included in a 
separate Statistical Analysis Plan. 
In general, data from the Phase 1 and Phase 2 safety lead-in will be summarized by dose level 
and schedule; while data from the Phase 2 dose expansion will be summarized by cohort, unless 
otherwise specified. 
9.1. 
Statistical Analysis  
9.1.1. 
Randomization Methods  
Not applicable. 
9.1.2. 
Analysis Sets  
The Safety Analysis Set includes all patients who received at least 1 dose of study drug(s). It will 
be the population for the safety and efficacy analyses. 
The Evaluable Analysis Set includes all dosed patients who have evaluable disease at baseline, 
and at least 1 evaluable postbaseline tumor response assessment unless any clinical PD or death 
occurred before the first scheduled postbaseline tumor assessment. It will be used for efficacy 
analysis only. 
The DLT Evaluable Analysis Set for Phase 1 includes patients who received at least 80% each of 
the assigned dose of BGB-A425 on Cycle 1 Day 1 and tislelizumab on Cycle 1 Day 8 (+2 days) 
and remained on study during the DLT observation period and had sufficient safety evaluation or 
patients who experienced a DLT within the DLT observation period. For safety lead-in in Phase 
2 with Cohort A and Cohort B, DLT Evaluable Analysis Set includes patients who received at 
least 80% each of the assigned dose of study drug(s) in the combination treatments. 
The PK Analysis Set includes all patients who received at least 1 dose of study drug(s) and have 
at least 1 derivable PK parameter. Subgroup analysis may be carried out based on requirement 
from local health authorities. 
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 discontinued 
will be summarized according to the categories in the eCRF. The end of study status (alive, dead, 
withdrew consent, or lost to follow-up) at the data cutoff date will be summarized using the data 
from the eCRF. 
Major protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized in the Safety Analysis Set 
using descriptive statistics. Continuous variables include age, weight, time since initial cancer 
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diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables include 
gender, ECOG, race, TNM staging, number of prior system therapies received, and tumor type. 
Other disease specific parameters might be summarized in the relevant cohort for Phase 2. 
9.1.5. 
Prior and Concomitant Medications  
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
drug codes. Concomitant medications will be further coded to the appropriate Anatomical 
Therapeutic Chemical code indicating therapeutic classification. Prior and concomitant 
medications will be summarized and listed by drug and drug class in the clinical study report for 
this protocol. Prior medications will be defined as medications that stopped before the day of 
first dose of study 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 (as of Safety Follow-up Visit). A listing of prior and concomitant medications will be 
included in the clinical study report for this protocol. 
9.2. 
Efficacy Analyses  
Efficacy endpoints will be based upon investigator derived tumor assessments per RECIST v1.1. 
The following efficacy endpoints will be analyzed and summarized in order to evaluate the 
antitumor activities of all combination treatments: 
• ORR is defined as the proportion of patients who had confirmed CR or PR assessed by 
investigator. 
• DOR is defined as the time from the first determination of an objective response, until the 
first documentation of progression or death, whichever comes first. 
• DCR is defined as the proportion of patients with BOR (as defined in Appendix 9 for 
RECIST v1.1) of a CR, PR, and stable disease. 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 or death, 
whichever occurs first. 
• OS is defined as time from the first dose of study drug(s) to the date of death due to any 
cause. 
9.2.1. 
Secondary Efficacy Analysis in Phase 1 and Phase 2 (Safety Lead-in)  
ORR, DOR, and DCR will be determined from investigator derived tumor assessments per 
RECIST v1.1. 
ORR and DCR will be summarized by dose cohort, along with their 95% confidence interval in 
the Safety and Evaluable Analysis Sets. 
9.2.2. 
Primary Efficacy Analysis in Phase 2 (Dose Expansion)  
ORR and its 95% confidence interval will be summarized in the Safety and Evaluable Analysis 
Sets. ORR in Phase 2 dose expansion will be presented by tumor expansion cohort.  
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9.2.3. 
Secondary Efficacy Analysis in Phase 2 (Dose Expansion)  
PFS, DOR, and DCR will be summarized by tumor expansion cohort. 
PFS and DOR will be estimated using the Kaplan-Meier method. The median PFS and the 
cumulative probability of PFS and event-free rate for DOR at every 3 months will be calculated 
and presented with 2-sided 95% CIs. PFS censoring rule will follow FDA Guidance for Industry 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007). 
DOR censoring rule will be implemented similarly as PFS, and analysis will be limited in the 
responders. 
DCR will be analyzed similarly to ORR in the Safety and Evaluable Analysis Sets. 
Waterfall plots of maximum tumor shrinkage per patient will be presented.  
9.2.4. 
Exploratory Efficacy Analysis  
OS will be analyzed similarly as described for PFS (Section 9.2.3) in all treated patients.  
Correlations between drug exposure and response (efficacy and safety endpoints) will also be 
assessed.  
Additionally, the following will be evaluated as appropriate: exploratory biomarkers from patient 
derived tumor tissue(s) and blood (or blood derivatives) samples obtained before, during and/or 
after the combination treatments. Candidate biomarkers may include, but are not limited to, 
PD-1, TIM-3, and LAG-3 RO and immune cell subpopulation in peripheral blood cells, 
concentrations of cytokine and soluble proteins in plasma or serum, ctDNA analysis in peripheral 
blood, PD-L1, TIM-3, LAG-3, and ligands expression, TIL assessment, gene expression 
profiling, and tumor mutation analysis in tumor tissue. 
9.3. 
Safety Analyses  
Safety will be determined by the spontaneous reporting of AEs and by laboratory values 
(hematology, clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, 
and ECG findings will also be used in determining the safety profile. The severity of AEs will be 
graded according to the NCI-CTCAE v5.0. The incidence of DLT events and TEAEs will be 
reported as the number (percentage) of patients with TEAEs by system organ class and preferred 
term. Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n [%] for categorical variables) and changes from baseline 
will be determined for laboratory parameters and vital signs. 
Safety data will be summarized in the Safety Analysis Set, and by study phase. 
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 because of AEs will be summarized for each study drug. Reasons of the above 
dose modification will be summarized as well. 
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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. Adverse events will be coded to Medical 
Dictionary for Regulatory Activities (version 18.1 or higher) lower level term, preferred term 
and primary system organ class. 
DLT will be summarized at each dose cohort in Phase 1 and Phase 2 (safety lead-in). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever comes first. The TEAE 
classification also applies to imAEs that are recorded up to 90 days after discontinuation from 
tislelizumab, regardless of whether or not the patient starts a new anticancer therapy. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE v5.0 within a system organ class and preferred term, even if the 
patient experienced more than 1 TEAE within a specific system organ class and preferred term. 
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug. 
TEAEs include those events considered by the investigator to be related to study treatment or 
with missing assessment of the causal relationship. SAEs, deaths, TEAE with ≥ Grade 3 severity, 
imAE, 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, coagulation, urinalysis) values will be 
evaluated for each laboratory parameter as appropriate. Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range. Reference (normal) 
ranges for laboratory parameters will be included in the clinical study report for this protocol. 
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, maximum 
for continuous variables; n [%] for categorical variables) for laboratory parameters and their 
changes from baseline will be calculated. Laboratory values will be summarized by visit and by 
worst postbaseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 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 (systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit for all 
visits. Vital signs will be listed by patient and visit. 
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9.3.5. 
Ophthalmologic Examination  
Ophthalmologic examination results will be listed by patient. 
9.4. 
Pharmacokinetic Analysis  
Noncompartmental analysis will be carried out in patients with serial BGB-A425 and LBL-007 
serum concentrations. PK parameters such as Cmax, Cmin, Tmax, t1/2, AUC0-21d, CL, and Vz may be 
derived and summarized with descriptive statistics, including means, medians, ranges, and 
standard deviations, as appropriate. BGB-A425, LBL-007, and tislelizumab serum concentration 
by time may be summarized in patients with sparse PK collection. 
Population PK analysis may be carried out if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
9.5. 
Immunogenicity Analyses  
Samples to assess anti-BGB-A425-antibodies, anti-LBL-007-antibodies as well as anti-
tislelizumab antibodies will be collected only in patients who receive the treatment and in sites 
that are able to adequately perform sampling, handling, and processing outlined in the laboratory 
manual. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 
9.6. 
Other Exploratory Analyses  
Summary statistics will be provided for pharmacodynamic biomarkers, including but not limited 
to immune cell subtypes in the blood and/or tumor tissue. An exploratory analysis on a potential 
correlation of these pharmacodynamic biomarkers with the dose, safety, and antitumor activity 
will be performed as appropriate. 
Exploratory predictive biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, such as efficacy. 
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9.7. 
Sample Size Consideration  
The study plans to enroll approximately 178 to 358 patients: 
• Phase 1 (dose escalation for BGB-A425 + tislelizumab): Approximately 20 to 42 patients 
• Phase 2 (safety lead-in for Cohort A and Cohort B): Approximately 18 to 36 patients 
• Phase 2 (dose expansion for 3 combinations in 7 cohorts): Approximately 140 to 280 
evaluable patients in 3 prespecified tumor type (HNSCC, NSCLC, and RCC) with a total 
of 7 cohorts (approximately 40 evaluable patients/cohort) and a built-in interim analysis 
of approximately the first 20 evaluable patients per cohort 
For Phase 1, 20 to 42 patients are sufficient to evaluate the safety and tolerability of increasing 
dose levels of BGB-A425 per the 3+3 design rules. 
For Phase 2 safety lead-in, approximately 18 to 36 patients will be enrolled to evaluate the safety 
and tolerability of increasing dose levels of Cohort A and Cohort B per the 3+3 design rules.  
In the Phase 2 dose expansion, 7 cohorts (approximately 40 evaluable patients per cohort) with 
3 combinations in 3 tumor types (HNSCC, NSCLC, and RCC) will be created:  
• Cohort 1: HNSCC - BGB-A425 + Tislelizumab 
• Cohort 2: NSCLC - BGB-A425 + Tislelizumab 
• Cohort 3: RCC - BGB-A425 + Tislelizumab 
• Cohort 4: HNSCC - BGB-A425 + LBL-007 + Tislelizumab 
• Cohort 5: NSCLC - BGB-A425 + LBL-007 + Tislelizumab 
• Cohort 6: HNSCC - LBL-007 + Tislelizumab 
• Cohort 7: NSCLC - LBL-007 + Tislelizumab 
There will be approximately 40 evaluable patients planned per cohort (up to 280 evaluable 
patients in total). For each cohort, the “success” is defined as posterior probability of true ORR 
greater than historical ORR, which is > 0.75; where historical ORRs from representative 
populations for HNSCC, NSCLC, and RCC are 15%, 20%, and 25%, respectively.  
A two-stage design is implemented in which Bayesian predictive probability of success (PPoS) 
based on unconfirmed response rate will be used at the interim analysis after approximately 20 
evaluable patients in a cohort have completed at least 1 tumor assessment. The use of response 
without confirmation requirement is to allow timely evaluation of preliminary efficacy results. If 
the PPoS is > 0. 5 for a given cohort, enrollment of that cohort will continue to approximately 40 
evaluable patients. If the PPoS is < 0.05 for a given cohort, enrollment may stop due to futility. If 
the PPoS is between 0.05 and 0.5, additional efficacy endpoints (eg, PFS, DOR) will be 
evaluated. The final decision to stop enrollment or terminate the cohorts early will be based on 
the totality of available data, such as additional efficacy endpoints, all available safety 
information, biomarker data, and internal and external emergent data..  
Given the criteria described above, HNSCC patients will be populated based on whether ≥ 4 
responders are observed in the first 20 evaluable patients of each cohort, enrollment will be 
allowed to proceed to approximately 40 evaluable patients, or if ≤ 1 responder out of the first 20 
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evaluable patients are observed, enrollment will be stopped. Similarly, in NSCLC patients, if 
≥ 5 responders are observed in the first 20 evaluable patients of each cohort, enrollment will be 
allowed to proceed to approximately 40 evaluable patients, if ≤ 2 responders out of the first 
20 evaluable patients are observed, enrollment will be stopped. Finally, in RCC patients (planned 
to be initiated only after Cohorts 1 and 2 being evaluated in interim analysis), if ≥ 7 responders 
are observed in the first 20 evaluable patients of each cohort, enrollment will be allowed to 
proceed to approximately 40 evaluable patients; if ≤ 4 responders out of the first 20 evaluable 
patients are observed, enrollment will be stopped.  
As noted earlier, interim analysis results that fall in-between the 2 thresholds may lead to further 
evaluation of additional efficacy endpoints (eg, PFS, DOR) for a GO/or NO-GO decision. If 
additional time is required to obtain sufficient data points for the interim analysis, enrollment 
may continue to approximately 25 to 30 evaluable patients for a respective cohort in order to 
accumulate sufficient data points without negatively impacting potential future enrollment of 
additional patients.  
Because the treatment landscape is rapidly evolving, the most current standard of care for a 
representative line of therapy, and patient population for which sufficient historical data is 
available, will be used in the calculation of predictive probability. As such, the analysis 
thresholds for additional enrollment may be modified accordingly. 
9.8. 
Interim Analyses  
Refer to Section 9.7 for Phase 2 interim analyses. 
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10. 
STUDY COMMITTEES  
10.1. 
Safety Monitoring Committee  
An SMC will be established to review the safety and efficacy data for this study. The SMC will 
be composed of representatives from the sponsor, including the medical monitor as the SMC 
lead, product safety physician, biostatistician, and other members as appropriate, and 
investigators from enrolling sites for the cohort(s) under discussion. The SMC will review all 
available safety, efficacy, PK, and exploratory data. 
The SMC may also be called upon by the sponsor on an ad hoc basis where applicable to the 
conduct of the study. 
For Phase 1 dose escalation, an SMC meeting will be held after completion of the DLT period of 
the last patient enrolled in each dosing cohort. The SMC will review all available safety data to 
evaluate a dosing decision (ie, dose escalation, dose de-escalation, and cohort expansion or 
suspension), in line with the 3 + 3 design rules as outlined in Section 3.1. Safety data from prior 
cohorts may also be presented. The decision to escalate the dose and the determination of the 
MTD/MAD will be based on the cohort safety reviews. The SMC will decide on the DLTs 
relevant for the treatment and will decide by consensus on dose escalation, dose de-escalation, or 
suspension of enrollment based on safety and/or PK data.  
Before moving to the next dose level, the SMC will review all safety data available to determine 
whether recruitment to the next cohort should be initiated. The SMC will determine when no 
further dose escalation is appropriate. The SMC will meet for cohort safety reviews after all 
patients in a dosing cohort have completed the first treatment cycle and after completing the 
DLT period . All available safety data will also be provided for patients who discontinue prior to 
this time. Safety data from prior cohorts may also be presented. The decision to escalate dose and 
the determination of the MTD/MAD will be based on the cohort safety reviews. The SMC will 
decide on DLTs relevant for the treatment and will decide by consensus on dose escalation, dose 
de-escalation, or suspension of enrollment based on safety and/or on PK data. Additionally, the 
SMC will review any protocol deviations that may have impacted evaluation of potential DLT.  
All voting members of the SMC will determine the key recommendations, including dose 
escalation, dose modification, and dose selection for Phase 1 dose escalation cohorts. Final 
recommendations will be made by consensus voting. Response from all SMC members, or their 
designees, shall be required for each escalation/review. Adequate time for review of results will 
be given to SMC members (approximately 1 to 2 business days). Enrollment in subsequent dose 
levels will be put “on hold” during each review period, pending the decision of the SMC. 
The SMC decision points may fall into one of the categories detailed below: 
• 
Escalate to a higher dose 
• 
Recruit additional patients into existing dose level 
• 
Explore any other dose levels; an intermediate, not predefined, previously evaluated, or 
not previously evaluated dose level below MTD/MAD 
• 
Stop escalation and investigate lower dose(s) 
Decisions will be made using the criteria defined within the protocol (see Section 3.5). The 
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SMC will make recommendations on dose escalation, dose modification, and dose selection for 
Phase 1 and Phase 2 safety lead-in. 
For Phase 2 dose expansion, routine offline safety reviews will be conducted on a quarterly basis 
(or less frequently) depending on the recruitment rate or the number of active patients on 
treatment. The clinical data summary will be circulated to all SMC members. 
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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 Conference on Harmonisation Good Clinical Practice 
guidelines, the study monitor must have direct access to the investigator’s source documentation 
in order to verify the data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The frequency of the monitoring visits should align with the 
expectations as outlined by the sponsor during the site initiation visit. 
 The investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
the sponsor may conduct a quality assurance audit. Regulatory agencies may also conduct a 
regulatory inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution agree to 
allow the auditor/inspector direct access to all relevant documents and to allocate his/her time 
and the time of his/her personnel to the auditor/inspector to discuss findings and any relevant 
issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes 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 
and quantities dispensed to patients, including lot number, date dispensed, patient identifier 
number, patient initials, if allowed, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements. At the end of the 
study, following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet 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. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted in full conformance with the International Conference on 
Harmonisation E6 guideline for Good Clinical Practice and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will also comply with the requirements 
of the International Conference on Harmonisation E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted to the IRB/IEC by the principal investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IRB/IEC. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
Investigational New Drug Safety Reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming their willingness to remain in the trial. 
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13.3. 
Informed Consent  
The sponsor’s sample Prescreening and Screening ICFs will be provided to each site. If 
applicable, they 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. 
The ICFs must be signed and dated by the patient or the patient’s legal representative (only 
outside Europe, when permitted by local laws) before his or her participation in the study. 
Moreover, any applicable supplementary ICFs will be provided for patients to sign and date 
when applicable. 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 Screening ICFs (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/IEC 
policy) during their participation in the study. Reconsenting of the Prescreening ICF is not 
required for any patients. For any updated or revised Screening 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 Screening ICFs for continued participation in the 
study. 
A copy of each signed ICF must be provided to the patient or the patient’s legal representative 
(only outside Europe, when permitted by local laws). All signed and dated ICFs must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
13.4. 
Patient and Data Confidentiality  
The investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The principal investigator and site shall code the personal and medical information obtained 
during the study with a unique patient identification number assigned to each patient enrolled in 
the study. The investigator must ensure that patients’ anonymity will be strictly maintained and 
that their identities are protected from unauthorized parties. Unless required to be provided by 
laws or regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the principal investigator and site must ensure that any personal and medical 
information transmitted to the sponsor or its service providers is: 1) required by the protocol, and 
2) appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
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• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law.  
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the principal 
investigator and site may provide certain of this personal or medical information to the sponsor 
or its representatives. Such personal or medical information may not be provided as part of the 
protocol (eg, as part of the eCRF, or on samples or reports submitted to the central lab). 
Investigator and site personnel must use only the specific forms and clinical trial systems, (eg, 
the electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) 
designated by the sponsor for sharing and transferal of personal and medical information. 
In the event of a breach of the confidentiality of a patient’s personal or medical information, the 
principal investigator, site personnel, and sponsor, as appropriate, shall fulfill all mediation steps 
and reporting obligations under applicable laws. If the sponsor identifies personal or medical 
information that was not properly de-identified, it may be required to report the disclosure under 
local applicable laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of the United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (China NMPA), the European Medicines Agency 
(EMA), and all other national and local health authorities; by sponsor monitors, representatives, 
and collaborators; and by the IRBs/IECs for each study site, as appropriate.  
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
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law) without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
13.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information, 
in accordance with regulations to allow the sponsor to submit complete disclosure or certification 
to the absence of certain financial interest of 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 an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The investigator or designee as identified on Form FDA 1572 
must sign the completed casebooks to attest to their 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, maintain confidentiality, and to avoid 
unauthorized access, disclosure, dissemination, alteration or loss of information and personal 
data processed. Data will be reviewed for outliers, logic, data inconsistencies and completeness. 
During the course of the study, a study monitor (clinical research associate) will make site visits 
to review protocol compliance, compare eCRFs against individual patient’s medical records and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs 
for completeness, clarity and cross checking with source documents is required to monitor the 
progress of the study. Direct access to source data is also required for inspections and audits, and 
will be carried out giving due consideration to data protection and medical confidentiality. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary. 
Concomitant diseases/medical history will be coded using the Medical Dictionary for Regulatory 
Activities. 
14.2. 
Data Integrity and In-house Blinding  
Because of the open-label design of the study, access to the unblinded patient level clinical data 
in the 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 from 
the EDC system with other functions/persons who do not have access to the EDC. If relevant, the 
central imaging vendor will perform the central imaging review without knowledge of treatment 
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assignment. Although the trial is open-label, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 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, 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) 
documents such as the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, X-ray, pathology 
and special assessment reports, consultant letters, screening and enrollment log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility or transfer of ownership of 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 International Conference on 
Harmonisation 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. As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors or 
stricter local criteria (International Committee of Medical Journal Editors 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission or presentation in 
accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The process of 
reviewing manuscripts and presentations that are based on the data from this study is detailed in 
the investigator’s clinical study agreement. Each investigator agrees that, in accordance with the 
terms of the clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings in advance of the publication/presentation. 
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14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• 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 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 for safety reasons, and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action. If 
required by applicable regulations, the investigator must inform the IEC/IRB promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must 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. 
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. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) 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 without the prior 
written consent of the sponsor. 
These restrictions do not apply to: 
• Information which becomes publicly available through no fault of the investigator or 
study center personnel 
• 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 provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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15. 
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16. 
 APPENDICES  
APPENDIX 1. SCHEDULE OF ASSESSMENTS  
APPENDIX 1A. PHASE 1 SCHEDULE OF ASSESSMENTS  
Phase 1 Assessment Screening1 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Cycle 1 
(28 Days) 
Cycle 2  
(21 Days) 
≥ Cycle 3 
(Every 21 
Days) 
EOT  
Visit2 
Visit Day  
-28 to -1 
1 
8  
15  
21 
1 
8  
15  
1  
0 to 7 Days +30 days  
+60 
Days  
+90 
Days  
Visit Window 
 
