A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination With Investigational Agents in Non-Small Cell Lung Cancer Patients Previously Treated With Anti-PD-(L)1 Antibody
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: BeiGene

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 
30 September 2024 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title: 
Protocol Identifier: 
Phase: 
Investigational Medicinal 
Product(s): 
Indication: 
Sponsor: 
Contact Information: 
Original Protocol Version 0.0: 
Amendment 1.0 
Amendment 2.0 
Amendment 3.0 
A Phase 2, Open-label, Randomized, Multi-arm Study 
of BGB-A445 in Combination With Investigational 
Agents in Non-Small Cell Lung Cancer Patients 
Previously Treated With Anti-PD-(L)1 Antibody 
BGB-LC-203 
2 
BGB-A445 and investigational agents 
Anti-PD-(L)1-pretreated non-small cell lung cancer 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive 
3rd Floor 
San Mateo, California 94404 
USA 
BeiGene Medical Officer 
Phone: 1.877.828.5568 
Email: clinicaltrials@beigene.com 
30 March 2023 
15 May 2023 
13 November 2023 
30 September 2024 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, 
Ltd., and its affiliates.  This document is for use by individuals and their designated 
representatives for their confidential review, consideration, and/or participation in investigational 
trial(s).  This document may not be copied or distributed for review by any unauthorized 
individuals without the prior written authorization of BeiGene, Ltd., or one of its affiliates.  Your 
acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without the prior written authorization from BeiGene, Ltd., or one of 
its affiliates. 
Approved Date
9/30/2024
NCT Number:                                      NCT06029127

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 
30 September 2024 
CONFIDENTIAL 
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FINAL PROTOCOL APPROVAL SHEET 
A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination With 
Investigational Agents in Non-Small Cell Lung Cancer Patients Previously Treated With 
Anti-PD-(L)1 Antibody 
BeiGene, Ltd., Approval: 
See electronic signature 
See electronic signature 
Sponsor Development Core Team Lead 
Date 
Approved Date
9/30/2024

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 
30 September 2024 
 
CONFIDENTIAL 
Page 3 
INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in 
Combination With Investigational Agents in Non-Small Cell Lung Cancer 
Patients Previously Treated With Anti-PD-(L)1 Antibody 
Protocol Identifier: 
BGB-LC-203 
This protocol is a confidential communication of BeiGene, Ltd., and its affiliates.  I confirm that 
I have read this protocol, I understand it, and I will work according to this protocol and the terms 
of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its affiliates. 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol.  PRINT your name, title, and the name 
and address of the center in which the study will be conducted. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: _______________________________ 
Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
Approved Date
9/30/2024

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 
30 September 2024 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................18 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Background Information on Non-Small Cell Lung Cancer ........................................20 
1.1.1. 
Current Treatment of CPI-pretreated Advanced or Metastatic Non-Small 
Cell Lung Cancer and Unmet Clinical Needs.............................................................21 
1.2. 
Background Information on BGB-A445 as an OX40 Agonist ...................................22 
1.2.1. 
Pharmacology .............................................................................................................22 
1.2.2. 
Toxicology ..................................................................................................................22 
1.2.3. 
Clinical Pharmacology ................................................................................................22 
1.2.4. 
Prior Clinical Experience With BGB-A445 ...............................................................23 
1.2.4.1. 
Safety Assessment of BGB-A445 ..............................................................................23 
1.2.4.2. 
Efficacy Assessment of BGB-A445 ...........................................................................25 
1.3. 
Background Information on Investigational Agents ...................................................25 
1.4. 
Study Rationale ...........................................................................................................25 
1.4.1. 
Rationale for BGB-A445-based Combination Treatment ..........................................25 
1.4.2. 
Rationale for Selection of Investigational Agents in Combination With 
BGB-A445 ..................................................................................................................26 
1.4.3. 
Rationale for Selection of Reference Treatment ........................................................26 
1.4.4. 
Rationale for BGB-A445 Dose ...................................................................................26 
1.4.5. 
Rationale for Biomarker Strategy ...............................................................................27 
1.5. 
Benefit-Risk Assessment ............................................................................................27 
1.5.1. 
BGB-A445 ..................................................................................................................27 
1.5.2. 
Investigational Agents ................................................................................................28 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
2.1. 
Study Objectives and Endpoints .................................................................................29 
3. 
STUDY DESIGN .......................................................................................................31 
3.1. 
Summary of Study Design ..........................................................................................31 
3.2. 
Screening Period .........................................................................................................34 
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3.3. 
Treatment Period ........................................................................................................34 
3.4. 
Details for Safety Lead-in ...........................................................................................35 
3.4.1. 
Assessment of Dose-Limiting Toxicity ......................................................................35 
3.4.2. 
Dose-Limiting Toxicity Definition .............................................................................35 
3.4.3. 
Safety Lead-in Data Review .......................................................................................36 
3.4.3.1. 
BGB-A445 Combined With Docetaxel ......................................................................37 
3.4.3.2. 
BGB-A445 Combined With Investigational Agents ..................................................37 
3.5. 
Patient Discontinuation From Study Treatment .........................................................37 
3.6. 
End of Treatment and Safety Follow-up ....................................................................38 
3.7. 
Survival Follow-up .....................................................................................................38 
3.8. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........38 
3.9. 
End of Study ...............................................................................................................38 
4. 
STUDY POPULATION .............................................................................................40 
4.1. 
Inclusion Criteria ........................................................................................................40 
4.2. 
Exclusion Criteria .......................................................................................................41 
5. 
STUDY TREATMENT ..............................................................................................46 
5.1. 
Formulation, Packaging, Labeling, and Handling ......................................................46 
5.1.1. 
BGB-A445 ..................................................................................................................46 
5.1.2. 
Docetaxel ....................................................................................................................46 
5.1.3. 
Ramucirumab ..............................................................................................................46 
5.1.4. 
Investigational Agents ................................................................................................46 
5.2. 
Dosage, Administration, and Compliance ..................................................................47 
5.2.1. 
BGB-A445 Administration .........................................................................................47 
5.2.2. 
Docetaxel Administration ...........................................................................................47 
5.2.3. 
Ramucirumab Administration ....................................................................................48 
5.2.4. 
Investigational Agents Administration .......................................................................48 
5.3. 
Overdose .....................................................................................................................48 
5.4. 
Dose Delay and Modification .....................................................................................48 
5.4.1. 
Dose Delay ..................................................................................................................49 
5.4.1.1. 
Dose Delay for BGB-A445 ........................................................................................50 
5.4.1.2. 
Dose Delay for Docetaxel ...........................................................................................50 
5.4.1.3. 
Dose Delay for Ramucirumab ....................................................................................50 
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5.4.1.4. 
Dose Delay for Investigational Agents .......................................................................51 
5.4.2. 
Dose Modification ......................................................................................................51 
5.4.2.1. 
Dose Modification for BGB-A445 .............................................................................53 
5.4.2.2. 
Dose Modification for Docetaxel ...............................................................................53 
5.4.2.3. 
Dose Modification for Ramucirumab .........................................................................54 
5.4.2.4. 
Dose Modification for Investigational Agents ...........................................................55 
5.5. 
Continued Access to Study Drug After the End of the Study ....................................55 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................56 
6.1. 
Prior Therapy ..............................................................................................................56 
6.2. 
Concomitant Therapy .................................................................................................56 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................56 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................56 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................56 
6.2.1.3. 
Hepatitis C Treatment .................................................................................................57 
6.2.1.4. 
Radiation Therapy ......................................................................................................57 
6.2.1.5. 
COVID-19 Vaccines ...................................................................................................57 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................57 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................58 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................58 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................59 
7.1. 
Screening ....................................................................................................................59 
7.1.1. 
Informed Consent and Screening Log ........................................................................59 
7.1.2. 
Patient Numbering ......................................................................................................60 
7.2. 
Enrollment ..................................................................................................................60 
7.2.1. 
Confirmation of Eligibility .........................................................................................60 
7.2.2. 
Enrollment and Randomization ..................................................................................60 
7.3. 
Safety Assessments .....................................................................................................60 
7.3.1. 
Vital Signs ..................................................................................................................60 
7.3.2. 
Physical Examinations ................................................................................................60 
7.3.3. 
Ophthalmologic Examination .....................................................................................61 
7.3.4. 
Pulmonary Function Tests ..........................................................................................61 
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7.3.5. 
Eastern Cooperative Oncology Group Performance Status ........................................61 
7.3.6. 
Laboratory Safety Tests ..............................................................................................61 
7.3.6.1. 
Cardiac Enzyme Monitoring .......................................................................................62 
7.3.7. 
Electrocardiograms .....................................................................................................62 
7.3.8. 
Adverse Events ...........................................................................................................62 
7.3.9. 
Hepatitis B and C Testing ...........................................................................................62 
7.4. 
Tumor and Response Evaluations ..............................................................................63 
7.5. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................64 
7.6. 
Biomarkers ..................................................................................................................65 
8. 
SAFETY MONITORING AND REPORTING .........................................................66 
8.1. 
Risks Associated With Study Drug ............................................................................66 
8.1.1. 
Risks Associated With BGB-A445 ............................................................................66 
8.1.2. 
Risks Associated With Docetaxel ...............................................................................66 
8.1.3. 
Risks Associated With Ramucirumab ........................................................................67 
8.1.4. 
Risks Associated With Investigational Agent ............................................................67 
8.2. 
General Plan to Manage Safety Concerns ..................................................................68 
8.2.1. 
Eligibility Criteria .......................................................................................................68 
8.2.2. 
Safety Monitoring Plan ...............................................................................................68 
8.3. 
Adverse Events ...........................................................................................................68 
8.3.1. 
Definitions and Reporting ...........................................................................................68 
8.3.2. 
Assessment of Severity ...............................................................................................69 
8.3.3. 
Assessment of Causality .............................................................................................69 
8.3.4. 
Follow-up of Adverse Events .....................................................................................70 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................71 
8.4. 
Definition of a Serious Adverse Event .......................................................................71 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................72 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................72 
8.6.1. 
Adverse Event Recording Period ................................................................................72 
8.6.2. 
Reporting Serious Adverse Events .............................................................................73 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................73 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................74 
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8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................74 
8.6.3. 
Eliciting Adverse Events ............................................................................................74 
8.6.4. 
Progressive Disease ....................................................................................................74 
8.6.5. 
Deaths .........................................................................................................................75 
8.6.6. 
Adverse Events of Special Interest .............................................................................75 
8.6.7. 
Pregnancies .................................................................................................................76 
8.6.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................76 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events ...................................76 
8.6.10. 
Recording Infusion-Related Reactions .......................................................................77 
8.6.11. 
Recording Anaphylaxis ..............................................................................................77 
8.7. 
Management of Events to be Monitored ....................................................................77 
8.7.1. 
Infusion-Related Reactions .........................................................................................77 
8.7.2. 
Immune-Mediated Adverse Events ............................................................................78 
8.7.3. 
Hepatic Function Abnormalities .................................................................................79 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................80 
9.1. 
Statistical Analysis ......................................................................................................80 
9.1.1. 
Randomization ............................................................................................................80 
9.1.2. 
Analysis Sets ...............................................................................................................80 
9.1.3. 
Patient Disposition ......................................................................................................80 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................80 
9.1.5. 
Prior and Concomitant Medications ...........................................................................80 
9.2. 
Efficacy Analyses .......................................................................................................81 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................81 
9.2.1.1. 
Stage 1 Primary Efficacy Analysis .............................................................................81 
9.2.1.2. 
Stage 2 Primary Efficacy Analysis .............................................................................81 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................82 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................82 
9.3. 
Safety Analyses ..........................................................................................................82 
9.3.1. 
Extent of Exposure .....................................................................................................82 
9.3.2. 
Adverse Events ...........................................................................................................82 
9.3.3. 
Laboratory Analyses ...................................................................................................83 
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9.3.4. 
Vital Signs ..................................................................................................................83 
9.4. 
Pharmacokinetic Analysis ..........................................................................................83 
9.5. 
Immunogenicity Analyses ..........................................................................................84 
9.6. 
Other Exploratory Analyses .......................................................................................84 
9.7. 
Sample Size Consideration .........................................................................................84 
9.8. 
Interim Monitoring .....................................................................................................84 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................86 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................87 
11.1. 
Access to Information for Monitoring ........................................................................87 
11.2. 
Access to Information for Auditing or Inspections ....................................................87 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................88 
12.1. 
Regulatory Authority Approval ..................................................................................88 
12.2. 
Quality Assurance .......................................................................................................88 
12.3. 
Study Site Inspections.................................................................................................88 
12.4. 
Drug Accountability ...................................................................................................88 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................90 
13.1. 
Ethical Standard ..........................................................................................................90 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................90 
13.2.1. 
Protocol Amendments ................................................................................................90 
13.3. 
Informed Consent .......................................................................................................90 
13.4. 
Patient and Data Confidentiality .................................................................................91 
13.5. 
Financial Disclosure ...................................................................................................92 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................94 
14.1. 
Data Collection and Management Responsibilities ....................................................94 
14.1.1. 
Data Entry in the Electronic Case Report Form .........................................................94 
14.1.2. 
Data Collection ...........................................................................................................94 
14.1.3. 
Data Management/Coding ..........................................................................................94 
14.2. 
Data Integrity and In-House Blinding ........................................................................95 
14.3. 
Study Records Retention ............................................................................................95 
14.4. 
Protocol Deviations ....................................................................................................96 
14.5. 
Study Report and Publications....................................................................................96 
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14.6. 
Study and Study Center Closure .................................................................................97 
14.7. 
Information Disclosure and Inventions ......................................................................97 
15. 
REFERENCES ...........................................................................................................99 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................104 
APPENDIX 2. BLOOD AND TUMOR TISSUE BIOMARKER ANALYSIS .......................109 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................111 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................112 
APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................113 
APPENDIX 6. PREEXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................123 
APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................125 
APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................126 
APPENDIX 9. MANAGEMENT OF INFUSION-RELATED REACTIONS ........................140 
APPENDIX 10. MANAGEMENT OF ANAPHYLAXIS ........................................................141 
APPENDIX 11. FORMULAE FOR ESTIMATING RENAL FUNCTION ............................142 
APPENDIX 12. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................143 
APPENDIX 13. LIST OF PROHIBITED CHINESE HERBAL AND PATENT 
MEDICINES .............................................................................................................145 
APPENDIX 14. BGB-15025.....................................................................................................147 
 