 
+ 2 
± 2 
± 2 
 
± 2 
± 2 
± 3 
 
± 7 
± 14 
± 14 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
medical history/ 
prior medications5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/ 
height and weight6 
x 
x6 
x6 
x 
x 
x6 
x 
x 
x6 
x 
x 
 
 
 
Physical 
examination7 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ECOG Performance 
Status 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
 
 
 
12-lead triplicate 
ECG8 
x 
Predose and 6 hours post study drug(s) infusion on Day 1 of Cycle 
1 and 5 
x 
x 
 
 
 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual 
acuity tests9 
x 
 
 
 
 
 
 
 
C4 then 
every 
15 wks 
(± 7 days)  
x10 
x10 
 
 
 
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Phase 1 Assessment Screening1 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Cycle 1 
(28 Days) 
Cycle 2  
(21 Days) 
≥ Cycle 3 
(Every 21 
Days) 
EOT  
Visit2 
Visit Day  
-28 to -1 
1 
8  
15  
21 
1 
8  
15  
1  
0 to 7 Days +30 days  
+60 
Days  
+90 
Days  
Visit Window 
 
 
+ 2 
± 2 
± 2 
 
± 2 
± 2 
± 3 
 
± 7 
± 14 
± 14 
Adverse events11 
x 
x 
x 
x12 
x12 
x 
x12 
x12 
x 
x 
x 
x 
x 
 
Concomitant 
medications/ 
procedures 
x 
x 
x 
x12 
x12 
x 
x12 
x12 
x 
x 
x 
x 
x 
 
Hematology13 
x13 
x13 
x13 
x 
x 
x13 
x 
x 
x13 
x2 
x 
 
 
 
Serum chemistry13 
x13 
x13 
x13 
x  
x 
x13 
x 
x 
x13 
x2 
x 
 
 
 
Coagulation 
parameters 13, 
x13 
x13 
As clinically indicated13 
x2 
x 
 
 
 
Urinalysis13 
x13 
As clinically indicated 
 
 
 
CK and CK-MB14 
x 
x 
x14 
x 
x 
x14 
x 
x 
x14 
x2 
x 
 
 
 
Pregnancy test15 
x15 
x15 
 
 
 
x15 
 
 
x15 
x 
x 
 
 
 
Thyroid function16 
x16 
 
 
 
 
x16 
 
 
Even # 
Cycles16 
 
x 
 
 
 
HBV/HCV tests17 
x17 
Every 4 cycles starting at C5 in HCC patients with detectable HBV 
DNA at screening or as clinically indicated in all patients17 
x17 
x17 
 
 
 
Pulmonary function 
tests18 
x18 
As clinically indicated  
 
 
 
Blood biomarkers 
x19 
Refer to Biomarker Table, Appendix 1H 
 
 
 
 
PD receptor 
occupancy20 
 
Refer to Biomarker Table, Appendix 1H 
 
 
 
 
Tumor assessment21 
x 
In the first 52 weeks, every 6 weeks. Every 12 weeks thereafter21 
x2 
 
 
 
x 
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Phase 1 Assessment Screening1 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Cycle 1 
(28 Days) 
Cycle 2  
(21 Days) 
≥ Cycle 3 
(Every 21 
Days) 
EOT  
Visit2 
Visit Day  
-28 to -1 
1 
8  
15  
21 
1 
8  
15  
1  
0 to 7 Days +30 days  
+60 
Days  
+90 
Days  
Visit Window 
 
 
+ 2 
± 2 
± 2 
 
± 2 
± 2 
± 3 
 
± 7 
± 14 
± 14 
Archival or fresh 
tumor tissue22 
x 
Refer to Biomarker Table, Appendix 1H 
 
 
 
 
BGB-A425 
administration23 
 
x 
  
 
 
x23 
 
 
x23 
 
 
 
 
 
Tislelizumab 
administration24 
 
 
x24 
 
 
x 
 
 
x 
 
 
 
 
 
Abbreviations: AE, adverse event; CK-MB, creatine kinase-cardiac muscle isoenzyme; C, cycle; CT, computed tomography; D, day; DNA, deoxyribonucleic 
acid; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; FFPE, formalin-fixed paraffin embedded; FT3, free 
triiodothyronine; FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, 
hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICF, informed consent form; imAE, immune-mediated AE; IRB, Institutional Review 
Board; IV, intravenous; MRI, magnetic resonance imaging; 18F-NaF PET, 18F-sodium fluoride position emission tomography; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Events; OCT, optical coherence tomography; PD-1, programmed cell death protein-1; RECIST, Response 
Evaluation Criteria in Solid Tumors; RNA, ribonucleic acid; SAE, serious adverse event; TSH, thyroid stimulating hormone; wks, weeks; v, version. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
1. Written informed consent is required prior to 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 enrollment may be used for screening assessments rather than repeating such tests unless 
otherwise noted (eg, hematology, serum chemistry, etc.). The ICF signature defines the start of the Screening Period. 
2. The EOT Visit is conducted within 7 days from the date the investigator determines that BGB-A425/tislelizumab will no longer be used. If specified 
laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT Visit, tests need not be repeated. Tumor assessment is not 
required at the EOT Visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of either of the study drugs, or before the initiation of a new 
anticancer treatment, whichever occurs first. In addition, telephone contacts and/or clinic visits with patients must be conducted to assess imAEs (serious and 
nonserious), anticancer therapy, and concomitant medications/procedures where appropriate (ie, associated with an imAE etc) 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. The EOT Visit may also be used as the Safety 
Follow-up Visit, provided that it occurred 30 days (± 7 days) after the last study treatment. If the EOT Visit and Safety Follow-up Visit are combined, all 
individual study assessments for both visits will need to be completed. 
4. Efficacy Follow-Up: Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor 
assessments following the original tumor plan (ie, every 6 weeks (± 7 days) during the first 52 weeks and every 12 weeks (± 7 days) thereafter) until the 
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patient experiences disease progression, withdraws consent, dies, or until the study terminates, whichever occurs first. The first tumor assessment will be 
performed 6 weeks (± 7 days) after the first administration of the study drugs. 
5. Includes history of treatment for the primary diagnosis, including prior medication, loco-regional treatment(s), and surgical treatment(s). Information on 
radiographic studies performed prior to study entry may be collected for review by the investigator. 
6. Height assessment is required only at screening. Vital signs collected on study include temperature, pulse rate, respiratory rate, and blood pressure. In the 
first cycle, vital signs will be collected at the following 3 timepoints: 1) within 60 minutes before infusion of each drug; 2) during infusion; 3) within 
30 minutes after the infusion of the study drugs. In the subsequent cycles, vital signs will be collected within 60 minutes before infusion of each drug. If 
clinically indicated, 2 additional vital signs will be collected: during infusion and 30 minutes after each infusion. If several timepoints are overlapping, then 
only 1 timepoint is needed. 
7. Refer to Section 7.5.2 for details regarding physical examination assessment requirements for screening and subsequent timepoints. Additionally, 
investigators should solicit patients for information regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit. For 
any change in vision, referral to an appropriate specialist will be made for further management guidance. 
8. The triplicate ECG recordings will be performed at screening; predose and 6 hours post study drug (s) infusions on Day 1 of Cycles 1 and 5; EOT Visit; 
30-day Safety Follow-up Visit, and when clinically indicated. Patients should be resting for at least 10 minutes in a semi-recumbent supine position prior to 
each ECG collection. When coinciding with blood draws, ECG assessment should be performed prior to blood draws. 
9. Eye examination, visual acuity test, and optical coherence tomography (OCT; or equivalent diagnostic test for retinal examination) captured prior to 
obtaining written informed consent but within 28 days of enrollment, may be used rather than repeating tests at screening. Eye examination, visual acuity 
test, and optical coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit, Cycle 4 Day 1 (± 7 days) and every 15 weeks 
(± 7 days) thereafter. 
10. The ophthalmologic assessments including eye examination, visual acuity test, and OCT (or equivalent diagnostic test) should only be performed once at 
either the EOT or during Safety Follow-up, within 30 days of study treatment end. 
11. The AEs and laboratory abnormalities will be graded per NCI-CTCAE version 5.0. All AEs will also be evaluated for seriousness. After the ICF has been 
signed, but prior to the administration of 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 drugs or initiation of new anticancer therapy, whichever occurs first. 
Immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of study drugs, 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 treatments at any time after treatment 
discontinuation. 
12. Review of AEs and concomitant medications/procedures may be conducted by telephone on Cycle 1 Days 15 and 21 and Cycle 2 Days 8 and 15 if patient is 
unable to come to the clinic. 
13. Central laboratory assessments will be conducted for serum chemistry, hematology, and coagulation while urinalysis will be performed locally as outlined in 
Appendix 2. Investigators may use results from local laboratories for assessing eligibility, safety monitoring, and dosing decision(s) but central laboratory 
assessments must still be collected for the timepoints outlined in the table above where applicable. Hematology and serum chemistry (data collected as 
specified in Appendix 2) will be performed weekly for the first 2 Cycles and then at the beginning of each subsequent cycle. After Cycle 1 Day 1, results are 
to be reviewed within 72 hours before study drug administration, where applicable. Urinalysis and/or coagulation lab(s) to be conducted during the treatment 
period only if clinically warranted. Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory 
abnormalities. 
14. CK and CK-MB will be performed by a central laboratory in addition to the local study site laboratory if immediate results are required. The test will be 
evaluated at screening; weekly for the first 2 Cycles, followed by Day 1 of each cycle thereafter; EOT Visit; 30-day Safety Follow-up Visit, and when 
clinically indicated. Except for Cycle 1 Day 1, results are to be reviewed within 72 hours before study drug administration where applicable. If your 
laboratory does not perform CK-MB testing, serum troponins (troponin I and/or T) measurements should be performed instead; if only either troponin is 
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assessed per local standards that same test should be evaluated throughout. If significant abnormalities are detected, please evaluate the affected patients for 
possible myocarditis/myositis per institutional guidelines, including additional serum CK/CK-MB, serum troponin levels, ECG, etc. 
15. Urine pregnancy test (local laboratory) (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 7 days before enrollment. A negative pregnancy test (by urine or blood) must be completed and recorded on the same day 
before the administration of study drug at each cycle. A serum pregnancy test (central laboratory) must be performed if the urine pregnancy test is positive or 
equivocal. 
16. Analysis of FT3, FT4, and TSH will be performed by a central laboratory in addition to the local study site laboratory if immediate results are required. 
Thyroid function tests will be performed at screening and Day 1 every 2 cycles starting at Cycle 2 (ie, Day 1 of Cycles 2, 4, 6, 8 etc.) and 30-day Safety 
Follow-up Visit. Results are to be reviewed within 72 hours before study drug administration where applicable. 
17. Testing will be performed by a central laboratory in addition to the local study site laboratory if immediate results are required at screening and will include 
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load assessment (HBV DNA and HCV RNA). Testing at screening is 
mandatory for patients with HCC. Additionally, for HCC patients who have detectable HBV DNA at screening, the respective viral load test will be 
performed every 4 cycles starting at Cycle 5 (ie, Day 1 of Cycle 5, 9, 13, etc), EOT Visit, and 30-day Safety Follow-up Visit. In patients without HCC, 
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 and as 
clinically indicated. 
18. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the underlying 
cancer will have pulmonary function testing which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
Screening Period to assist the determination of suitability on the study and as clinically indicated while on study. 
19. Blood biomarker: Refer to Appendix 1H. 
20. PD receptor occupancy assay: Refer to Appendix 1H. 
21. Radiological images captured as standard of care prior to obtaining written informed consent and within 28 days of enrollment may be used rather than 
repeating tests. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. An MRI (or CT scan if MRI is 
contraindicated or not readily available) of the head may be required at screening based on clinical judgement; bone scan or 18F-NaF PET is required if 
clinically indicated. The same radiographic procedure must be used throughout the study for each patient. The investigator must review radiograph results 
before dosing at the next cycle. Patients will undergo tumor assessments approximately every 6 weeks (± 7 days) during the first 52 weeks and every 12 
weeks (± 7 days) thereafter (based on RECIST v1.1 assessment). The investigator may perform additional scans or more frequent assessments if clinically 
indicated. Patients who continue BGB-A425/tislelizumab beyond initial radiographic disease progression must have a follow-up scan 4 to 12 weeks from the 
date of initial documentation of disease progression before discontinuing BGB-A425/tislelizumab treatment. See Section 7.6 for more information. 
22. Archival or fresh tumor tissue: Refer to Appendix 1H. 
23. BGB-A425 will be given IV on Cycle 1 Day 1, Cycle 2 Day 1 and once every 21 days thereafter (see Section 5.3 for details). If tislelizumab is delayed 
beyond Cycle 1 Day 8 (+2 days), the dose level of BGB-A425 will be reduced starting on Cycle 2 Day 1 (Section 5.6). Note: BGB-A425 must always be 
prepared and administered separately from any other systemic medication including tislelizumab. When BGB-A425 infusion coincides with tislelizumab, 
BGB-A425 infusion must always occur after infusion of tislelizumab has completed. Refer to Section 5.6 regarding dose delays and/or modifications.  
24. Tislelizumab will be given IV on Cycle 1 Day 8, Cycle 2 Day 1 and once every 21 days thereafter for the remainder of treatment (see Section 5.3 for details). 
If tislelizumab is delayed beyond Cycle 1 Day 8 (+2 days), it will not be administered in Cycle 1 (Section 5.6). Note: Tislelizumab must always be prepared 
and administered separately from any other systemic medication including BGB-A425. When tislelizumab infusion coincides with BGB-A425, BGB-A425 
infusion must always occur after infusion of tislelizumab has completed. Refer to Section 5.6 and Section 7.6 regarding dose delays. 
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APPENDIX 1B.  PHASE 2 SAFETY LEAD-IN SCHEDULE OF ASSESSMENTS  
Phase 2 Safety Lead-In 
Assessment 
Screening1 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-up4 
Cycle 1-2 
(Every 21 Days) 
≥ Cycle 3 
(Every 
21 Days) 
End of 
Treatment  
Visit2 
Visit Day 
-28 to ~ -1 
1* 
8 
15 
1 
0 to 
7 Days 
+30 
Days  
+60 
Days  
+90 
Days  
+120 
Days 15 
Visit Window 
 
 
± 2 
± 2 
± 3 
 
± 7 
± 14 
± 14 
± 14 
Screening informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/prior 
medications5 
x 
 
 
 
 
 
 
 
 
 
 
Height6 
x 
 
 
 
 
 
 
 
 
 
 
Weight and vital signs6 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Physical examination7 
x 
x 
 
 
x 
x 
x 
 
 
 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
x 
x 
 
 
 
 
12-lead triplicate ECG8 
x 
As clinically indicated 
x 
x 
 
 
 
 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual acuity 
tests9 
x 
 
 
 
C4 then every 
15 wks 
(± 7 days) or 
5 cycles from 
C1D1 
x10 
x10 
 
 
 
 
Adverse events11 
x 
x 
x12 
x12 
x 
x 
x 
x 
x 
 
 
Concomitant 
medications/ 
procedures 
x 
x 
x12 
x12 
x 
x 
x 
x 
x 
 
 
Hematology13 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Serum chemistry13 
x 
x 
x  
x  
x 
x 
x 
 
 
 
 
Coagulation 
parameters13 
x 
As clinically indicated 
x 
x 
 
 
 
 
Urinalysis13 
x 
As clinically indicated 
 
 
CK and CK-MB14 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Pregnancy test15 
x 
x 
 
 
x 
x 
x 
 
 
x 
 
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Phase 2 Safety Lead-In 
Assessment 
Screening1 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-up4 
Cycle 1-2 
(Every 21 Days) 
≥ Cycle 3 
(Every 
21 Days) 
End of 
Treatment  
Visit2 
Visit Day 
-28 to ~ -1 
1* 
8 
15 
1 
0 to 
7 Days 
+30 
Days  
+60 
Days  
+90 
Days  
+120 
Days 15 
Visit Window 
 
 
± 2 
± 2 
± 3 
 
± 7 
± 14 
± 14 
± 14 
Thyroid function16 
x 
 
 
 
C3 and every 
3 Cycles 
 
x 
 
 
 
 
Cortisol testing17 
x 
 
 
 
C3 and every 
3 Cycles 
 
x 
 
 
 
 
HBV/HCV tests18 
x 
Every 4 cycles starting at C5 in patients with 
detectable HBV DNA at screening or as clinically 
indicated in all patients 
x 
 
 
 
 
Pulmonary function 
tests19 
x 
As clinically indicated 
 
 
 
 
Blood biomarkers20 
x 
Refer to Biomarker Table, Appendix 1I 
 
 
 
 
Tumor assessment21 
x 
In the first 52 weeks, every 6 weeks. 
Every 12 weeks thereafter20 
x 
 
 
 
 
x 
Archival or fresh tumor 
tissue22 
x 
Refer to Biomarker Table, Appendix 1I 
 
 
 
 
 
BGB-A425 
administration23 
 
x 
 
 
x 
 
 
 
 
 
 
Tislelizumab 
administration24 
 
x 
 
 
x 
 
 
 
 
 