LIST OF TABLES  
Table 1: 
Primary Objectives and Endpoints .............................................................................29 
Table 2: 
Secondary Objectives and Endpoints .........................................................................29 
Table 3: 
Exploratory Objectives and Endpoints .......................................................................30 
Table 4: 
Administration of BGB-A445 ....................................................................................47 
Table 5: 
Administration of BGB-A445 and Docetaxel and Monitoring Time .........................48 
Table 6: 
Management of Nonimmune-Mediated Adverse Events ...........................................51 
Table 7: 
BGB-A445 Dose Reduction Levels ............................................................................53 
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Table 8: 
Guidelines for Docetaxel Dose Modifications ...........................................................54 
Table 9: 
A Summary of the Commonly Reported Toxicities of Docetaxel .............................66 
Table 10: A Summary of Adverse Drug Reactions Reported in Patients Treated With 
Ramucirumab in Combination With Chemotherapy or Erlotinib In Phase 3 
Clinical Trials .............................................................................................................67 
Table 11: Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Cohorts ................................................................................................73 
Table 12: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................73 
Table 13: Examples of Immune-Mediated Adverse Events .......................................................79 
Table 14: Safety Stopping Boundaries for Number of Patients With TR-Deaths ......................85 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................33 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Medicinal Product(s): BGB-A445 and investigational agents 
Title of Study: A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination 
With Investigational Agents in Non-Small Cell Lung Cancer Patients Previously Treated With 
Anti-PD-(L)1 Antibody  
Protocol Identifier: BGB-LC-203 
Phase of Development: 2 
Number of Patients: The total number of patients of this study may vary depending on the number 
combinations where investigational agents are combined with BGB-A445 and the timing of when these 
agents are added to the study.  In both Stage 1 and Stage 2, approximately 20 patients will be enrolled 
or randomized into each treatment cohort.  
Study Centers: Approximately 30 centers in the Asia Pacific region for Stage 1 and expanded to North 
America, Europe, and additional Asia Pacific countries in Stage 2 
Study Objectives and Endpoints: 
Primary: 
Objectives 
Endpoints 
To assess the antitumor activity of BGB-A445 
plus investigational agent(s) in non-small cell 
lung cancer (NSCLC) patients pretreated with 
anti-programmed cell death protein-1 
(anti-PD-1)/anti-programmed cell death protein 
ligand-1 (anti-PD-L1) antibody 
Overall response rate (ORR) as assessed by the 
investigators per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version (v)1.1 
Secondary: 
Objectives 
Endpoints 
To assess the safety and tolerability of 
BGB-A445 plus investigational agent(s)  
The incidence and severity of adverse events 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 in experimental cohorts 
(BGB-A445 plus investigational agent) 
To further assess the antitumor activity of 
BGB-A445 plus investigational agent(s)  
Duration of response (DOR), disease control rate 
(DCR), and clinical benefit rate (CBR) as 
assessed by the investigator per RECIST v1.1 
To characterize the pharmacokinetics (PK) of 
BGB-A445 and investigational agent(s) 
Plasma or serum concentrations of BGB-A445 
and investigational agents at specified 
timepoints  
To assess host immunogenicity to BGB-A445 
and investigational protein therapeutics 
Immunogenic responses to BGB-A445 and 
investigational protein therapeutics, evaluated 
through the detection of antidrug antibodies 
(ADA) 
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Exploratory: 
Objectives 
Endpoints 
To evaluate the potential association of 
exploratory biomarkers with response or 
resistance to study treatment and with patient 
prognosis 
Evaluate exploratory biomarkers in various 
sample types (ie, tumor tissue and/or blood) at 
various timepoints (ie, before study treatment, 
after study treatment, and/or at disease 
progression or recurrence) and the association 
between these biomarkers and clinical efficacy, 
disease status, and resistance 
Exploratory biomarkers may include, but are not 
limited to: tumor necrosis factor receptor 
superfamily, member 4 (CD134, OX40) 
expression; PD-L1 expression; soluble OX40 
(sOX40); investigational agent-specific protein 
expression; gene expression profiling; 
tumor-infiltrating immune cells in tumor tissue; 
tumor mutation burden/microsatellite 
instability/genetic mutation profile; circulating 
tumor DNA (ctDNA), cytokines, and soluble 
proteins in plasma or serum  
Other assessments may be conducted as 
indicated and as allowed by local regulations 
To further assess the preliminary antitumor 
activity including by time-to-event of 
BGB-A445 plus investigational agent(s) 
Progression-free survival (PFS) as determined 
from tumor assessments by investigators per 
RECIST v1.1  
To assess overall survival (OS) 
OS defined as the date of randomization to the 
date of death because of any cause 
Study Design: 
This is a Phase 2, open-label, randomized, multicenter, multi-arm study designed to evaluate the 
efficacy and safety of BGB-A445 in combination with investigational agent(s) in patients with 
advanced or metastatic NSCLC whose tumors do not harbor actionable gene alterations and who have 
received no more than 2 lines of prior systemic therapies which must include anti-PD-(L)1 treatment.  
The study is designed to include 2 stages, with the flexibility of adding treatment cohorts become 
available or discontinuing treatment cohorts that demonstrate minimal clinical activity or unacceptable 
toxicity.   
Stage 1: Patients will be equally enrolled or randomized into different experimental cohorts to receive 
BGB-A445 plus investigational agent(s).  Approximately 20 patients per cohort will be enrolled.  For 
an investigational agent in combination with BGB-A445, a safety lead‑in with approximately 6 patients 
enrolled/randomized will be initiated for the confirmation of the safe dosage.  After the dosage is 
deemed as safe, enrollment or randomization will be continued until approximately 20 patients are 
enrolled into a cohort. 
Stage 2: Only investigational agent(s) with promising efficacy signal and acceptable safety and 
tolerability in Stage 1 will be selected for each cohort in Stage 2.  Patients will be equally enrolled or 
randomized into different cohorts including: 1) experimental cohorts with treatments of BGB-A445 
plus selected investigational agent(s), 2) the reference cohort, and 3) the selected cohort for dose 
optimization. Approximately 20 patients per cohort will be enrolled. 
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The study design schematic is presented below. 
Study Schema 
Abbreviations: NSCLC, non-small cell lung cancer; PD-(L)1, programmed cell death protein-1 
/programmed cell death protein ligand-1; Q3W, once every 3 weeks; QD, once a day; R, 
randomization.  
In the current protocol, the treatments in either stage will be administered as follows: 
Stage 1 
• 
Experimental cohorts: BGB-A445 + investigational agent(s) 
− 
Investigational agents include, but are not limited to, BGB-15025 and docetaxel in 
Stage 1. 
− 
A safety lead-in will be implemented for the combination of investigational agents 
with BGB-A445. 
Stage 2 
• 
Experimental cohorts: BGB-A445 + selected investigational agent(s) 
− 
Investigational agents are selected based on the efficacy signal and acceptable safety 
and tolerability shown in Stage 1. 
• 
Reference cohort: Docetaxel + ramucirumab 
• 
Dose optimization for selected cohort: Different dose levels of the investigational agents 
may be explored to more fully characterize exposure-response relationships to enable 
future development 
In both stages, study treatments in all cohorts will be administered until disease progression, intolerable 
toxicity, withdrawal of informed consent, or another discontinuation criterion is met, whichever occurs 
first (see Section 3.8). 
Tumor response will be assessed by investigators using standard RECIST v1.1 criteria.  Tumor 
imaging (computed tomography [CT] with or without contrast and/or magnetic resonance imaging 
[MRI]) must be performed within 28 days before randomization.  Tumor assessments will occur every 
6 weeks (± 7 days) from randomization for the first 9 months, and every 12 weeks (± 7 days) thereafter.  
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments following the original plan until the patient experiences 
disease progression, dies, withdraws consent, is lost to follow-up, or until the study terminates, 