 
LBL-007 
administration25 
 
x 
 
 
x 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE, adverse event; C, cycle; D, day; DNA, deoxyribonucleic acid; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, 
end of treatment; FFPE, formalin-fixed paraffin embedded; FT3, free triiodothyronine; FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAb, hepatitis 
B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ICF, informed consent form; imAE, immune-mediated 
AE; IV, intravenous; MRI, magnetic resonance imaging; 18F-NaF PET, 18F-sodium fluoride position emission tomography; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Events; OCT, optical coherence tomography; PD, pharmacodynamic; PK, pharmacokinetic; RECIST, 
Response Evaluation Criteria in Solid Tumors; RNA, ribonucleic acid; SAE, serious adverse event; TSH, thyroid stimulating hormone; wks, weeks; v, version. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
*If needed, some safety laboratory procedures including chemistry, hematology, coagulation, ECOG, and physical examination for C1D1 and C2D1 can be done 
1-2 days before dosing.  
1. In Phase 2 (safety lead-in), the Screening ICF is required prior to 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 enrollment may be used for Screening assessments rather than 
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repeating such tests unless otherwise noted (eg, hematology, serum chemistry, etc.). The ICF signature defines the start of the Screening Period. Refer to 
Section 7.1 and Section 7.2 for more information on the Prescreening and Screening Visits. 
2. The EOT Visit is conducted when the investigator determines that any of the study drugs (ie, LBL-007, BGB-A425, and tislelizumab) will no longer be 
used. If specified laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT Visit, tests need not be repeated. Tumor 
assessment is not required at the EOT Visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of any of the study drugs (ie, LBL-007, BGB-A425, and 
tislelizumab), or before the initiation of a new anticancer treatment, whichever occurs first. In addition, telephone contacts and/or clinic visits with patients 
must be conducted to assess imAEs (serious and nonserious), anticancer therapy, and concomitant medications/procedures where appropriate (ie, associated 
with an imAE etc) 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. 
The EOT Visit may also be used as the Safety Follow-up Visit, provided that it occurred 30 days (± 7 days) after the last study treatment. If the EOT Visit 
and Safety Follow-up Visit are combined, all individual study assessments for both visits will need to be completed. 
4. Efficacy Follow-Up: Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor 
assessments following the original tumor plan (ie, every 6 weeks [± 7 days] during the first 52 weeks and every 12 weeks [± 7 days] thereafter) until the 
patient experiences disease progression, withdraws consent, dies, or until the study terminates, whichever occurs first. The first tumor assessment will be 
performed 6 weeks (± 7 days) after the first administration of the study drugs. 
5. Includes history of treatment for the primary diagnosis, including prior medication, loco-regional treatment(s), and surgical treatment(s). Information on 
radiographic studies performed prior to study entry may be collected for review by the investigator. 
6. Height assessment is only required for screening. Vital signs collected on study include temperature, pulse rate, respiratory rate, and blood pressure. The 
patient’s vital signs are required to be recorded within 60 minutes before and 30 minutes after the first infusion of study drug(s) (LBL-007). For subsequent 
infusions (tislelizumab or tislelizumab and BGB-A425), vital signs will be collected within 60 minutes before infusion of each study drug and if clinically 
indicated, and 30 minutes after each study drug infusion. If several timepoints are overlapping, then only 1 timepoint is needed. 
7. Refer to Section 7.5.2 for details regarding physical examination assessment requirements for screening and subsequent timepoints. Additionally, 
investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance. 
8. The triplicate ECG recordings will be obtained during screening, the 30-day Safety Follow-up Visit, and as clinically indicated. Assessments that occur on 
the same day as study drug administration should occur approximately 30 minutes after study drug(s) infusion. Patients should be resting for at least 10 
minutes in a semi-recumbent supine position prior to each ECG collection. 
9. Eye examination, visual acuity test, and optical coherence tomography (OCT; or equivalent diagnostic test for retinal examination) captured as standard of 
care prior to obtaining written informed consent and within 28 days of enrollment may be used rather than repeating tests. Eye examination, visual acuity 
test, and optical coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeat assessments 
approximately every 15 weeks or 5 Cycles (± 7 days) thereafter. 
10. The ophthalmologic assessments by an ophthalmologist including eye examination, visual acuity test, and OCT (or equivalent diagnostic test) should only be 
performed once at either the EOT or during the 30-day Safety Follow-up. 
11. The AEs and laboratory abnormalities will be graded per NCI-CTCAE version 5.0. All AEs will also be evaluated for seriousness. After the Prescreening 
ICF has been signed, but prior to the administration of 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 drugs or initiation of new anticancer therapy, whichever 
occurs first. Immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of study drugs, 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 treatments, at any time after 
treatment discontinuation. 
12. Review of AEs and concomitant medications/procedures may be conducted by telephone on Days 8 and 15 if patient is unable to come to the clinic. 
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13. Local laboratory assessments will be conducted for serum chemistry, hematology, coagulation and urinalysis as outlined in Appendix 2. Hematology and 
serum chemistry (data collected as specified in Appendix 2) will be performed at screening, and weekly for Cycle 1 and 2 followed by Day 1 of each 
subsequent cycle, EOT Visit, 30-day Safety Follow-up Visit, and when clinically indicated. After Cycle 1 Day 1, results are to be reviewed within 72 hours 
before study drug administration, where applicable. Coagulation assessment is required at screening, EOT Visit, and 30-day Safety Follow-up Visit as well 
as during the treatment period but only if clinically warranted. Urinalysis assessment is required at screening only and otherwise performed when clinically 
warranted. Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. If screening 
safety laboratory tests including chemistry, hematology, and coagulation are completed within 7 days prior to C1D1, then no additional blood will be 
collected for safety laboratory tests. 
14. CK and CK-MB testing will be performed locally. The test will be evaluated at screening; weekly for the first 2 Cycles, followed by Day 1 of each cycle 
thereafter; EOT Visit; 30-day Safety Follow-up Visit, and when clinically indicated. Except for Cycle 1 Day 1, results are to be reviewed within 72 hours 
before study drug administration where applicable. If your laboratory does not perform CK-MB testing, serum troponins (troponin I and/or T) measurements 
should be performed instead; if only either troponin is assessed per local standards that same test should be evaluated throughout. If significant abnormalities 
are detected, please evaluate the affected patients for possible myocarditis/myositis per institutional guidelines, including additional serum CK/CK-MB, 
serum troponin levels, ECG, etc. 
15. Urine pregnancy test (local laboratory) (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 enrollment. A negative pregnancy test (by urine or blood) must be completed and recorded on the same day 
before the administration of study drug at each cycle. An additional pregnancy test must be performed for women of childbearing potential at approximately 
120 days after the last dose of study treatment. A serum pregnancy test (local laboratory) must be performed if the urine pregnancy test is positive or 
equivocal.  
16. Analysis of FT3, FT4, and TSH will be performed locally. Thyroid function tests will be performed at screening and every 3 cycles (ie, Day 1 of Cycles 3, 6, 
9, etc.), and at the Safety Follow-up Visit. Results are to be reviewed within 72 hours before study drug administration, where applicable. 
17. Cortisol blood test will be performed at screening and every 3 cycles (ie, Day 1 of Cycles 3, 6, 9, etc), and at the Safety Follow-up Visit according to local 
guidelines. 
18. HBV/HCV testing will be performed locally at screening and the 30-day Safety Follow-up Visit (only if positive at screening) and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody). In case of positive HBsAg or positive HCV antibody 
results, these tests will be followed by viral load assessment (HBV DNA and HCV RNA). Viral load assessment (HBV DNA and HCV RNA) may be 
performed at the same time as HBV/HCV serology at investigator’s discretion in line with the clinical history of the patient. Patients who have detectable 
HBV DNA at screening but remain eligible for enrollment will have their respective viral load tested every 4 cycles. Testing should also be performed as 
needed for any patient during treatment where clinically indicated. 
19. Patients who are suspected or known to have serious/severe respiratory conditions, exhibit significant respiratory symptoms unrelated to the underlying 
cancer, or patients with NSCLC enrolled in Phase 2 will have pulmonary function testing which may include, but is not limited to, spirometry and 
assessment of diffusion capacity done during the Screening Period to assist the determination of suitability on the study. Pulmonary function testing may 
also be required during treatment if clinically indicated. 
20. Blood biomarkers: Refer to Appendix 11. 
21. Radiological images captured as standard of care prior to obtaining written informed consent and within 56 days of enrollment may be used rather than 
repeating tests. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. The required radiographic procedure 
for Phase 2 (safety lead-in and dose expansion) during the screening and the treatment is detailed in Section 7.6. The investigator must review radiograph 
results before dosing at the next cycle. Patients will undergo tumor assessments approximately every 6 weeks (± 7 days) from the first administration of the 
study drugs during the first 52 weeks and every 12 weeks (± 7 days) thereafter. The investigator may perform additional scans or more frequent assessments 
if clinically indicated. Tumor response will be assessed per RECIST v1.1. Patients who continue the combination treatment as assigned beyond initial 
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radiographic disease progression per RECIST v1.1 must have a follow-up scan 4 to 12 weeks from the date of initial documentation of disease progression 
before discontinuing the assigned treatment (Section 7.6). 
22. Archival or fresh tumor tissue: Refer to Appendix 1I. 
23. BGB-A425 will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohort B. Note: BGB-A425 must always 
be prepared and administered separately from any other systemic medication including tislelizumab and LBL-007. When BGB-A425 infusion coincides with 
tislelizumab, BGB-A425 infusion must always occur after infusion of tislelizumab has completed. When BGB-A425 infusion coincides with LBL-007, 
BGB-A425 infusion must always occur after infusion of LBL-007 has completed. 
24. Tislelizumab will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohort A and Cohort B. Note: 
Tislelizumab must always be prepared and administered separately from any other systemic medication including BGB-A425 and LBL-007. When 
tislelizumab infusion coincides with BGB-A425, BGB-A425 infusion must always occur after infusion of tislelizumab has completed. When tislelizumab 
infusion coincides with LBL-007, tislelizumab infusion must always occur after infusion of LBL-007 has completed. 
25. LBL-007 will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohort A and Cohort B. Note: LBL-007 must 
always be prepared and administered separately from any other systemic medication including BGB-A425 and tislelizumab. When LBL-007 infusion 
coincides with BGB-A425, BGB-A425 infusion must always occur after infusion of LBL-007 has completed. When LBL-007 infusion coincides with 
tislelizumab, tislelizumab infusion must always occur after infusion of LBL-007 has completed. 
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APPENDIX 1C. PHASE 2 DOSE EXPANSION SCHEDULE OF ASSESSMENTS  
Phase 2 Dose 
Expansion 
Assessment 
Prescreening1 Screening1 
 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Survival 
Follow-
up27 
Cycle 1 
(Every 
21 Days) 
Cycle
 2 
≥ Cycle 3 
(Every 
21 Days) 
End of 
Treatment  
Visit2 
Visit Day 
-56 to ~ -28 
-28 to ~ -1 
1* 
8 
15 
1 
1 
0 to 7 
Days 
+30 
Days  
+60 
Days  
+90 
Days  
+120 
Days 15 
Visit Window 
 
 
 
± 2 
± 2 
± 3 
± 3 
 
± 7 
± 14 
± 14 
± 14 
Prescreening 
informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
informed consent 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
medical history/ 
prior 
medications5 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Height6 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and vital 
signs6 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Physical 
examination7 
 
x 
x 
 
 
x 
x 
x 
x 
 
 
 
 
 
ECOG 
Performance 
Status 
 
x 
x 
 
 
x 
x 
x 
x 
 
 
 
 
 
12-lead triplicate 
ECG8 
 
x 
As clinically indicated 
 
x 
 
 
 
 
 
Optical coherence 
tomography (or 
equivalent 
diagnostic test) 
and visual acuity 
tests9 
 
x 
 
 
 
 
C4 then 
every 
15 weeks 
(± 7 days) 
or 
5 cycles 
from 
C1D1 
x10 
x10 
 
 
 
 
 
Adverse events11 
x 
x 
x 
x12 
x12 
x 
x 
x 
x 
x 
x 
 
 
 
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Phase 2 Dose 
Expansion 
Assessment 
Prescreening1 Screening1 
 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Survival 
Follow-
up27 
Cycle 1 
(Every 
21 Days) 
Cycle
 2 
≥ Cycle 3 
(Every 
21 Days) 
End of 
Treatment  
Visit2 
Visit Day 
-56 to ~ -28 
-28 to ~ -1 
1* 
8 
15 
1 
1 
0 to 7 
Days 
+30 
Days  
+60 
Days  
+90 
Days  
+120 
Days 15 
Visit Window 
 
 
 
± 2 
± 2 
± 3 
± 3 
 
± 7 
± 14 
± 14 
± 14 
Concomitant 
medications/ 
procedures 
 
x 
x 
x12 
x12 
x 
x 
x 
x 
x 
x 
 
 
 
Hematology13 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Serum 
chemistry13 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Coagulation 
parameters13 
 
x 
As clinically indicated 
x 
x 
 
 
 
 
 
Urinalysis13 
 
x 
 
As clinically indicated 
 
 
 
CK and CK-MB14 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Pregnancy test15 
 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Thyroid 
function16 
 
x 
 
 
 
 
C3 and 
every 
3 cycles 
 
x 
 
 
 
 
 
Cortisol testing 17 
 
x 
 
 
 
 
C3 and 
every 
3 cycles 
 
x 
 
 
 
 
 
HBV/HCV tests18 
 
x 
 
Every 4 cycles starting at C5 in 
patients with detectable HBV 
DNA at screening or as 
clinically indicated in all 
patients 
x 
 
 
 
 
 
Pulmonary 
function tests19 
 
x 
As clinically indicated 
 
 
 
 
 
Blood 
biomarkers20 
 
x 
 
Refer to Biomarker Table, Appendix 1J 
 
 
 
 
 
Tumor 
assessment21 
 
x 
 
In the first 
52 weeks, every 
6 weeks. Every 
12 weeks 
thereafter20 
x 
 
 
 
 
x 
 
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Phase 2 Dose 
Expansion 
Assessment 
Prescreening1 Screening1 
 
Treatment Cycles 
Safety Follow-up3 
Efficacy 
Follow-
up4 
Survival 
Follow-
up27 
Cycle 1 
(Every 
21 Days) 
Cycle
 2 
≥ Cycle 3 
(Every 
21 Days) 
End of 
Treatment  
Visit2 
Visit Day 
-56 to ~ -28 
-28 to ~ -1 
1* 
8 
15 
1 
1 
0 to 7 
Days 
+30 
Days  
+60 
Days  
+90 
Days  
+120 
Days 15 
Visit Window 
 
 
 
± 2 
± 2 
± 3 
± 3 
 
± 7 
± 14 
± 14 
± 14 
Archival or fresh 
tumor tissue22 
x 
x 
 
 
Refer to Biomarker 
Table, Appendix 1J 
 
 
 
 
 
 
PD-L1 test23 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
BGB-A425 
administration24 
 
 
x 
 
 
x 
x 
 
 
 
 
 
 
 
Tislelizumab 
administration25 
 
 
x 
 
 
x 
x 
 
 
 
 
 
 
 
LBL-007 
administration26 
 
 
x 
 
 
x 
x 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: AE, adverse event; C, cycle; D, day; DNA, deoxyribonucleic acid; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, 
end of treatment; FFPE, formalin-fixed paraffin embedded; FT3, free triiodothyronine; FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAb, hepatitis 
B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ICF, informed consent form; imAE, immune-mediated 
AE; IV, intravenous; MRI, magnetic resonance imaging; 18F-NaF PET, 18F-sodium fluoride position emission tomography; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Events; OCT, optical coherence tomography; PD, pharmacodynamic; PD-1, programmed cell death 
protein-1; PD-L1, programmed cell death protein-ligand 1; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; RNA, ribonucleic 
acid; SAE, serious adverse event; TSH, thyroid stimulating hormone; wks, weeks; v, version. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
*If needed, some safety laboratory procedures including chemistry, hematology, coagulation, ECOG, and physical examination for C1D1 and C2D1 can be done 
1-2 days before dosing.  
1. 
In Phase 2 (dose expansion only), the Prescreening Period is 56 days before the first dose of study drug(s). A longer Prescreening Period may be granted on 
a case-by-case basis following discussion and written approval from the sponsor. The purpose of the Prescreening Period is to allow time for confirmation 
of the PD-L1 test for HNSCC and NSCLC patients only. A Prescreening ICF is required for HNSCC and NSCLC patients in Phase 2 (dose expansion only). 
RCC patients are not required to sign a Prescreening ICF. Patients with HNSCC and NSCLC who sign the Prescreening ICF and are confirmed PD-L1 
positive may be allowed into the Screening Period. All RCC patients are allowed into screening.  
The Screening ICF is then required prior to 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 enrollment may be used for Prescreening or Screening assessments rather than repeating 
such tests unless otherwise noted (eg, hematology, serum chemistry, etc.). The ICF signature defines the start of the Prescreening and Screening Period. 
Refer to Section 7.1 and Section 7.2 for more information on the Prescreening and Screening Visits. 
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2. 
The EOT Visit is conducted when the investigator determines that any of the study drugs (ie, LBL-007, BGB-A425, and tislelizumab) will no longer be 
used. If specified laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT Visit, tests need not be repeated. Tumor 
assessment is not required at the EOT Visit provided that fewer than 6 weeks have passed since the last assessment. 
3. 
The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of any of the study drugs (ie, LBL-007, BGB-A425, and 
tislelizumab), or before the initiation of a new anticancer treatment, whichever occurs first. In addition, telephone contacts and/or clinic visits with patients 
must be conducted to assess imAEs (serious and nonserious), anticancer therapy, and concomitant medications/procedures where appropriate (ie, associated 
with an imAE etc) 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. 
The EOT Visit may also be used as the Safety Follow-up Visit, provided that it occurred 30 days (± 7 days) after the last study treatment. If the EOT Visit 
and Safety Follow-up Visit are combined, all individual study assessments for both visits will need to be completed. 
4. 
Efficacy Follow-Up: Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor 
assessments following the original tumor plan (ie, every 6 weeks (± 7 days) during the first 52 weeks and every 12 weeks (± 7 days) thereafter) until the 
patient experiences disease progression, withdraws consent, dies, or until the study terminates, whichever occurs first. The first tumor assessment will be 
performed 6 weeks (± 7 days) after the first administration of the study drugs. 
5. 
Includes history of treatment for the primary diagnosis, including prior medication, loco-regional treatment(s), and surgical treatment(s). Information on 
radiographic studies performed prior to study entry may be collected for review by the investigator. 
6. 
Height assessment is only required for screening. Vital signs collected on study include temperature, pulse rate, respiratory rate, and blood pressure. For 
Cohorts 1 to 3, the patient’s vital signs are required to be recorded within 60 minutes before and 30 minutes after the first infusion of study drug(s) 
(tislelizumab). For subsequent infusions of BGB-A425, vital signs will be collected within 60 minutes before infusion of each study drug and if clinically 
indicated, and 30 minutes after each study drug infusion. For Cohorts 4-7, the patient’s vital signs are required to be recorded within 60 minutes before and 
30 minutes after the first infusion of study drug(s) (LBL-007). For subsequent infusions (tislelizumab or tislelizumab and BGB-A425), vital signs will be 
collected within 60 minutes before infusion of each study drug and if clinically indicated, and 30 minutes after each study drug infusion. If several 
timepoints are overlapping, then only 1 timepoint is needed. 
7. 
Refer to Section 7.5.2 for details regarding physical examination assessment requirements for screening and subsequent timepoints. Additionally, 
investigators should solicit patients for information regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit. 
For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
8. 
The triplicate ECG recordings will be obtained during screening, the 30-day Safety Follow-up Visit, and as clinically indicated. Assessments that occur on 
the same day as study drug administration should occur approximately 30 minutes following study drug(s) infusion. Patients should be resting for at least 
10 minutes in a semirecumbent supine position prior to each ECG collection. 
9. 
Eye examination, visual acuity test, and optical coherence tomography (OCT; or equivalent diagnostic test for retinal examination) captured as standard of 
care prior to obtaining written informed consent and within 28 days of enrollment may be used rather than repeating tests. Eye examination, visual acuity 
test, and optical coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeat assessments 
approximately every 15 weeks or 5 Cycles (± 7 days) thereafter. 
10. The ophthalmologic assessments by an ophthalmologist including eye examination, visual acuity test, and OCT (or equivalent diagnostic test) should only 
be performed once at either the EOT or during the 30-day Safety Follow-up. 
11. The AEs and laboratory abnormalities will be graded per NCI-CTCAE Version 5.0. All AEs will also be evaluated for seriousness. After the Prescreening 
ICF has been signed, but prior to the administration of 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 drugs or initiation of new anticancer therapy, whichever 
occurs first. Immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of study drugs, 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 treatments, at any time after 
treatment discontinuation. 
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12. Review of AEs and concomitant medications/procedures may be conducted by telephone on Days 8 and 15 if patient is unable to make it to the clinic. 
13. Local laboratory assessments will be conducted for serum chemistry, hematology, coagulation and urinalysis as outlined in Appendix 2. Hematology and 
serum chemistry (data collected as specified in Appendix 2) will be performed at screening, and weekly for Cycle 1 and 2 followed by Day 1 of each 
subsequent cycle, EOT Visit, 30-day Safety Follow-up Visit, and when clinically indicated. After Cycle 1 Day 1, results are to be reviewed within 72 hours 
before study drug administration, where applicable. Coagulation assessment is required at screening, EOT Visit, and 30-day Safety Follow-up Visit as well 
as during the treatment period but only if clinically warranted. Urinalysis assessment required at screening only and otherwise performed when clinically 
warranted. Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. If screening 
safety laboratory tests including chemistry, hematology, and coagulation are completed within 7 days prior to C1D1, then no additional blood will be 
collected for safety laboratory tests. 
14. CK and CK-MB will be performed locally. The test will be evaluated at screening; weekly for the first 2 Cycles, followed by Day 1 of each cycle thereafter; 
EOT Visit; 30-day Safety Follow-up Visit, and when clinically indicated. Except for Cycle 1 Day 1, results are to be reviewed within 72 hours before study 
drug administration where applicable. If your laboratory does not perform CK-MB testing, serum troponins (troponin I and/or T) measurements should be 
performed instead; if only either troponin is assessed per local standards that same test should be evaluated throughout. If significant abnormalities are 
detected, please evaluate the affected patients for possible myocarditis/myositis per institutional guidelines, including additional serum CK/CK-MB, serum 
troponin levels, ECG, etc. 
15. Urine pregnancy test (local laboratory) (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 enrollment. A negative pregnancy test (by urine or blood) must be completed and recorded on the same day 
before the administration of study drug at each cycle. An additional pregnancy test must be performed for women of childbearing potential at approximately 
120 days after the last dose of study treatment. A serum pregnancy test (local laboratory) must be performed if the urine pregnancy test is positive or 
equivocal.  
16. Analysis of FT3, FT4, and TSH will be performed locally. Thyroid function tests will be performed at screening and every 3 cycles (ie, Day 1 of Cycles 3, 
6, 9, etc), and at the Safety Follow-up Visit. Results are to be reviewed within 72 hours before study drug administration, where applicable. 
17. Cortisol blood test will be performed at screening and every 3 cycles (ie, Day 1 of Cycles 3, 6, 9, etc), and at the Safety Follow-up Visit according to local 
guidelines. 
18. HBV/HCV testing will be performed locally at screening and the 30-day Safety Follow-up Visit (only if positive at screening) and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody). In case of positive HBsAg or positive HCV antibody 
results, these tests will be followed by viral load assessment (HBV DNA and HCV RNA). Viral load assessment (HBV DNA and HCV RNA) may be 
performed at the same time as HBV/HCV serology at investigator’s discretion in line with the clinical history of the patient. Patients who have detectable 
HBV DNA at screening but remain eligible for enrollment will have their respective viral load tested every 4 cycles. Testing should also be performed as 
needed for any patient during treatment where clinically indicated.  
19. Patients who are suspected or known to have serious/severe respiratory conditions, exhibit significant respiratory symptoms unrelated to the underlying 
cancer, or patients with NSCLC enrolled in Phase 2 will have pulmonary function testing which may include, but is not limited to, spirometry and 
assessment of diffusion capacity done during the Screening Period to assist the determination of suitability on the study. Pulmonary function testing may 
also be required during treatment if clinically indicated.  
20. Blood biomarkers: Refer to  Appendix 1J. 
21. Radiological images captured as standard of care prior to obtaining written informed consent and within 56 days of enrollment may be used rather than 
repeating tests. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. The required radiographic 
procedure for Phase 2 (safety lead-in and dose expansion) during the screening and the treatment is detailed in Section 7.6. The investigator must review 
radiograph results before dosing at the next cycle, and provide measurements and response assessment based on RECIST v1.1 criteria, before the next 
cycle. Patients will undergo tumor assessments approximately every 6 weeks (± 7 days) from the first administration of the study drugs during the first 
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52 weeks and every 12 weeks (± 7 days) thereafter (the date of each further scan is based on the actual date of the last scan). The investigator may perform 
additional scans or more frequent assessments if clinically indicated. Tumor response will be assessed per RECIST v1.1. Patients who continue the 
combination treatment as assigned beyond initial radiographic disease progression per RECIST v1.1 must have a follow-up scan 4 to 12 weeks from the 
date of initial documentation of disease progression before discontinuing the assigned treatment. For patients with confirmed PD, they can continue the 
treatment as assigned, under the conditions outlined in Section 7.6.  
22. Archival or fresh tumor tissue: Refer to Appendix 1J. 
23. During the prescreening period, HNSCC and NSCLC patients will undergo PD-L1 positivity confirmation with either central analysis or local documented 
results. If a central analysis is used, PD-L1 CPS ≥ 1 or TPS ≥ 1% by IHC 22C3 pharmDx assay is acceptable for HNSCC and NSCLC patients, 
respectively. If local testing is used, PD-L1 (CPS ≥ 1) by IHC 22C3 pharmDx assay (preferred) or PD-L1 (CPS ≥ 1, vCPS or TAP ≥ 1%) by VENTANA 
PD-L1 (SP263) are acceptable for HNSCC patients (Note: PD-L1 positivity determined by PD-L1 IHC 22C3 pharmDx assay will be used for HNSCC 
patients in the EU); PD-L1 (TPS or TC ≥ 1%) by IHC 22C3 or 28-8 pharmDx or VENTANA PD-L1 (SP263) assay are acceptable for NSCLC patients 
(Note: If PD-L1 IHC 28-8 assay is to be used for determining PD-L1 positivity, it will be used for nonsquamous NSCLC patients only in the EU). This 
requires tissue samples obtained recently within 2 years. For patients who have known PD-L1 positivity, a historically documented result is acceptable for 
PD-L1 positivity confirmation by specified PD-L1 assay at the prescreening phase. Tissue obtained within 2 years or fresh biopsy is required prior to the 
patient commencing first drug administration on C1D1. It is highly recommended to provide the same tissue that was tested for the local PD-L1 assay. If a 
patient has more than 1 archival tumor tissue, the most recent one is preferred. Positivity confirmation of the PD-L1 test must be obtained before HNSCC 
and NSCLC patients are allowed to continue to screening. The PD-L1 test is not required for RCC patients as part of prescreening or screening. The PD-L1 
status of all cohorts will also be retrospectively evaluated by VENTANA PD-L1 (SP263) assay. 
24. BGB-A425 will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohorts 1 to 5. Note: BGB-A425 must 
always be prepared and administered separately from any other systemic medication including tislelizumab and LBL-007. When BGB-A425 infusion 
coincides with tislelizumab, BGB-A425 infusion must always occur after infusion of tislelizumab has completed. When BGB-A425 infusion coincides with 
LBL-007, BGB-A425 infusion must always occur after infusion of LBL-007 has completed. 
25. Tislelizumab will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohorts 1 to 7. Note: Tislelizumab must 
always be prepared and administered separately from any other systemic medication including BGB-A425 and LBL-007. When tislelizumab infusion 
coincides with BGB-A425, BGB-A425 infusion must always occur after infusion of tislelizumab has completed. When tislelizumab infusion coincides with 
LBL-007, tislelizumab infusion must always occur after infusion of LBL-007 has completed. 
26. LBL-007 will be infused IV on Cycle 1 Day 1 and once every 21 days thereafter (see Section 5.3 for details) in Cohorts 4 to 7. Note: LBL-007 must always 
be prepared and administered separately from any other systemic medication including BGB-A425 and tislelizumab. When LBL-007 infusion coincides 
with BGB-A425, BGB-A425 infusion must always occur after infusion of LBL-007 has completed. When LBL-007 infusion coincides with tislelizumab, 
tislelizumab infusion must always occur after infusion of LBL-007 has completed.  
27. Survival Follow-up: Patients will be followed for survival and further anticancer therapy information after discontinuation of study treatment via telephone 
calls, patient medical records, and/or clinic visits, including follow up of any ongoing AE, approximately every 3 months (every 90 days ± 14 days) after the 
90 days Safety Follow-up phone call and/or clinic visit (at the expected date), or after the 120 days Safety Follow-up Visit for women of childbearing 
potential, or as directed by the sponsor until death, withdrawal of consent, loss to follow-up, or end of study.  
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APPENDIX 1D. PHASE 1 AND PHASE 2 SAFETY LEAD-IN PHARMACOKINETIC AND 
IMMUNOGENICITY SAMPLING SCHEDULE WITH SERIAL SAMPLE 
COLLECTION  
This appendix applies to serial PK and immunogenicity sampling for: 1) BGB-A425 in patients in Phase 1 dose escalation; 
2) LBL-007 in patients in Phase 2 safety lead-in.  
 