whichever occurs first. 
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Safety will be assessed throughout the study by monitoring adverse events (AE), serious adverse events 
(SAEs) (toxicity grades assigned per NCI-CTCAE v5.0), and laboratory results.  Vital signs, physical 
examinations, Eastern Cooperative Oncology Group (ECOG) Performance Status changes, 
electrocardiogram (ECG) results, and other examinations will also be used for safety assessments.  
A Safety Monitoring Committee (SMC) will be established to review safety data for patients enrolled 
in the safety lead-in and to perform regular safety monitoring on this study.  The SMC will review 
available safety and other relevant data, as appropriate, to make recommendations regarding dose 
selection, modification, and further enrollment.  
Duration of Patient Participation: 
This study will consist of 5 periods: 
• 
The Screening Period is within 28 days before the randomization. 
• 
The Treatment Period starts with the first study drug administration and ends when the 
patient is discontinued from study treatment for any reason. Patients will receive study 
drug until they 1) are no longer considered to be achieving clinical benefit, 2) have 
unacceptable toxicity, or 3) withdraw informed consent, whichever occurs first. 
• 
The End-of-Treatment (EOT) or Safety Follow-up Period: Patients who discontinue 
treatment for any reason will be asked to return to the clinic for the EOT or Safety 
Follow-up Visit (to occur approximately 30 days [± 7 days] after the last dose of study 
drug[s] or before the initiation of a new anticancer treatment, whichever occurs first). In 
addition, patients should be contacted by telephone to assess AEs (serious and non-serious) 
and related concomitant medications, if appropriate, at 60 days (± 14 days) and 90 days 
(± 14 days) after the last dose of study drug(s), regardless of whether the patient starts a 
new anticancer therapy. If a patient reports a suspected new or worsening AE at a 
telephone follow-up contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
• 
The Efficacy Follow-up Period: Patients who discontinue study treatment early for reasons 
other than disease progression (eg, toxicity) will continue to undergo tumor assessments 
following the original plan until the patient meets any of the discontinuation criteria or 
starts a new anticancer therapy. 
• 
The Survival Follow-up Period: Overall survival data will be collected via telephone calls 
approximately every 8 weeks (± 7 days) after the Safety Follow-up Visit or as directed by 
the sponsor until death, loss to follow-up, withdrawal of consent, or the end of the study by 
the sponsor. 
Study Population: Patients with NSCLC who have advanced disease during or after anti-PD-(L)1 
treatment with no more than 2 lines of prior systemic therapies and whose tumors do not harbor 
actionable gene alterations. 
Key Eligibility Criteria: 
Inclusion Criteria 
• 
Patients (age ≥ 18 years) with advanced or metastatic NSCLC (nonsquamous or squamous) 
that is histologically or cytologically confirmed.  
• 
Patients who have received no more than 2 lines of prior systemic therapies which must 
include anti-PD-(L)1 treatment and a platinum-based chemotherapy administered in 
combination with, or sequentially before or after the anti-PD-(L)1 treatment.   
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• 
Patients must agree to provide archival tissue. 
• 
At least 1 measurable lesion as defined per RECIST v1.1. 
• 
ECOG Performance Status of 0 or 1. 
• 
Adequate organ function. 
Exclusion Criteria 
• 
Patients who received prior therapy containing docetaxel and/or ramucirumab for advanced 
or metastatic NSCLC.  
• 
Patients with known gene actionable alterations.  
• 
Patients with active leptomeningeal disease or uncontrolled and untreated brain metastasis. 
• 
Patients who received prior therapy targeting OX40 or any other T-cell agonists. 
• 
Patients with active autoimmune diseases or history of autoimmune diseases that may 
relapse, or history of life-threatening toxicity related to prior immune therapy. 
• 
Patients with prior immunodeficiency or who received allogenic stem cell transplantation 
or organ transplantation. 
• 
Patients with a history of severe hypersensitivity reactions to other monoclonal antibodies. 
Investigational Product, Dose, and Mode of Administration: 
• 
BGB-A445: 
 administered by intravenous infusion once every 3 weeks. 
• 
Refer to the respective appendix for detailed instructions on drug dosage, preparation, 
storage, and administration of other investigational products. 
Reference Therapy, Dose, and Mode of Administration: 
• 
Docetaxel: 75 mg/m2 administered by intravenous infusion once every 3 weeks. 
• 
Ramucirumab: 10 mg/kg administered by intravenous infusion once every 3 weeks. 
Statistical Methods: 
Sample Size: 
The total number of patients of this study may vary depending on the number of combinations where 
investigational agents are combined with BGB-A445 and the timing of when these agents are added to 
the study.  In both Stage 1 and Stage 2, approximately 20 patients will be enrolled or randomized into 
each treatment cohort. 
Statistical Analysis: 
Efficacy 
The Intent-to-Treat (ITT) Analysis Set will be used as the primary efficacy analysis population.  The 
ORR assessed by the investigator and the corresponding 95% CIs will be reported using the 
Clopper-Pearson method.  The CBR and DCR will be analyzed similarly to ORR.  The time-to-event 
endpoints, including DOR, PFS, and OS, will be estimated using the Kaplan-Meier method.  
Stage 1 Efficacy Analysis: 
Confirmed ORR assessed by the investigator will be reported for each cohort.  The corresponding 
95% CIs will be reported using the Clopper-Pearson method.   
Stage 2 Efficacy Analysis: 
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In Stage 2, the ORR difference between any experimental cohort and the concurrent reference cohort 
(ΔORR) and the corresponding 95% CIs will be reported.  For investigational agents evaluated in both 
stages, an analysis by combing the data from two stages will be conducted if deemed necessary. 
Safety 
Safety and tolerability will be determined by the AEs observed 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 of the study treatment(s). The severity of AEs will be 
graded according to NCI-CTCAE v5.0.  The incidence of treatment-emergent adverse events (TEAE) 
will be reported as the number (percentage) of patients with TEAEs by Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and Preferred Term. Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, and maximum for continuous variables; n 
[%] for categorical variables) and changes from baseline will be determined for laboratory parameters 
and vital signs. 
Pharmacokinetics 
Serum or plasma concentration of BGB-A445 and other investigational agent(s) will be tabulated and 
summarized by the visit/cycle when these samples are collected.  Descriptive statistics will include 
means, medians, ranges, and standard deviations, as appropriate. 
Immunogenicity 
Antidrug antibody (ADA) samples will be collected for BGB-A445 and relevant investigational agents, 
as appropriate.  The immunogenicity results will be summarized using descriptive statistics by the 
number and percentage of patients who develop detectable ADAs.   
Interim Monitoring: 
Futility Analysis 
A futility analysis will be conducted when approximately 20 patients are enrolled or randomized in any 
of the experimental cohorts at the end of Stage 1 and when these patients have been followed up for ≥ 2 
postbaseline tumor assessments.  Bayesian posterior probability will be used to evaluate clinical 
antitumor activity in Stage 1 for BGB-A445 in combination with investigational agents in each cohort.  
An experimental cohort will be considered futile and not proceed to Stage 2 if the ORR in this group is 
unlikely to exceed a historical benchmark (eg, Posterior Probability [true ORR ≥ 23%] ≤ 20%).  The 
historical benchmark will be assessed periodically and may be updated based on the emergent data 
during the cause of the study. 
Safety Stopping Rules 
To control the number of patients at risk in the event of a major safety concern, a pause in enrollment 
will be triggered by unacceptable conditions, including any death because of reasons other than disease 
progression and at least possibly related to the study treatment.  After evaluating the totality of the data, 
recommendations from the SMC, and benefit-risk evaluation, the sponsor will take appropriate actions 
for safety concern. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-A317 
Tislelizumab 
CR 
complete response 
CPI 
checkpoint inhibitor 
CT 
computed tomography 
DLT 
dose-limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
EDC 
electronic data capture (system) 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PFS 
progression-free survival 
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Abbreviation 
Definition 
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
TME 
tumor microenvironment 
ULN 
upper limit of normal 
 