Cycle 
PK Assessment (Planned CxDx) 
ADA Assessment 
Treatment Period 
1 
Predose  
EOI (Within 30-min after EOI) 
6 hrs (± 2 hr) from SOI – C1D1  
24 hrs (± 2 hr) from SOI – C1D2  
72 hrs (± 2 hr) from SOI – C1D4  
168 hrs (± 4 hr) from SOI – C1D8  
336 hrs (± 4 hr) from SOI – C1D15  
**504 hrs (± 4 hr) from SOI – C1D22  
Predose 
2 
Predose (-60 min to predose) 
EOI (Within 30-min after EOI) 
Predose 
3 
Predose  
Predose 
5 
Predose  
EOI (Within 30-min after EOI) 
6 hrs (± 2 hr) from SOI – C5D1  
24 hrs (± 2 hr) from SOI – C5D2  
72 hrs (± 2 hr) from SOI – C5D4  
168 hrs (± 4 hr) from SOI – C5D8  
336 hrs (± 4 hr) from SOI – C5D15  
Predose 
6 
Predose – C6D1 
Predose 
9 
Predose – C9D1 
Predose 
13 
Predose – C13D1 
Predose 
17 
Predose – C17D1 
Predose 
25* 
Predose – C25D1 
Predose 
Safety Follow-up 
(30 days ± 7 days after last dose) 
* No PK/ADA samples need to be collected after the completion of cycle 25, except at the safety follow-up. 
** PK assessment at 504 hrs only applies to BGB-A425 not for LBL-007. 
Abbreviations: ADA, antidrug antibody; CxDx, Cycle x and Day x; EOI, end of infusion; PK, pharmacokinetic; SOI, start of infusion 
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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 unless otherwise specified. 
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APPENDIX 1E. PHASE 1 AND PHASE 2 SAFETY LEAD-IN PHARMACOKINETIC AND 
IMMUNOGENICITY SAMPLING WITH SPARSE PK SAMPLE COLLECTION  
This appendix applies to sparse PK and immunogenicity sampling for: 1) BGB-A425 in patients in Phase 2 safety lead-in; 
2) Tislelizumab in patients in Phase 1 dose escalation and Phase 2 safety lead-in 
 
Cycle 
PK Assessment 
ADA Assessment 
Treatment Period 
1* 
Predose 
EOI (Within 30-min after EOI) 
Predose 
2 
Predose  
Predose 
3 
Predose  
Predose 
5 
Predose  
EOI (Within 30-min after EOI) 
Predose 
6 
Predose  
Predose 
9 
Predose  
Predose 
13 
Predose  
Predose 
17 
Predose  
Predose 
25** 
Predose  
Predose 
Safety Follow-up 
(30 days ± 7 days after last dose) 
* The Cycle 1 Day 8 (+2 days) sample collection must only occur on the day that tislelizumab is given. If Cycle 1 Day 8 (+2 days) tislelizumab administration is 
not given, samples should not be collected at this timepoint. Please refer to the laboratory manual for additional details. 
** No PK/ADA samples need to be collected after the completion of cycle 25, except at the safety follow-up. 
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 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 1F. PHASE 2 DOSE EXPANSION PHARMACOKINETIC AND IMMUNOGENICITY 
SAMPLING FOR BGB-A425, LBL-007, AND TISLELIZUMAB IN PATIENTS WITH 
SPARSE SAMPLE COLLECTION  
This appendix applies to sparse PK and immunogenicity sampling for: 1) BGB-A425 in patients in Phase 2 dose expansion; 
2) LBL-007 in patients in Phase 2 dose expansion; 3) Tislelizumab in patients in Phase 2 dose expansion.  
 
Cycle 
PK Assessment* 
ADA Assessment 
Treatment Period 
1 
Predose#  
EOI (Within 30-min after EOI) 
Predose 
2 
Predose  
Predose 
5 
Predose  
EOI (Within 30-min after EOI) 
Predose 
6 
Predose  
Predose 
9 
Predose  
Predose 
13 
Predose  
Predose 
17 
Predose  
Predose 
25* 
Predose  
Predose 
Safety Follow-up 
(30 days ± 7 days after last dose) 
* No PK/ADA samples need to be collected after completion of cycle 25, except at the safety follow-up. 
#  “Predose” in this table refers to a timeframe before the administration of the first study drug in the combination treatments. 
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 and ADA should be from a different site. For the patients with poor venous access, blood collection from a vein in the leg or foot will be suggested. 
Window: ± 30 minutes for EOI and ± 60 minutes for all other timepoints.  
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APPENDIX 1G. PHASE 2 DOSE EXPANSION PHARMACOKINETIC AND IMMUNOGENICITY 
SAMPLING FOR BGB-A425 IN PATIENTS WITH SERIAL SAMPLE COLLECTION  
This appendix applies to PK and immunogenicity sampling for BGB-A425 only in Cohorts 1, 2, 3 of Phase 2 dose expansion in 
approximately 15 patients enrolled, with 10 patients from South Korea and 5 patients from Australia. These patients will also be 
collected for sparse immunogenetic samples for tislelizumab (as described in Appendix 1F). 
 
Cycle 
PK Assessment (Planned CxDx) 
ADA Assessment** 
Treatment Period 
1 
Predose#  
EOI (Within 30-min after EOI) 
6 hrs (± 2 hr) from SOI – C1D1  
24 hrs (± 2 hr) from SOI – C1D2  
72 hrs (± 2 hr) from SOI – C1D4  
168 hrs (± 4 hr) from SOI – C1D8  
336 hrs (± 4 hr) from SOI – C1D15  
Predose 
2 
Predose  
End of infusion (Within 30-min after EOI) 
Predose 
5 
Predose  
EOI (Within 30-min after EOI) 
6 hrs (± 2 hr) from SOI – C5D1  
24 hrs (± 2 hr) from SOI – C5D2  
72 hrs (± 2 hr) from SOI – C5D4  
168 hrs (± 4 hr) from SOI – C5D8  
336 hrs (± 4 hr) from SOI – C5D15  
Predose 
6 
Predose – C6D1 
Predose 
9 
Predose – C9D1 
Predose 
13 
Predose – C13D1 
Predose 
17 
Predose – C17D1 
Predose 
25* 
Predose – C25D1 
Predose 
Safety Follow-up 
(30 days ± 7 days after last dose) 
* No PK/ADA samples need to be collected after the completion of cycle 25, except at the safety follow-up. 
#  “Predose” in this table refers to a timeframe before the administration of the first study drug in the combination treatments. 
Abbreviations: ADA, antidrug antibody; CxDx, Cycle x and Day x; EOI, end of infusion; PK, pharmacokinetic; SOI, start of infusion 
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. For the patients with poor venous access, blood collection from a vein in the leg or foot will be suggested. 
Window: ± 30 minutes for EOI and as noted for all other timepoints 
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APPENDIX 1H. PHASE 1 BLOOD AND TUMOR TISSUE BIOMARKER ANALYSIS  
Biomarker assessment Screening 
Treatment period 
Cycle 11 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Patients with 
confirmed PR 
or CR 
EOT 
Visit 
Visit Day 
-28 to 
~ -1 
1 
2 
8 
15 
1 
1 
1 
1 
0 to 
7 days 
Immunophenotyping2 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Cytokine or soluble 
proteins in blood3 
 
X 
X (24 hr±2 hrs 
post 
BGB-A425 
infusion) 
X 
X 
X 
X 
X 
 
X 
X 
PBMC3 
 
X 
X (24 hr±2 hrs 
post 
BGB-A425 
infusion) 
X 
X 
X 
X 
X 
 
X 
X 
Archival or fresh tumor 
tissue4 
X 
 
 
 
 
 
X 
 
 
 
X 
BGB-A425/TIM-3 
receptor occupancy5 
 
X (Predose AND 
6 hr ±2 hrs post 
BGB-A425 
infusion) 
X (24 hr±2 hrs 
post 
BGB-A425 
infusion) 
X (On the day of visit 
if tislelizumab not 
given OR 6 hr ±2 hrs 
post tislelizumab) 
X 
X 
X 
 
X  
 
 
Tislelizumab/PD-1 
receptor occupancy6 
 
X 
 
X (On the day of visit 
if tislelizumab not 
given OR 6 hr±2hrs 
post tislelizumab) 
X 
X 
X 
 
X  
 
 
Abbreviations: CR, complete response; EOT, end of treatment; FFPE, formalin fixed paraffin embedded; hrs, hours; PBMC, peripheral blood mononuclear cells; 
PR, partial response 
1. From the protocol, patients may or may not receive tislelizumab on Cycle 1 Day 8. If a patient receives tislelizumab on Cycle 1 Day 8, then the PD-1 and 
TIM-3 receptor occupancy sample will be collected 6 hours (±2 hours) post tislelizumab infusion while the other blood samples for biomarker analysis 
(immunophenotyping, cytokines and soluble protein, PBMC) will be collected before tislelizumab infusion on the same day. If tislelizumab is not given on 
Cycle 1 Day 8, receptor occupancy samples will be collected together with the blood-based biomarker samples. 
2. Blood samples for immunophenotyping will be collected at screening, Cycle 1 Day 1 (predose), Cycle 1 Day 8*, Cycle 1 Day 15, Cycle 2 Day 1 (predose), 
and Cycle 3 Day 1 (predose). *If tislelizumab is given on Cycle 1 Day 8, the sample should be collected before tislelizumab infusion (see footnote 1). Please 
refer to the laboratory manual for additional detailed information. 
3. Blood samples for cytokine and PBMC analysis will be collected on Cycle 1 Day 1 (predose), Cycle 1 Day 2 (24 hours ± 2 hours post BGB-A425 infusion), 
Cycle 1 Day 8*, Cycle 1 Day 15, Cycle 2 Day 1 (predose), Cycle 3 Day 1 (predose), Cycle 4 Day 1 (predose), before the next study treatment following 
confirmation of PR or CR, and End of Treatment Visit for patients who have confirmed when disease progression. *If tislelizumab is given on Cycle 1 
Day 8, the sample should be collected before tislelizumab infusion (see footnote 1). Please refer to the laboratory manual for additional detailed information. 
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4. Archival or fresh tumor tissue: Patients will provide archival tumor tissues (FFPE blocks or approximately 15 freshly cut unstained slides) for biomarker 
analysis if available. If archival tissue is not available, fresh tumor biopsy is strongly encouraged but not mandatory. An optional biopsy after 2 cycles of 
treatment (approximately Cycle 3 Day 1) is also strongly encouraged and an optional biopsy is also recommended from patients who have confirmed disease 
progression. If feasible, post treatment biopsy should be ideally taken from the same tumor lesion as the baseline biopsy/archival tumor tissues. Written 
patient consent is required for any fresh tumor biopsies. 
5. BGB-A425/TIM-3 receptor occupancy assay: Blood will be collected Cycle 1 Day 1 predose and 6 hours (± 2 hours) post BGB-A425 infusion, Cycle 1 
Day 2 (24 hours ± 2 hours post BGB-A425 infusion), Cycle 1 Day 8*, Cycle 1 Day 15, Cycle 2 Day 1 (predose), Cycle 3 Day 1 (predose), and Cycle 5 Day 1 
(predose). *If tislelizumab is given to the patient on Cycle 1 Day 8, samples should be collected 6 hours (±2 hours) post tislelizumab infusion (see 
footnote 1). Please refer to laboratory manual for additional details. 
6. Tislelizumab/PD-1 receptor occupancy assay: Blood will be collected on Cycle 1 Day 1 (predose), Cycle 1 Day 8*, Cycle 1 Day 15, Cycle 2 Day 1 
(predose), Cycle 3 Day 1 (predose), and Cycle 5 Day 1 (predose). *If tislelizumab is given on Cycle 1 Day 8, the sample should be collected at 6 hours 
(±2 hours) post tislelizumab infusion (see footnote 1). Please refer to laboratory manual for additional details. 
 
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APPENDIX 1I. PHASE 2 (SAFETY LEAD-IN) BLOOD AND TUMOR TISSUE BIOMARKER 
ANALYSIS  
Biomarker assessment 
Screening 
Treatment period 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 5 
Patients 
with 
confirmed 
PR or CR 
EOT 
Visit 
Visit Day 
-28 to 
~ -1 
1 
2 
8 
15 
1 
1 
1 
0 to 
7 days 
LBL-007/LAG-3 receptor 
occupancy1 
 
X (Predose AND 
6 hr ±2 hrs post 
LBL-007 infusion) 
X (24 hr±2 hrs post 
LBL-007 infusion) 
X 
X 
X 
(Predose) 
X 
(Predose) 
X 
(Predose) 
 
 
Cytokine or soluble 
proteins in blood2 
 
X (Predose) 
X (24 hr±2 hrs post 
LBL-007 infusion) 
X 
X 
X 
(Predose) 
X 
(Predose) 
 
 
 
Immunophenotyping3 
 
X (Predose) 
X (24 hr±2 hrs post 
LBL-007 infusion) 
X 
X 
X 
(Predose) 
X 
(Predose) 
 
 
 
ctDNA analysis4 
 
X (Predose) 
 
 
 
 
 
 
X 
X 
Archival or fresh tumor 
tissue5 
X 
 
 
 
 
 
X 
 
 
 
X 
Abbreviations: CR, complete response; ctDNA, circulating tumor DNA; EOT, end of treatment; FFPE, formalin fixed paraffin embedded; hrs, hours; PBMC, 
peripheral blood mononuclear cells; PR, partial response 
1. LBL-007/LAG-3 receptor occupancy assay: Blood will be collected Cycle 1 Day 1 predose and 6 hours (± 2 hours) post LBL-007 infusion, Cycle 1 Day 2 
(24 hours ± 2 hours post LBL-007 infusion), Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 (predose), Cycle 3 Day 1 (predose), and Cycle 5 Day 1 
(predose). Please refer to laboratory manual for additional details. 
2. Blood samples for cytokine or soluble protein analysis will be collected on Cycle 1 Day 1 (predose), Cycle 1 Day 2 (24 hours ± 2 hours post LBL-007 
infusion), Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 (predose), Cycle 3 Day 1 (predose). Please refer to the laboratory manual for additional detailed 
information. 
3. Blood samples for immunophenotyping analysis will be collected on Cycle 1 Day 1 (predose), Cycle 1 Day 2 (24 hours ± 2 hours post LBL-007 infusion), 
Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 (predose), Cycle 3 Day 1 (predose). Please refer to the laboratory manual for additional detailed information. 
4. Blood samples for ctDNA analysis will be collected at Cycle 1 Day 1 (predose), before the next study treatment after confirmation of PR or CR (for patients 
achieving confirmed PR or CR only), and End of Treatment Visit for patients who have confirmed disease progression. Please refer to the laboratory manual 
for additional detailed information. 
5. Archival or fresh tumor tissue: Patients will provide archival tumor tissues (FFPE blocks or approximately 15 freshly cut unstained slides) for biomarker 
analysis if available. If archival tissue is not available, fresh tumor biopsy is strongly encouraged but not mandatory. An optional biopsy after 2 cycles of 
treatment (approximately Cycle 3 Day 1) is also strongly encouraged and an optional biopsy is also recommended from patients who have confirmed disease 
progression. If feasible, post treatment biopsy should be ideally taken from the same tumor lesion as the baseline biopsy/archival tumor tissues. Written 
patient consent is required for any fresh tumor biopsies. 
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APPENDIX 1J. PHASE 2 (DOSE EXPANSION) BLOOD AND TISSUE BIOMARKER ANALYSIS  
Biomarker 
assessment 
Prescreening 
Screening 
Treatment period 
Cycle 1 
Cycle 2 
Cycle 3 
Patients with 
confirmed PR 
or CR 
End of 
Treatment Visit 
Visit Day 
-56 to ~ -28 
-28 to ~ -1 
1 
2 
8 
1 
1 
0 to 7 Days 
LBL-007/LAG-3 
receptor occupancy1 
 
 
X (Predose) 
 
X 
X (Predose) 
X (Predose) 
 
 
Cytokine or soluble 
proteins in blood2 
 
 
X (Predose) 
X 
X 
X (Predose) 
X (Predose) 
 
 
ctDNA3 
 
 
X (Predose) 
 
 
 
 
X 
X 
Archival or fresh  
tumor tissue4 
X 
X 
 
 
 
 
X  
 
X 
PD-L1 test5 
X 
 
 
 
 
 
 
 
 
Abbreviations: CR, complete response; ctDNA, circulating tumor DNA; FFPE, formalin fixed paraffin embedded; hrs, hours; PD-L1, programmed cell death 
protein-ligand 1; PR, partial response. 
1. LBL-007/LAG-3 receptor occupancy assay: Blood will be collected Cycle 1 Day 1 (predose), Cycle 1 Day 8, Cycle 2 Day 1 (predose), and Cycle 3 Day 1 
(predose). Blood samples for LBL-007/LAG-3 RO assay will be collected only for Cohort 4 to Cohort 7 in expansion phase, approximately 5 patients (in 
APAC region only) in each cohort. More patients might be added for RO sample collection in case there are missing samples or incorrect collection. Please 
refer to laboratory manual for additional details. 
2. Blood samples for cytokine or soluble protein analysis will be collected on Cycle 1 Day 1 (predose), Cycle 1 Day 2*, Cycle 1 Day 8*, Cycle 2 Day 1 
(predose), Cycle 3 Day 1 (predose). Cytokine or soluble proteins analysis is including but not limited to soluble TIM-3, and soluble LAG-3. *Blood samples 
on Cycle 1 Day 2 will be collected only for Cohort 1 to Cohort 3; blood samples for Cycle 1 Day 2 will be collected for patients who have serial PK visits; 
blood samples on Cycle 1 Day 8 will be collected only for Cohort 4 to Cohort 7. Please refer to the laboratory manual for additional detailed information. 
3. Blood samples for ctDNA analysis will be collected at Cycle 1 Day 1 (predose), before the next study treatment after confirmation of PR or CR (for patients 
achieving confirmed PR or CR only), and End of Treatment Visit for patients who have confirmed disease progression. Please refer to the laboratory manual 
for additional detailed information. 
4. Archival or fresh tumor tissue: During the prescreening period, HNSCC and NSCLC patients will undergo PD-L1 positivity confirmation with either local 
documented results or central testing. This includes archival tissue samples obtained within 2 years. For patients who have known PD-L1 positivity, a 
historically documented result is acceptable for PD-L1 positivity confirmation by specified PD-L1 assay at prescreening phase. Tissue samples obtained 
within 2 years or fresh biopsy is required prior to the patient commencing first drug administration on C1D1. It is highly recommended to provide the same 
tissue that was tested for the local PD-L1 assay. If a patient has more than 1 archival tumor tissue, the most recent one is preferred. Patients in all cohorts 
must provide archival tumor tissue obtained within 2 years or fresh tumor tissues (FFPE blocks or approximately 15 freshly cut unstained slides). If recently 
obtained tumor tissue is insufficient, a fresh tumor biopsy is mandatory. If qualified tumor tissues were received in the prescreening period then a repeat 
tumor biopsy does not need to be done. Optional biopsy after 2 cycles of treatment (approximately Cycle 3 Day 1) and at EOT from patients who have 
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confirmed disease progression is also strongly encouraged. If feasible, post treatment biopsy should be ideally taken from the same tumor lesion as the 
baseline biopsy/fresh tumor tissues. Written patient consent is required for any fresh tumor biopsies. 
5. During the prescreening period, HNSCC and NSCLC patients will undergo PD-L1 positivity confirmation with either local documented results or central 
testing. If a central analysis is used, PD-L1 CPS ≥ 1 or TPS ≥ 1% by IHC 22C3 pharmDx assay is acceptable for HNSCC and NSCLC patients, respectively. 
If local testing is used, PD-L1 (CPS ≥ 1) by IHC 22C3 pharmDx assay (preferred) or PD-L1 (CPS ≥ 1, vCPS or TAP ≥ 1%) by VENTANA PD-L1 (SP263) 
are acceptable for HNSCC patients (Note: PD-L1 positivity determined by PD-L1 IHC 22C3 pharmDx assay will be used for HNSCC patients in the EU); 
PD-L1 (TPS or TC ≥ 1%) by IHC 22C3 or 28-8 pharmDx or VENTANA PD-L1 (SP263) assay are acceptable for NSCLC patients (Note: If PD-L1 IHC 
28-8 assay is to be used for determining PD-L1 positivity, it will be used for nonsquamous NSCLC patients only in the EU). This requires tissue samples 
obtained recently within 2 years. For patients who have known PD-L1 positivity, a historically documented result is acceptable for PD-L1 positivity 
confirmation by local documented testing at the prescreening phase. If a patient has more than 1 archival tumor tissue, the most recent one is preferred. 
Tissue obtained within 2 years or fresh biopsy is required prior to the patient commencing first drug administration on C1D1. Positivity confirmation of the 
PD-L1 test must be obtained before HNSCC and NSCLC patients are allowed to continue to screening. The PD-L1 test is not required for RCC patients as 
part of prescreening or screening. The PD-L1 status of all cohorts will also be retrospectively evaluated by VENTANA PD-L1 (SP263) assay.
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Hematocrit 
Prothrombin time 
pH 
Alanine aminotransferase 
Hemoglobin 
Partial thromboplastin 
time or activated partial 
thromboplastin time 
Specific gravity 
Aspartate 
aminotransferase 
Platelet counts 
International Normalized 
Ratio 
Glucose 
Albumin 
WBC count  
 
Protein 
Total bilirubin 
Neutrophil count 
 
Ketones 
Blood urea nitrogen or 
urea 
Lymphocyte count 
 
Blood 
Potassium 
 
 
24-hour proteinb 
Sodium 
 
 
 
Calcium 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Testosteronea 
 
 
 
Lipase 
 
 
 
Amylase 
 
 
 
Creatine Kinase (CK) 
 
 
 
CK-MBc 
 
 
 
Cortisol (blood test)d 
 
 
 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme; pH, negative of the logarithm to base 10 of the activity 
of the (solvated) hydronium ion; 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 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 
c In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. If only 
either troponin is assessed per local standards, that same should be evaluated throughout. 
d Cortisol testing will be performed only for patients in Phase 2 (safety lead-in and dose expansion).  
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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 MD, Group Chair. 
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APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES 
ORAUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions. 
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 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 studies include the use of highly effective forms of birth control 
(Clinical Trials Facilitation and Coordination Group 2020). These methods include the 
following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
• Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation: 
• Oral, injectable, or implantable 
Note: Oral birth control pills are not considered a highly effective form of birth control, 
and if they are selected, they must be used with a barrier method of contraception (eg, 
condoms with or without spermicide) as well. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized male partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. See also the definition of sterile male 
below. 
• 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, sympto-thermal, or postovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception. If used, this method must be 
combined with another acceptable method listed above. 
Patients using hormonal contraceptives (eg, birth control pills or devices) must use a barrier 
method of contraception (eg, condoms) as well. 
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Definition of “Sterile Man” 
For the purposes of this study, a sterile man is one for whom azoospermia, in a semen sample, 
has been demonstrated as definitive evidence of infertility. Men with known “low sperm counts” 
(consistent with “sub-fertility”) are not to be considered sterile for purposes of this study. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
• ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
• < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 mIU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months have been 
ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If a follicle-stimulating hormone measurement is required to confirm postmenopausal state, 
concomitant use of hormonal contraception or hormonal replacement therapy should be 
excluded. 
Adapted from Clinical Trials Facilitation and Coordination Group 2020. 
 