 
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1. 
INTRODUCTION  
1.1. 
Background Information on Non-Small Cell Lung Cancer  
Lung cancer is one of the most common malignancies in adults, with approximately 2.21 million 
new diagnoses and 1.8 million deaths worldwide in 2020, which corresponds to the second 
highest incidence among cancers and the most common cancer-related mortality (Sung et al 
2021).  In 2022, an estimated 236,740 new cases of lung cancer will be diagnosed, and 130,180 
deaths are estimated to occur because of the disease in the United States of America (USA) 
(NCCN Guideline v1 2023).  Lung cancer is also the most commonly diagnosed malignancy, and 
it remains one of the deadliest in China, with an estimated 787,000 diagnoses and 630,500 deaths 
in 2015 (Gao et al 2020).  The prognosis of advanced stage non-small cell lung cancer (NSCLC) 
remains poor despite the availability of newer anti-cancer therapy.  The overall 5-year survival 
rate for patients with Stage IV NSCLC is 5% (Goldstraw et al 2016; Sung et al 2021).  
NSCLC accounts for 80% to 85% of all lung cancers (American Cancer Society 2020).  The 
disease is more common in men than women, representing 16.8% of all cancers in men and 8.8% 
of all cancers in women.  For NSCLC patients without driver molecular alterations, the treatment 
strategy has shifted from traditional doublet chemotherapy to immunotherapy-based treatments 
with or without chemotherapy because of significant improvements in overall survival when 
compared with standard platinum-based chemotherapy (Planchard et al 2018).  In these patients 
with pretreated late-stage advanced NSCLC, overall survival (OS) remains at approximately 9 to 
13 months.  The improvements of approximately 3 to 4 months have been achieved with 
anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed cell death protein ligand-1 
(anti-PD-L1) monotherapy compared with docetaxel (Borghaei et al 2015; Brahmer et al 2015; 
Herbst et al 2016; Rittmeyer et al 2017).  However, for these NSCLC patients without actionable 
gene alterations, 7% to 27% and 20% to 44% of them will develop primary resistance to the 
CPI-based treatments in the first-line or the second-line settings, respectively (Walsh and Soo 
2020), and there are limited treatment options for checkpoint inhibitor (CPI)-pretreated patients. 
Different biomarkers have been proposed or are currently under investigation to better select 
patients that could benefit from immunotherapy (Di Liello et al 2020).  Nevertheless, beyond the 
established role of PD-L1 expression (with all its limitations), none of these new biomarkers are 
able to guide clinicians to establish a targeted therapeutic algorithm for individual patients. The 
best treatment option remains challenging both in first line and after immunotherapy failure.  
Currently available options of treatment after the failure of a first line immunotherapy with or 
without with chemotherapy are represented by single agent chemotherapy eventually combined 
with anti-angiogenic drugs (Insa et al 2022). 
The therapeutic index of these second-line NSCLC therapies has been restricted both by limited 
survival benefit and significant toxicities, such as myelosuppression and neuropathy (docetaxel), 
diarrhea (pemetrexed and erlotinib), and rash (erlotinib) (Stinchcombe and Socinski 2008).  
Outcomes are poor for patients with previously treated, advanced or metastatic NSCLC; 
systemic chemotherapy (eg, docetaxel) or erlotinib provide modest benefits (Al-Farsi and Ellis 
2014; Stinchcombe and Socinski 2008). 
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1.1.1. 
Current Treatment of CPI-pretreated Advanced or Metastatic Non-Small Cell 
Lung Cancer and Unmet Clinical Needs  
Chemotherapy is used in the subsequent-line setting for NSCLC after the first-line treatment 
including CPI treatments.  Chemotherapy including docetaxel or docetaxel plus ramucirumab 
demonstrated an overall response rate (ORR) ranging from 10% to 20% but did not translate to 
durable disease control or OS benefit, with significant toxicities reported in patients who 
received docetaxel. 
Docetaxel was the first agent to demonstrate a survival benefit in comparison with best 
supportive care (BSC) in patients with relapsed NSCLC following platinum-containing therapy.  
In the first randomized Phase 3 study (TAX317), 103 eligible patients were stratified by 
performance status (PS) and best response to cisplatin chemotherapy and were then randomized 
to treatment with docetaxel 100 mg/m2 or 75 mg/m2 (55 patients) or BSC.  Time to progression 
was longer for docetaxel-treated patients than for BSC-treated patients (10.6 versus 6.7 weeks, 
respectively; p < 0.001), as was median OS (7.0 versus 4.6 months; log-rank test, p = 0.047).  
The difference was more significant for patients treated with docetaxel 75 mg/m2 than with 
docetaxel 100 mg/m2 and there was less toxicity with docetaxel 75 mg/m2 than with docetaxel 
100 mg/m2 (Shepherd et al 2000).  Subsequent studies comparing other treatment options with 
docetaxel in a second-line setting showed a response rate of 6% to 11% and median OS of 5 to 
10 months (Barnfield and Ellis 2016).   
Pemetrexed appears to be a non-inferior agent compared with docetaxel.  A Phase 3 study 
demonstrated non-inferiority for OS between pemetrexed and docetaxel (8.3 versus 7.9 months; 
hazard ratio [HR] 0.99; 95% CI: 0.8 to 1.2). However, pemetrexed showed a better toxicity 
profile with a significantly lower rate of neutropenia and alopecia, as well as lower rates of 
gastrointestinal adverse events (AEs) (Hanna et al 2004).  The use of pemetrexed is limited to 
patients with nonsquamous histology.  In addition, its use as a first-line agent has become much 
more prevalent, thus limiting its administration in the second-line setting. 
Ramucirumab was approved by the Food and Drug Administration (FDA) in combination with 
docetaxel for treatment of patients with metastatic NSCLC with whose disease progressed on or 
after platinum-based chemotherapy.  The efficacy of ramucirumab was evaluated in REVEL 
(NCT01168973), a multinational, randomized, double-blind study in patients with NSCLC 
whose disease progressed on or after one platinum-based therapy for locally advanced or 
metastatic disease.  The major efficacy outcome measure was OS.  Additional efficacy outcome 
measures included progression free survival (PFS) and ORR.  A total of 1253 patients were 
randomized: 628 to the ramucirumab with docetaxel group and 625 to the placebo with docetaxel 
group.  Median overall survival was 10.5 months (interquartile range [IQR] 5.1 to 21.2) for 628 
patients allocated ramucirumab plus docetaxel and 9.1 months (IQR 4.2 to 18.0) for 625 patients 
who received placebo plus docetaxel (HR 0.86; 95% CI 0.75 to 0.98; p = 0.023).  Median 
progression-free survival was 4.5 months (IQR 2.3 to 8.3) for the ramucirumab group compared 
with 3.0 months (IQR 1.4 to 6.9) for the control group (HR 0.76; 95% CI 0.68 to 0.86; 
p < 0.0001).  The overall response rate (complete response plus partial response) was 23% (95% 
CI: 20 to 26) for ramucirumab with docetaxel and 14% (95% CI: 11 to17) for placebo with 
docetaxel, p < 0.001 (Garon et al 2014). 
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Nintedanib was approved in the European Union (EU) for patients with lung cancer with 
advanced adenocarcinoma after first-line chemotherapy.  The Phase 3 LUME-Lung 1 study 
assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for NSCLC; 
A total of 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to 
receive docetaxel plus placebo.  Data from the study demonstrated that compared to docetaxel 
alone, nintedanib when added to docetaxel significantly extended median overall survival from 
10.3 to 12.6 months (p = 0.0359; HR: 0.83) for patients with adenocarcinoma, with a quarter of 
patients surviving for 2 years or more (survival at 24 months: nintedanib plus docetaxel [25.7% 
of patients] versus placebo plus docetaxel [19.1% of patients], p = 0.0359; HR: 0.83) (Reck et al 
2014). 
1.2. 
Background Information on BGB-A445 as an OX40 Agonist  
BGB-A445 is a humanized IgG 1, Fc-competent, monoclonal agonist antibody against OX40 
under clinical development for the treatment of human malignancies. 
1.2.1. 
Pharmacology  
BGB-A445 binds to the extracellular domain of human OX40 with high specificity and affinity, 
while it does not block the binding of OX40 to its native ligand OX40L.  In in vitro cell-based 
assays and in the mouse models, BGB-A445 functions as an agonist of the OX40 receptor to 
costimulate T cells secreting Interleukin-2 (IL-2) and shows antitumor activities alone or in 
combination with anti-mouse PD-1 antibody.  Refer to the BGB-A445 Investigator’s Brochure 
for detailed information regarding pharmacology studies. 
1.2.2. 
Toxicology  
The acute toxicity was evaluated in the single-dose pharmacokinetics (PK) study at doses up to 
50 mg/kg and in the repeated-dose toxicity study at doses up to 100 mg/kg intravenous in 
cynomolgus monkeys.  No acute toxicity was observed in cynomolgus monkeys in toxicity 
studies.  Also, overall, no apparent test article-related toxicity, including local effects, was noted 
at ≤ 20 mg/kg following repeated administration once every 2 weeks for 13 weeks in 
cynomolgus monkeys.   
Refer to the BGB-A445 Investigator’s Brochure for detailed information regarding additional 
toxicology studies. 
1.2.3. 
Clinical Pharmacology  
Preliminary pharmacokinetic data in humans indicate that BGB-A445 exposure (Cmax and 
AUC21d) increased approximately 
 in the 
 monotherapy dose 
range and 
 dose range in combination with 
 tislelizumab.  Serum 
concentrations declined in a biexponential manner after intravenous infusion, and preliminary 
terminal half-life (t1/2) estimates range from 7.9 to 12.7 days.   
Preliminary immunogenicity data are available from a total of 99 patients treated with 
BGB-A445 monotherapy or combination therapy at dose levels ranging from 
 (up 
to 
 for combination therapy) in the ongoing Phase 1a/1b Study BGB-A317-A445-101.  
Fifteen of 71 patients (21.1%) treated with BGB-A445 ranging from 
 
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monotherapy and 9 of 28 patients (32.1%) treated with BGB-A445 ranging from 
 
 in combination with 
 of BGB-A317, which is a BeiGene-developed anti-PD-1 
monoclonal antibody, namely tislelizumab, tested positive for BGB-A445 treatment-emergent 
antidrug antibody (ADAs).  Neutralizing antibody (NAb) information is not available yet.  The 
immunogenicity assessments will be continued in this study and other planned BGB-A445 
studies.   
Preliminary immunogenicity data for tislelizumab (dosed at 
 once every 3 weeks) are 
available from a total of 23 ADA-evaluable patients treated with tislelizumab in combination 
with BGB-A445.  Ten of 23 patients (43.5%) tested positive for tislelizumab treatment-emergent 
ADAs.  The ADA positivity rate for the tislelizumab in combination with BGB-A445 was found 
to be somewhat higher than that observed for tislelizumab monotherapy based on historical data. 
In both treatment parts, OX40 receptor occupancy was saturated (> 90%) at dose levels 
≥ 
.  In both treatment parts, a stronger trend of soluble OX40 induction was found after 
long term treatment at higher doses (≥ 
). 
Refer to the BGB-A445 Investigator’s Brochure for detailed information regarding additional 
toxicology studies. 
1.2.4. 
Prior Clinical Experience With BGB-A445  
BGB-A317-A445-101 is an ongoing, open-label, multicenter, nonrandomized, first-in-human 
Phase 1a/1b study investigating the safety, tolerability, pharmacokinetics, and preliminary 
antitumor activity of the anti-OX40 agonist monoclonal antibody BGB-A445 alone or in 
combination with the anti-PD-1 monoclonal antibody tislelizumab in patients with advanced 
solid tumors.  As of the 05 January 2023 data cutoff date, 166 patients had received study drug 
across monotherapy and in combination dose escalation cohorts as follows: 
• BGB-A445 monotherapy in dose escalation and expansion phases (n = 119): As of 
the data cutoff date, 8 dose levels have been evaluated including 
 (n = 1), 
 (n = 4), 
 (n = 3), 
 (n = 6), 
 (n = 12), 
 (n = 44), 
 (n = 45), and 
 (n = 4) every 3 weeks. 
• BGB-A445 in combination with tislelizumab 
 in dose escalation phase 
(n = 47): As of the data cutoff date, 6 dose levels of BGB-A445 have been evaluated 
including 
 (n = 6), 
 (n = 5), 
 (n = 8), 
 (n = 14), 
 (n = 10), and 
 (n = 4) every 3 weeks. 
1.2.4.1. 
Safety Assessment of BGB-A445  
As of 05 January 2023, 119 dose-limiting toxicity (DLT)-evaluable patients had received 
≥ 1 dose of BGB-A445 alone, and 47 patients received a combined dose of BGB-A445 with 
tislelizumab 
 every 3 weeks in the dose-escalation stage.  No DLTs were observed, and 
no deaths were reported related to the treatment.  BGB-A445, alone up to 
 and in 
combination up to 
, was generally safe and well-tolerated.  The safety profile of 
BGB-A445 given as monotherapy or in combination with tislelizumab is well tolerated in 
patients with advanced solid tumors at doses up to 
 both in monotherapy and in 
combination with tislelizumab 
 once every 3 weeks. 
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BGB-A445 monotherapy 
Among 119 patients who received BGB-A445 monotherapy, 99 (83.2%) had at least 
1 treatment-emergent adverse event (TEAE).  Fifty-six patients (47.1%) experienced TEAEs that 
were assessed as related to treatment.  Thirty-seven patients (31.1%) experienced TEAEs of 
≥ Grade 3, 5 (4.2%) of which were considered related to treatment.  Thirty-eight patients 
(31.9%) experienced serious TEAEs, 6 (5.0%) of which were considered related to treatment.   
Among 37 patients (31.1%) who experienced ≥ 1 TEAE of ≥ Grade 3 severity, the most 
commonly occurring ≥ Grade 3 TEAEs were Death (4 patients, 3.4%), followed by 
Haemoptysis, Pleural effusion, and Hypertension (3 patients each, 2.5%), as well as Nausea, 
Pneumonia, Sepsis, Arthralgia, Back pain, Cancer pain, and Anaemia (2 patients each, 1.7%).   
A total of 20 of 119 patients (16.8%) experienced ≥ 1 immune-mediated AEs (imAEs) which are 
of Grade 1 to 2 in severity.   The most commonly occurring immune-mediated AEs were Pruritus 
and Rash maculo-papular (4 patients each, 3.4%), followed by Pyrexia (2 patients, 1.7%). The 
remaining immune-mediated AEs occurred in single instances (0.8% each).  Additionally, 16 
(13.4%) of 119 patients experienced ≥ 1 infusion-related reactions, with 1 patient at the dose 
level of 
 experiencing ≥ 1 infusion-related reactions of Grade 3 severity.   
Ten patients (8.4%) had a TEAE leading to death; 1 patient each from the 
 and 
 
cohorts, 5 patients from the 
 cohort, and 3 patients from the 
 cohort.  None of 
these fatal TEAEs were assessed as related to the study treatment.  
BGB-A445 in combination with tislelizumab  
Among 47 patients who received BGB-A445 in combination with tislelizumab, 46 (97.9%) had 
at least 1 TEAE, with 34 patients (72.3%) experienced TEAEs assessed as related to treatment.  
Twenty-three patients (48.9%) experienced a ≥ Grade 3 TEAE, 6 (12.8%) of which were 
considered related to treatment.  Twenty patients (42.6%) experienced serious TEAEs, 4 (8.5%) 
of which were considered related to treatment.  
Among 23 patients (48.9%) who experienced ≥ 1 TEAE of ≥ Grade 3 severity, the most 
commonly occurring ≥ Grade 3 TEAEs were Abdominal pain and Diarrhoea (3 patients each, 
6.4%), followed by Fatigue, Pyrexia, and Pleural effusion (2 patients each, 4.3%).  The 
remaining ≥ Grade 3 TEAEs were single occurrences. 
Immune-mediated AEs were reported in 17 patients (36.2%), including imAEs with incidence 
≥ 5% of Rash maculo-papular (5 patients, 10.6%), Diarrhoea (4 patients, 8.5%), Arthralgia and 
Hypothyroidism (3 patients each, 6.4%).  Three of 47 patients experienced ≥ 1 imAEs of Grade 3 
severity.  These imAEs included Immune-mediated arthritis, Rash maculo-papular, Diarrhoea, 
and Rash, and all of them occurred only once.  Nine patients (19.1%) experienced an 
infusion-related reaction, with 1 patient that experienced 1 infusion-related reaction with Grade 3 
severity at the dose level of 
.   
Of the 47 patients in the BGB-A445 combination therapy with tislelizumab cohort, 3 patients 
(6.4%) experienced a TEAE leading to death in the BGB-A445 
 + tislelizumab 
 