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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 to 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 Study equation. National Kidney Disease 
Education Program calculators rely on creatinine determinations which are isotope dilution mass 
spectrometry traceable. All laboratories should be using creatinine methods calibrated to be 
isotope dilution mass spectrometry traceable. 
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. 
This equation is recommended when estimated GFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × 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 female patients and 0.9 for male patients, 
α is 0.329 for female patients and -0.411 for male patients, 
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 
1. 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-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any imAE are intended as a 
guidance. This document should be used in conjunction with expert clinical judgement (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs. In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of study drug(s) and the AE? 
• How did the patient respond to withdrawal of study drug(s)? 
• Did the event recur when study drug(s) was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked. 
Recommended Diagnostic Tests in the Management of Possible Immune-mediated Adverse 
Events 
Immune-mediated Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, 
such as an upper respiratory infection, new cough, shortness of breath or hypoxia 
should be assessed by high-resolution CT. Consider pulmonary function test 
including DLCO. 
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction 
study for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
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Recommended Diagnostic Tests in the Management of Possible Immune-mediated Adverse 
Events 
Immune-mediated Toxicity 
Diagnostic Evaluation Guideline 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: 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 ≥3 to 4; every 2 to 3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including hepatitis A/B/C serology, hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a hepatologist 
and consider liver biopsy.  
Renal toxicity 
Review hydration status and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to 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 I and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, troponin I, and refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; 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-mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, with 
patients is required 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice and contact the 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 medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to 
normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat 
with a beta blocker and consider 
oral prednisolone 0.5 mg/kg/day 
for thyroid pain. Taper 
corticosteroids over 2 to 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 to 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 to 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 to 3 
days. 
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: 
exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if 
symptoms/appearance persist for 
48 hours or worsen. Consider 
Pneumocystis infection 
prophylaxis. Taper 
corticosteroids over at least 
6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. If there is no 
improvement, or worsening after 
48 hours, add infliximab 5 mg/kg 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
(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. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5 
to 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 to 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 to 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 to 4 weeks, 
consider endoscopy if symptoms 
are recurring. 
Hold study 
treatment; resume 
when 
resolved/improved to 
baseline grade. 
3 
Severe symptoms: 
> 6 liquid stools per 
day over baseline, or 
if episodic within 
1 hour of eating 
 
Initiate IV methylprednisolone 1-
2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Consider prophylaxis for adverse 
steroid effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
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 
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 to 1 mg/kg/day 
for 3 days then taper over 2 to 
4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5 to 
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. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment 
if LFTs are 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
If LFTs are worsening, recheck 
every 48 to 72 hours until 
improvement is seen. 
worsening until 
improvement is seen. 
2 
ALT or AST 3 to 5X 
ULN 
Recheck LFTs every 48 to 72 
hours: 
For persistent ALT/AST 
elevation: consider oral 
prednisolone 0.5 to 1 mg/kg/day 
for 3 days then taper over 2 to 4 
weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and 
taper over 2 to 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 to 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 to 1000 mg twice a day 
 If worsens on MMF, consider addition of tacrolimus 
 Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X 
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 to 72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-
hour urine collection. Discuss 
with nephrologist the need for 
kidney biopsy. 
Hold study treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
If attributed to study drug, initiate 
oral prednisolone 0.5 to 1 mg/kg 
and taper over at least 2 weeks. 
Repeat creatinine/U&E every 48 
to 72 hours. 
Restart study drug if 
tapered to < 10 mg 
prednisolone. 
3 
Creatinine > 3X 
baseline or > 3X-6X 
ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat 
creatinine every 24 hours; refer to 
a nephrologist and discuss need 
for biopsy. If worsening, initiate 
IV (methyl)prednisolone 
1-2 mg/kg. Taper corticosteroids 
over at least 4 weeks. 
Hold study treatment 
until the cause is 
investigated. 
If study drug 
suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where 
renal replacement therapy is 
available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat 
according to local guideline. 
Check for C-peptide and 
antibodies against glutamic acid 
decarboxylase and islet cells are 
recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160 to 250 mg/dL; 8.9 
to 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 to 500 mg/dL; 
13.9 to 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 
Refer patient to an 
ophthalmologist for assessment 
Continue study 
treatment or hold 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Anterior uveitis or 
mild symptoms 
and topical corticosteroid 
treatment. Consider a course of 
oral steroids. 
treatment if 
symptoms worsen or 
if there are symptoms 
of visual disturbance. 
3 
Posterior 
uveitis/panuveitis or 
significant symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; 
reintroduce only after 
discussion with the 
study medical 
monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, 
nausea and vomiting 
Admit to hospital for urgent 
management. Initiate IV 
(methyl)prednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone when 
amylase/lipase improved to 
Grade 2, and taper over at least 
4 weeks. 
Hold study 
treatment; 
reintroduce only after 
discussion with the 
study medical 
monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate 
referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, 
swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
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 to 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, 
reduced oral intake, 
limited instrumental 
activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care. Ensure 
adequate hydration. If symptoms 
worsen or there is sepsis or 
bleeding, manage as a Grade 3 
event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management. Initiate IV 
(methyl)prednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone when symptoms 
improved to Grade 2 and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider IV corticosteroids 
if not contraindicated by 
infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated 
and patient has symptoms, 
consider oral steroids and treat as 
Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse 
initiate oral prednisolone 0.5 to 
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 
and1-2 mg/kg/day maintenance 
for severe activity restriction or 
dysphagia. If symptoms do not 
improve add immunosuppressant 
therapy. Taper oral steroids over 
at least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1. 
Discontinue if any 
evidence of 
myocardial 
involvement 
Myocarditis 
1 
Asymptomatic but 
abnormal CK-MB, 
cardiac troponin I or 
intraventricular 
conduction delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac 
symptoms or any increase in 
cardiac serum markers to the 
coronary care unit. 
Initiate oral prednisolone or IV 
(methyl)prednisolone at 1-2 
Hold study treatment 
until completely 
resolved or 
myocarditis has been 
ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3 
Severe symptoms with 
mild exertion 
mg/kg/day. Manage symptoms of 
cardiac failure according to local 
guidelines. 
If no immediate response change 
to pulsed doses of 
(methyl)prednisolone 1g/day and 
add MMF, infliximab or anti-
thymocyte globulin 
has been excluded 
and symptoms have 
completely resolved 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CK, creatine kinase; CK-MB, creatine kinase- cardiac muscle isoenzyme; CHF, congestive heart 
failure; 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, 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). Assumes a scan slice thickness no greater than 5 
mm. 
• 10 mm caliper measurement by clinical examination (when superficial). 
• 20 mm by chest Xray (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 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), 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. 
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Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are nonmeasurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) 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 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions under 
which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
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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”). 
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 ≥10 mm diameter as assessed using calipers (eg, skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical examination and imaging, imaging evaluation should be undertaken since it is 
more objective and may also be reviewed at the end of the trial. 
• Chest Xray: Chest CT is preferred over chest Xray, particularly when progression is an 
important endpoint, since CT is more sensitive than Xray, particularly in identifying new 
lesions. However, lesions on chest Xray 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 > 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 
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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 CA125 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 CA125 
progression criteria which are to be integrated with objective tumor assessment for use in 
firstline trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (eg, with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or stable disease in order to differentiate between 
response (or stable disease) and PD. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) 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 : 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 
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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, stable disease and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 
• Target lesions that become “too small to measure”. While on study, all lesions (nodal and 
nonnodal) 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 nonreproducible, therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if 
the radiologist is able to provide an actual measure, that should be recorded, even if it is 
below 5 mm. 
• Lesions that split or coalesce on treatment: When nonnodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. All 
lymph nodes must be nonpathological in size (<10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of 1 or more nontarget 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 nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of stable disease or 
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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 nontarget lesions 
is usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in nontarget disease in the face of stable 
disease or PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
Phase 3 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 
nonmeasurable disease burden. Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly nonmeasurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in nonmeasurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: 
ie, an increase in tumor burden representing an additional 73% increase in “volume” 
(which is equivalent to a 20% increase diameter in a measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large”, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”. If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to nonmeasurable disease, the very nature of that 
disease makes it impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up 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 
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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 preexisting site 
of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
• Timepoint Response 
• It is assumed that at each protocol-specified timepoint, a response assessment occurs. The 
following table provides a summary of the overall response status calculation at each 
timepoint for patients who have measurable disease at baseline: 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
Stable disease 
Non-PD or not all evaluated 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial 
response;. 
• When patients have nonmeasurable (therefore nontarget) disease only, the following table 
is to be used: 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
SD (Non-CR/non-PD) 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable 
disease. 
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Evaluation of Best Overall Response 
The best overall response (BOR) is the best response recorded from the start of the study drug 
treatment until the end of treatment taking into account any requirement for confirmation. On 
occasion a response may not be documented until after the end of therapy so protocols should be 
clear if post-treatment assessments are to be considered in determination of BOR. Protocols must 
specify how any new therapy introduced before progression will affect best response 
designation. The patient’s BOR assignment will depend on the findings of both target and 
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 BOR is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all timepoints (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a BOR of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero”. In trials where confirmation of response is required, repeated ‘NE’ 
timepoint 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 timepoint 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
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 
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recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a CR in 
a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
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 SD 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 < 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall 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 SD varies in different studies and diseases. If the 
proportion of patients achieving SD 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 SD. 
Note: The duration of response and SD as well as the PFS are influenced by the frequency of 
follow-up after baseline evaluation. It is not in the scope of this guideline to define a standard 
follow-up frequency. The frequency should take into account many parameters including disease 
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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. 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, 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, et al. 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 
INRg 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Events. 
a. Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion.  
N Engl J Med. 1996;274(9):473-481. 
b. Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c. Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5CPS waves. 
d. Grade 2: Lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e. Grade 3: Drowsiness, coma, orientation disorder, over-reflection, stiff/slow wave. 
f. Grade 4: Cannot wake up from coma, no independent personality/behavior, irrational, slow 2-3CPS Delta 
activity. 
g. Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637. 
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APPENDIX 11. LIST OF HERBAL MEDICINE OR CHINESE PATENT 
MEDICINES WHICH HAVE EFFECT OF CONTROL CANCER OR 
BOOST IMMUNITY  
The following table lists those medications that require a 14-day wash-out and should be 
prohibited during the study: 
Drug Name (Chinese) 
Drug Name (English) 
Rg3 参一胶囊 
Ginsenoside-Rg3 capsule 
养正消积胶囊 
Yangzheng Xiaoji Jiaonang 
化癥回生口服液 
Huazheng Huisheng Koufuye 
十全大补汤 
Juzentaihoto 
华蟾素注射液 
Cinobufacini/Huachansu injection 
华蟾素片/胶囊 
Cinobufacini/Huachansu Pian/Capsules 
博尔宁胶囊 
Boerning capsule 
去甲斑蝥素片 
Norcantharidin Pian 
参丹散结胶囊 
Shendan Sanjie Jiaonang 
参芪扶正注射液 
Shengqi Fuzheng Zhusheye 
参莲胶囊/颗粒 
Shen Lian Jiao Nang/Ke Li 
吗特灵注射液 
Ma Te Ling injection 
回生口服液 
Hui Sheng Kou Fu Ye 
复方斑蝥胶囊 
Fufang Banmao Jiaonang 
复方红豆杉胶囊 
Fufang Hongdoushan Jiaonang 
复方苦参注射液 
Fufang Kushen Zhusheye 
天仙胶囊 
Tian Xian capsule 
奇宁注射液 
Qining injection 
威麦宁胶囊 
Weimaining Jiao Nang 
安尔欣注射液 
Anerxin/Ginseng polysaccharide injection 
安康欣胶囊 
Ankangxin Jiaonang 
安替可胶囊 
Antike capsule 
岩舒注射液 
Yanshu injection 
平消片/胶囊 
Ping Xiao Pian/Jiao Nang 
康力欣胶囊 
Kanglixin Jiaonang 
康艾注射液 
Kang’ai Zhusheye 
康莱特注射液 
Kanglaite Injection 
康莱特软胶囊 
Kanglaite Soft Capsules 
慈丹胶囊 
CIDAN Capsule 
槐耳颗粒 
Huaer Keli 
海生素注射液 
Haishengsu injection 
消癌平丸/片/胶囊/颗粒 
Xiaoaiping Wan/Pian/Jiao Nang/Ke Li 
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Drug Name (Chinese) 
Drug Name (English) 
消癌平注射液 
Xiaoaiping Zhusheye 
牛黄醒消丸 
Niuhuang Xingxiao pill 
猪苓多糖注射液 
Polyporus polysaccharide injection 
白花蛇舌草注射液 
Hedyotis Dissusa wild injection 
紫龙金片 
Zi Long jin pian 
肝复乐片/胶囊 
Ganfule Jiaonang / GFL tablet 
肿节风片 
Zhongjiefeng tablet 
胃复春片 
Weifuchun pill 
艾迪注射液 
Ai Di Zhu She Ye 
芪珍胶囊 
Qizhen Jiaonang 
莪术油注射液 
Zedoary turmeric oil injection 
金复康口服液 
Kanglixin Jiaonang 
金蒲胶囊 
Jinpu capsule 
金龙胶囊 
Jinlong Capsules 
香菇多糖 
Lentinan 
鸦胆子油乳注射液 
Yadanzi/Brucea javanica Youru Zhusheye 
鸦胆子油软胶囊/口服乳液 
Yadanziyou Ruan jiao nang/Kou Fu Ru Ye 
Terminology list: Pian = tablet, Jiao Nang/Jiaonang = capsule, Ke Li/Keli = granules, Zhue She ye/Zhusheye = 
injections, Kou Fu Ye/koufuye = oral liquid, Wan = Pill/bolus, He Ji/Heji = mixture, Gao = ointment 
Note: This list of Chinese herbal medicines or Chinese patent medicines is provided as an example and is not 
intended to be all-inclusive. 
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