cohort.  None of these fatal TEAEs were assessed as related to the study treatment. 
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1.2.4.2. 
Efficacy Assessment of BGB-A445  
As of the data cutoff date, 06 January 2023, 2 patients with unconfirmed partial response (PR) 
and 2 patients with stable disease ≥ 24 weeks in BGB-A445 monotherapy and 9 patients with 
unconfirmed PR in the combination therapy of BGB-A445 and tislelizumab have been 
observed in the BGB-A317-A445-101 study. 
1.3. 
Background Information on Investigational Agents  
Background information on each investigational agent is presented in the appendices. 
1.4. 
Study Rationale  
1.4.1. 
Rationale for BGB-A445-based Combination Treatment  
Successful antitumor immune response following immunotherapy with PD-1/PD-L1 immune 
checkpoint inhibitors, requires the reactivation and clonal proliferation of antigen-experienced 
T cells present in the tumor microenvironment (TME) (Jenkins et al 2018; Sharma et al 2017).  
Additionally, an immunosuppressive TME, which is characterized by high levels of 
immune-suppressing cytokines and/or metabolites with high levels of immune suppressive cells 
(eg, myeloid-derived suppressor cells, and regulatory T cells [Tregs]) is also growing in 
recognition as another driver of acquired resistance to treatment with anti-PD-1/PD-L1 
antibodies (Jenkins et al 2018; Topalian et al 2015). 
One strategy for increasing tumor immunity would be to activate and expand tumor-associated 
antigen T cells via activation of immunogenic costimulatory pathways such as OX40 (Jensen et 
al 2010).  The mechanisms of action of agonistic anti-OX40 monoclonal antibody-mediated 
antitumor effects are attributed to their ability to directly improve the effector function of T cells 
while counteracting the immunosuppressive effects of Tregs (Ito et al 2006; St Rose et al 2013; 
Voo et al 2013; Aspeslagh et al 2016).   
OX40 (also known as ACT35, CD134, or tumor necrosis factor receptor [TNFR] superfamily, 
member 4 [TNFRSF4]) is an immune costimulatory receptor primarily expressed on activated 
T cells and to a lesser extent on neutrophils, natural killer cells, and natural killer T cells.  A 
large body of literature suggests that OX40 plays a key role in promoting T-cell survival, 
proliferation, and proinflammatory cytokine expression in the tumor microenvironment.  When 
expressed on effector T cells, OX40 binds with its sole ligand (OX40L) and activates both the 
NF-κB1 and NF-κB2 pathways, which play key roles in the regulation of T-cell survival, 
differentiation, expansion, cytokine production, and effector function.   
Some studies reported that higher expression of OX40 on tumor-infiltrating lymphocytes was 
correlated with better OS (Petty et al 2002; Ladanyi et al 2004; Sarff et al 2008).  Indeed, the 
sponsor and others have shown nonclinically that treatment with an OX40 agonist induces tumor 
regression in a large number of distinct in vivo tumor models (Redmond and Weinberg 2007; 
Piconese et al 2008).   
It was hypothesized that the BGB-A445-based combination treatment may overcome the 
resistance to anti-PD-(L)1 antibodies in NSCLC.  This study is designed to establish proof of 
concept for multiple novel investigational agents, in a randomized setting, in combination with 
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OX40 agonist BGB-A445, to identify novel combination therapies that could improve responses 
and clinical benefit in the second or third line treatment for anti-PD-(L)1-pretreated patients with 
NSCLC without actionable gene alterations.  
1.4.2. 
Rationale for Selection of Investigational Agents in Combination With 
BGB-A445  
In this study, docetaxel is selected to be administered in combination with BGB-A445. 
In the second- and third-line treatment setting for NSCLC, docetaxel remains a commonly used 
standard treatment option for both squamous and non-squamous histologies in China and 
worldwide.  It has demonstrated a survival benefit relative to BSC in patients with relapsed 
NSCLC following first-line therapy and is associated with a response rate between 6% and 11% 
and a median OS of 5 to 10 months as mentioned in Section 1.1.1.  The doses of docetaxel in 
combination of BGB-A445 are based on product labelling, literature, and local guidelines. 
While docetaxel alone or combined with ramucirumab has previously demonstrated a tolerable 
safety profile in the second- and third-line treatment of NSCLC regardless of the add-on of CPI 
such as anti-PD-(L)1 antibody, the response rate and OS of docetaxel remain far from 
satisfactory.  The addition of immunotherapy to chemotherapy has been proven to be a good 
strategy with improved ORR and survival in NSCLC, but for those patients who already had 
been treated with PD-1/PD-L1 inhibitors, rechallenge with PD-1/PD-L1 inhibitors in the second- 
and third-lines settings yielded limited efficacy (Furuya et al 2021; Takahara et al 2022) and was 
associated with an increased toxicity burden.  
Accumulating preclinical data suggest that BGB-A445 can modulate the tumor 
microenvironment as mentioned above, and synergic effects were observed for BGB-A445 in 
combination with chemotherapy in mouse models.  Collectively, the add-on of BGB-A445 may 
benefit the NSCLC patients in the second and third lines of treatment setting. 
For other investigational agents selected to be administered in combination with BGB-A445 in 
the treatment of anti-PD-(L)1-pretreated NSCLC, the rationale is provided in Appendix 14. 
1.4.3. 
Rationale for Selection of Reference Treatment  
As described in Section 1.1.1, patients with anti-PD-(L)1-pretreated NSCLC that do not have 
actionable gene alterations typically receive a standard of care that includes ramucirumab in 
combination with docetaxel, which depends on the local guidelines (NCCN Guideline v1 2023).  
Reference treatments may be amended in this study accordingly because the standard of care 
may evolve in the future. 
1.4.4. 
Rationale for BGB-A445 Dose  
BGB-A445 will be administered by intravenous infusion at a dose of 
 once every 
3 weeks with additional investigational agents.  This dose was selected based on acceptable 
safety, tolerability, PK, pharmacodynamic activity, and antitumor activity of BGB-A445 
observed in the ongoing Phase 1 study BGB-A317-A445-101.  Most antitumor activity was 
observed in the 
, leading to 2 patients with unconfirmed partial responses 
(1 patient each at the 
 and 
monotherapy dose levels), while 2 patients at the 
 dose level have presented ongoing durable stable disease lasting > 36 weeks.  Although 
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saturation of receptor occupancy in peripheral blood at dose levels of ≥ 
 has been 
observed, peripheral receptor occupancy is not a robust measure of occupancy at the tumor tissue 
target, which could be because of several contributing factors, such as lower biodistribution of 
monoclonal antibodies into tissue (Shah and Betts 2013) or kinetics of OX40 expression on 
T cells (Willoughby et al 2017).  Data from this study and Study BGB-A317-A445-101 dose 
expansion will inform and may further refine the dose of BGB-A445 in clinical development. 
1.4.5. 
Rationale for Biomarker Strategy   
Exploratory biomarker analyses will be performed to study the following aspects of BGB-A445 
in combination with investigational agent(s): 1) potential predictive biomarkers for response and 
resistance of each combination therapy; 2) treatment and pharmacodynamic effects induced in 
patients.  Soluble OX40 is a marker of T-cell activation and can serve as a predictive biomarker 
and for mechanisms of action (MOA) exploration (Wang et al 2018).  OX40 agonist antibodies 
have been shown to enhance naive T-cell differentiation to effector T cells or memory T cells, 
increase pro-inflammatory cytokines and deplete regulatory T cells through antibody-dependent 
cellular cytotoxicity (ADCC) (Piconese et al 2008; Aspeslagh et al 2016).  The expression levels 
of OX40, PD-L1, and other investigational agent-specific proteins at baseline as determined by 
immunohistochemistry will be correlated to response and may serve as predictive biomarkers.  
Tumor-mutation, gene-expression profiles, and tumor-infiltrating lymphocytes may be explored 
in these tissues as possible predictive markers.  
Circulating tumor DNA (ctDNA) levels, as well as cytokines/soluble proteins in peripheral blood 
at baseline and after treatment, may serve as possible predictive markers and/or 
pharmacodynamic markers that may help to explore the depth of response and the understanding 
of MOA for the combination treatment effect of each investigational agent (Ricciuti et al 2021).  
Besides predictive biomarkers, mechanisms of resistance to immunotherapy are also not well 
understood and need more exploration.  Identifying tumor and immune-mediated features that 
are associated with progressive disease or acquired resistance to the treatments may increase the 
understanding of disease pathobiology and provide biological evidence for combination 
strategies. 
1.5. 
Benefit-Risk Assessment  
The BGB-LC-203 study will evaluate the efficacy, pharmacodynamics, and safety of BGB-A445 
in combination with investigational agents in checkpoint inhibitors-pretreated patients with 
NSCLC.  Based on general assessment, the sponsor hypothesizes that BGB-A445 in combination 
with investigational agents may provide clinical benefit by enhancing the tumor response and 
reducing disease recurrence. 
1.5.1. 
BGB-A445  
The human experience with BGB-A445 as either monotherapy or in combination with other 
antitumor agents is still evolving; therefore, clinical benefit in patients with advanced solid 
tumors has not been assessed.  Based on the BGB-A445 MOA, in vivo and in vitro preclinical 
data, and preliminary antitumor activity observed in the ongoing dose-escalation phase of 
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Study BGB-A317-A445-101, BGB-A445 as a single agent or in combination with tislelizumab 
has the potential to address unmet medical needs in patients with advanced solid tumors. 
A total of 166 patients as of 05 January 2023 have been treated with BGB-A445 monotherapy or 
in combination with tislelizumab in multiple tumor types.  Generally, BGB-A445 is well 
tolerated when used in combination with tislelizumab therapy.  However, these data should be 
interpreted with some caution because the sample sizes are relatively small for the ongoing 
studies.  Refer to the Investigator’s Brochure for more detailed information on BGB-A445 safety 
and efficacy data when given as monotherapy or in combination. 
1.5.2. 
Investigational Agents  
The agent-specific benefit-risk assessment is presented in the respective appendix. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives and Endpoints  
Table 1: 
Primary Objectives and Endpoints 
Objectives 
Endpoints 
To assess the antitumor activity of BGB-A445 
plus investigational agent(s) in non-small cell lung 
cancer (NSCLC) patients pretreated with anti-
programmed cell death protein 1 (anti-PD-1)/anti-
programmed cell death protein ligand 1 (anti-PD-
L1) antibody 
Overall response rate (ORR) as assessed by the 
investigators per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version (v)1.1 (as 
described in Section 9.2)   
Table 2: 
Secondary Objectives and Endpoints 
Objectives 
Endpoints 
To assess the safety and tolerability of BGB-A445 
plus investigational agent(s)  
The incidence and severity of adverse events 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 in experimental cohorts 
(BGB-A445 plus investigational agent) 
To further assess the antitumor activity of 
BGB-A445 plus investigational agent(s) 
Duration of response (DOR), disease control rate 
(DCR), and clinical benefit rate (CBR) as assessed 
by the investigator per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 (as 
described in Section 9.2) 
To characterize the pharmacokinetics (PK) of 
BGB-A445 and investigational agent(s) 
Plasma or serum concentrations of BGB-A445 
and investigational agents at specified timepoints  
 
To assess host immunogenicity to BGB-A445 and 
investigational protein therapeutics 
Immunogenic responses to BGB-A445 and 
investigational protein therapeutics, evaluated 
through the detection of antidrug antibodies 
(ADA) 
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Table 3: 
Exploratory Objectives and Endpoints 
Objectives 
Endpoints 
To evaluate the potential association of 
exploratory biomarkers with response or 
resistance to study treatment and with patient 
prognosis 
Evaluate exploratory biomarkers in various 
sample types (ie, tumor tissue and/or blood) at 
various timepoints (ie, before study treatment, 
after study treatment, and/or at disease 
progression or recurrence) and the association 
between these biomarkers and clinical efficacy, 
disease status, and resistance 
Exploratory biomarkers may include, but are not 
limited to: tumor necrosis factor receptor 
superfamily, member 4 (CD134, OX40) 
expression; PD-L1 expression; soluble OX40 
(sOX40); investigational agent-specific protein 
expression; gene expression profiling; 
tumor-infiltrating immune cells in tumor tissue; 
tumor mutation burden/microsatellite 
instability/genetic mutation profiles; circulating 
tumor DNA (ctDNA), cytokines, and soluble 
proteins in plasma or serum  
Other assessments may be conducted as indicated 
and as allowed by local regulations 
To further assess the preliminary antitumor 
activity including by time-to-event of BGB-A445 
plus investigational agent(s) 
Progression-free survival (PFS) as determined 
from tumor assessments by investigators per 
Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1  
To assess overall survival (OS) 
OS defined as the date of randomization to the 
date of death because of any cause (as described 
in Section 9.2)  
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a Phase 2, open-label, randomized, multicenter, multi-arm study designed to evaluate the 
efficacy and safety of BGB-A445 in combination with investigational agent(s) in previously 
treated NSCLC patients whose tumors do not harbor EGFR-sensitizing mutations, ALK 
translocations, BRAF V600E mutations, RET rearrangement, ROS1 mutations, or another 
actionable mutation with targeted therapy approved by the local health authority.  The patient 
must not have received more than 2 lines of prior systemic therapies, which must include an 
anti-PD-(L)1 treatment.  
The study is designed to include 2 stages, with the flexibility of adding treatment cohorts when 
new treatments become available or discontinuing treatment cohorts that demonstrate minimal 
clinical activity or unacceptable toxicity.  Approximately 20 patients will be enrolled or 
randomized into each cohort in Stage 1 and Stage 2.  New BGB-A445-based combination 
cohort(s) may be added in accordance with emerging preclinical or clinical evidence via a 
protocol amendment.  The total number of patients in this study may vary depending on the 
number of combinations where investigational agents are combined with BGB-A445 and the 
timing of when these agents are added to the study. 
Stage 1: Patients will be equally enrolled or randomized into different experimental cohorts to 
receive BGB-A445 plus investigational agent(s).   
A safety lead‑in with approximately 6 patients enrolled will be initiated in each cohort for 
confirmation of the safe dosage (Section 3.4).  After the dosage is deemed as safe, the 
randomization will be continued until approximately 20 patients are enrolled into a cohort.  
Efficacy and safety will be evaluated to determine if the experimental cohort(s) could be selected 
for further development in Stage 2, as described in Section 9.2.1.1 and Section 9.8, respectively.  
Stage 2: Patients will be equally enrolled or randomized into the experimental cohort(s) selected 
from Stage 1. 
See Section 7.2.2 and Section 9.1.1 for details of randomization.  Efficacy and safety will be 
evaluated as described in Section 9.2.1.2 and Section 9.3, respectively. 
The study design schematic is presented in Figure 1.  In Stage 1, the combination treatments to 
be administered in this study include the following: 
• BGB-A445 + docetaxel 
• BGB-A445 + BGB-15025 
In Stage 2 of the current protocol, the combination treatments to be administered in this study 
include the following: 
• Experimental cohorts: BGB-A445 + selected investigational agent(s) from Stage 1  
• Reference cohort: Docetaxel + ramucirumab 
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• Dose optimization for selected cohort: Different dose levels of the investigational 
agents may be explored to more fully characterize exposure-response relationships to 
enable future development. 
In both stages, study treatments in all cohorts will be administered (1 cycle consists of 3 weeks 
based on the schedule of administration of BGB-A445) until disease progression, intolerable 
toxicity, withdrawal of informed consent, or another discontinuation criterion is met, whichever 
occurs first (see Section 3.8). 
Patients will be required to sign an informed consent form (ICF) to undergo screening 
procedures.  Patients will also be required to provide tissue samples for retrospective analysis of 
biomarkers. 
For all study procedures, see Section 7 and Appendix 1. 
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Figure 1: 
Study Schema 
  
Abbreviations: NSCLC, non-small cell lung cancer; PD-(L)1, programmed cell death protein-1/programmed cell death protein ligand-1; Q3W, once 
every 3 weeks; QD, once a day; R, randomization. 
 
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3.2. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before randomization (see Appendix 1).  
Patients who agree to participate in this study will sign the ICF before undergoing any screening 
procedure.  Screening evaluations may be repeated as needed within the screening period; the 
investigator is to assess preliminary patient eligibility according to the latest screening 
assessment results.  For rescreening requirements, see Section 7.1. 
During the screening period, patients are required to provide archival tumor tissue 
(formalin-fixed paraffin-embedded [FFPE] blocks containing tumor [preferred] or approximately 
15 [at least 10] freshly cut unstained slides).  The most recently collected tissue is preferred. 
Refer to Section 7.6 for more details. 
3.3. 
Treatment Period  
After completing all screening activities, eligible patients will be equally enrolled or randomized 
into cohorts of Stage 1 and Stage 2 (Section 3.1), where applicable (Figure 1), to receive the 
study treatment as described in Section 5. 
Study treatments in all cohorts will be administered up to 36 cycles (ie, approximately 2 years, 
every cycle consists of 3 weeks based on the schedule of administration of BGB-A445) until 
disease progression, intolerable toxicity, withdrawal of informed consent, or another 
discontinuation criterion is met, whichever occurs first.   
Treatment beyond the initial investigator-assessed, Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1-defined disease progression is permitted in all cohorts if the criteria 
below are met: 
• Absence of clinical symptoms and signs of progressive disease (including clinically 
significant worsening of laboratory values) 
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, spinal cord compression) that requires urgent alternative medical 
intervention 
• The investigator must obtain written informed consent for treatment beyond 
radiologic disease progression and inform patients that doing so would not be 
considered standard practice in the treatment of cancer.  Patients must be informed 
that by continuing treatment on this study despite progression, they may be forgoing a 
treatment option that may be more beneficial for tumor control. 
• The decision to continue study drug(s) beyond the initial investigator-assessed 
progression must be made following discussion with the sponsor’s medical monitor. 
Patients who receive study treatment beyond initial progression will have tumor assessments 
performed according to the original schedule until study treatment discontinuation.  If the 
response assessment performed following treatment beyond progression shows continued 
progression of disease, treatment must be discontinued.   
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Tumor response will be assessed by investigators using standard RECIST v1.1 criteria.  Tumor 
assessments are required to be performed on schedule regardless of whether study treatment has 
been administered or held (ie, their schedule should not be adjusted for delays in cycles).  See 
Section 7.4 for details. 
Safety will be assessed throughout the study by monitoring AEs, serious AEs (SAEs) (toxicity 
grades assigned per the National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0 [NCI-CTCAE v5.0]), and laboratory results.  Safety assessments are further 
detailed in Section 7.3. 
3.4. 
Details for Safety Lead-in  
This protocol includes a dose-confirmation component for novel combinations where the safety 
profile of the combination has not been characterized.  For such combination, a safety lead-in is 
planned included to evaluate the safety of the dosage of the combination.   
Approximately 6 patients will be randomized into the safety lead-in of each cohort in Stage 1 and 
treated at the proposed dose deemed safe based on the previous studies.  Safety and tolerability 
data will be reviewed by the Safety Monitoring Committee (SMC).   
Additional details including the definition and assessment of DLTs will be provided in Section 
3.4.1 and Section 3.4.2. 
The information for the safety lead-in planned for specific investigational agents will be 
provided in the respective appendices. 
3.4.1. 
Assessment of Dose-Limiting Toxicity  
For patients enrolled in the safety lead-in, AEs will be assessed per the DLT criteria 
(Section 3.4.2) during a 21-day DLT assessment window.  
Patients will be considered evaluable for DLTs if they 1) received ≥ 80% of each scheduled 
study drug(s) administration during the DLT assessment window, and had sufficient safety 
evaluation, and/or 2) experienced a DLT.  Patients who are not evaluable for DLT may be 
replaced. 
Clinically important or persistent AEs that are not part of the DLT criteria (Section 3.4.2) may 
also be considered a DLT following review by the sponsor in consultation with the investigators.  
Any patient who experiences a DLT may be withdrawn from treatment or may continue at a 
lower dose level following discussion with and approval by the sponsor’s medical monitor. 
3.4.2. 
Dose-Limiting Toxicity Definition  
All toxicities or AEs will be graded according to NCI-CTCAE v5.0.  A DLT is defined as one of 
the following toxicities occurring during the DLT assessment window and considered by the 
investigator to be related to study drug(s):  
Hematologic: 
1. Grade 4 neutropenia lasting ≥ 7 days 
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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 clinically significant infection  
4. Grade 3 thrombocytopenia with clinically significant bleeding (≥ Grade 2 hemorrhage) 
5. Grade 4 thrombocytopenia  
6. ≥ Grade 4 anemia 
Nonhematologic: 
1. Any death not clearly defined because of underlying disease or extraneous causes 
2. ≥ Grade 4 toxicity 
3. Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 3 days after initiating optimal supportive care (unless excluded in the listed 
criteria) 
4. Confirmed drug-induced liver injury meeting Hy’s law criteria 
Note: Some AEs may be considered DLTs based on the mechanism of action and expected 
toxicity of the compound being studied.  The following AEs will not be considered DLTs: 
• Grade 3 hypothyroidism that is adequately controlled by hormonal replacement 
• Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumors) 
• Grade 3 rash 
• Grade 3 fatigue ≤ 7 days 
Investigational agent-specific DLT criteria or exceptions to the DLT definition above are 
provided in the investigational agent-specific appendix.  
3.4.3. 
Safety Lead-in Data Review  
The proposed dose cohort will be deemed as safe in the case of no more than 1 DLT event out of 
6 DLT-evaluable patients, and the randomization/enrollment will be continued until 
approximately 20 patients are randomized/enrolled into a cohort.  In addition to the DLT 
evaluation, other available relevant data (eg, safety data, available PK analyses) will be reviewed 
by the SMC with input from other members, as appropriate, to make the final decision.  If the 
proposed dose is deemed not tolerable, the enrollment will be paused or the dose level will be 
changed for further evaluation.  Please refer to the respective appendix for more information. 
Only DLTs that occur within the DLT assessment window will be considered for the 
corresponding dose level for the purpose of data review in the safety lead-in. Additionally, 
clinically important or persistent AEs (eg, imAEs) that are not part of the DLT criteria and are 
observed outside of the DLT assessment window may also be considered regarding subsequent 
decision. 
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3.4.3.1. 
BGB-A445 Combined With Docetaxel  
A safety lead-in is planned for the combination of BGB-A445 and docetaxel.   
If the combination of BGB-A445 and docetaxel is deemed not tolerable, the enrollment will be 
paused for further evaluation. 
3.4.3.2. 
BGB-A445 Combined With Investigational Agents  
For the details of data review during safety lead-in for the combination of BGB-A445 with other 
investigational agents, please refer to the agent-specific appendix. 
3.5. 
Patient Discontinuation From Study Treatment  
Patients have the right to discontinue study treatment at any time for any reason.  If necessary, 
the investigator has the right to discontinue a patient from the study treatment at any time.  
Patients who discontinue study treatment for reasons other than disease progression should be 
followed for assessments of antitumor activity (Section 7.4), safety (Section 7.3), and survival 
(Section 3.7), if possible.  The primary reason for discontinuation from the study treatment 
should be documented on the appropriate electronic case report form (eCRF).  Patients may 
discontinue study treatment for reasons that include but are not limited to the following: 
• Disease progression 
• Adverse event(s) 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she were to continue the study treatment 
• Use of any concurrent systemic anticancer therapy (ie, chemotherapy, hormonal 
therapy, immunotherapy, or standard or investigational agents [including Chinese (or 
other country) herbal medicine and Chinese (or other country) patent medicines] for 
the treatment of cancer) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study drug 
compliance and drug accountability.  The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
Patients who discontinue study treatment before disease progression will continue to undergo 
tumor assessments as outlined in Section 7.4. 
 
 
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3.6. 
End of Treatment and Safety Follow-up  
The End-of-Treatment (EOT) Visit will be conducted ≤ 7 days after the investigator determines 
that study treatment will no longer be administered or the patient discontinues the study 
treatment.  Patients will undergo the Safety Follow-up Visit at approximately 30 days (± 7 days) 
after the last dose or before initiation of any new anticancer therapy, whichever occurs first.   
Patients will be contacted by telephone to assess AEs (serious and nonserious) and relevant 
concomitant medications (ie, those associated with an AE or any new anticancer therapy).  These 
contacts should be made at 60 days (± 14 days) and 90 days (± 14 days) after the last dose of 
study drug(s), regardless of whether the patient starts a new anticancer therapy.  If a patient 
reports a suspected new or worsening AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visit. 
3.7. 
Survival Follow-up  
Overall survival data will be collected via telephone calls approximately every 8 weeks 
(± 7 days) after the Safety Follow-up Visit or as directed by the sponsor until death, withdrawal 
of consent, loss to follow-up, or the end of the study (see Section 3.9). 
3.8. 
Patient Discontinuation From Study (End of Study for an Individual 
Patient)  
Patients may discontinue from the study for reasons that include, but are not limited to, the 
following: 
• Patient withdrawal of consent 
• Adverse events 
• Noncompliance 
• Toxicity 
• Death 
• Loss to follow-up 
• Patient completion of all study assessments 
3.9. 
End of Study  
The end of the study is defined as the timepoint when the final data point is collected from the 
last patient in the study.  This is when the last patient dies, withdraws consent, completes all 
study assessments, or is lost to follow-up.  Alternatively, the end of the study is when the sponsor 
decides to terminate the study. 
The sponsor has the right to terminate this study at any time.  Reasons for terminating the study 
early may include, but are not limited to, the following: 
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• 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/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 the Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs) of the early termination of the study. 
The sponsor has the right to close a site at any time.  Whenever possible, the site will be notified 
of the decision in advance.  Reasons for closing a site may include, but are not limited to, the 
following:  
• Excessively slow recruitment  
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• Good Clinical Practice (GCP) noncompliance 
• Study activity is completed (ie, all patients have completed the study and all 
obligations have been fulfilled). 
• The sponsor has the right to terminate any of the experimental cohorts at any time 
based on the available data. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for the selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all of the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments.  
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the 
jurisdiction in which the study is taking place). 
3. Advanced or metastatic NSCLC (nonsquamous or squamous) that is histologically or 
cytologically confirmed. 
Note: Tumors of mixed non-small cell histology will be categorized by the predominant 
cell type.  
4. Patients who have received no more than 2 lines of prior systemic therapies which must 
include anti-PD-(L)1 treatment and a platinum-based chemotherapy administered in 
combination with, or sequentially before or after the anti-PD-(L)1 treatment.  Patients 
who have received prior neoadjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for nonmetastatic disease must have experienced 
disease progression within 6 months from the last dose of systemic therapy and/or 
radiotherapy.   
Note: Systemic treatment line number will be counted on the basis of interval disease 
progression and not the number of agents or switches in agents (eg, a first‑line therapy 
that consists of several cycles of a platinum doublet and subsequent maintenance therapy 
that introduces or switches to a new chemotherapy agent without interval disease 
progression will all be considered one line treatment).  Anti-PD(L)-1 maintenance 
therapy following platinum-based chemotherapy is not considered as a separate line of 
treatment.  
5. Agreement to provide archival tumor tissue (FFPE block containing tumor [preferred] or 
approximately 15 [at least 10] freshly cut unstained slides). 
6. At least 1 measurable lesion as defined per RECIST v1.1. 
Note: A lesion in an area subjected to prior locoregional therapy, including previous 
radiotherapy, is not considered measurable unless there has been demonstrated 
progression in the lesion since such therapy as defined by RECIST v1.1. 
7. ECOG Performance Status of 0 or 1. 
8. Adequate organ function as indicated by the following laboratory values during 
screening: 
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
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i. Absolute neutrophil count ≥ 1.5 x 109/L 
ii. Platelets ≥ 100 x 109/L 
iii. Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate (eGFR) or creatinine clearance ≥ 60 mL/min 
using the equations described in Appendix 11 
c. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin must be 
< 3 x ULN for patients with Gilbert syndrome) 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN  
9. Women of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study and for at least 120 days after the last dose of 
study drug(s).   
Note: If receiving docetaxel-containing combination treatment, women of childbearing 
potential must be willing to use a highly effective method of birth control for the duration 
of the study and at least 180 days after the last dose of study drug(s). 
They must also have a negative urine or serum pregnancy test result at screening and 
≤ 7 days before the first dose of study drug(s).  See Appendix 12 for details. 
10. Nonsterile male patients must be willing to use a highly effective method of birth control 
for the duration of the study and for at least 120 days after the last dose of study drug(s) 
Note: If receiving docetaxel-containing combination treatment, nonsterile male patients 
must be willing to use a highly effective method of birth control for the duration of the 
study and at least 180 days after the last dose of study drug(s). 
a. A sterile male patient is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
b. Male patients with known “low sperm counts” (consistent with “subfertility”) are not 
to be considered sterile for the purposes of this study. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. With mixed small cell lung cancer. 
2. With known actionable alterations (including, but not limited to, EGFR, ALK, BRAF, 
RET, and ROS1 mutations) for which targeted therapy has been approved by the 
respective local health authority in the current treatment setting at the time of patient 
enrollment.  
3. Has received prior therapy targeting OX40 or any other T-cell agonists including, but not 
limited to, 4-1BB and GITR.  
4. Has received prior therapy containing docetaxel and/or ramucirumab for advanced or 
metastatic NSCLC. 
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5. Has received any Chinese herbal medicine or Chinese patent medicines used to control 
cancer ≤ 14 days before the first dose of study drug(s). 
6. Active leptomeningeal disease or uncontrolled and untreated brain metastasis. 
Patients with a history of treated and, at the time of screening, stable central nervous 
system (CNS) metastases are eligible, provided they meet all of the following: 
a. Brain imaging at screening shows no evidence of interim progression, and there is no 
evidence of new brain metastases 
b. Patient is clinically stable for ≥ 4 weeks 
c. Brain metastases are not the only site of disease 
d. No ongoing requirement for corticosteroids as therapy for CNS disease; off 
corticosteroids 4 weeks before the first dose of study drugs; anticonvulsants at a 
stable dose are allowed  
e. No stereotactic radiation or whole-brain radiation ≤ 14 days before the first dose of 
study drug(s) 
7. Active autoimmune diseases or history of autoimmune diseases that may relapse, or 
history of life-threatening toxicity related to prior immune therapy (Appendix 6). 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type 1 diabetes 
b. Hypothyroidism (managed with hormone replacement therapy only) 
c. Celiac disease controlled by diet alone 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
8. Any active malignancy ≤ 2 years before randomization/enrollment except for the specific 
cancer under investigation in this study, those with a negligible risk of metastasis or 
death, and any locally recurring cancer that has been treated curatively (eg, resected basal 
or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, 
carcinoma in situ of the cervix or breast). 
9. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
the first dose of study drug(s). 
Note: Patients who are currently or have previously been on any of the following 
corticosteroid regimens are not excluded: 
a. Adrenal replacement corticosteroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
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c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy, premedication before pemetrexed or paclitaxel) or for the treatment of a 
nonautoimmune condition (eg, delayed-type hypersensitivity reaction caused by 
contact allergen) 
10. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before the first dose of study drug(s).  
11. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence ≤ 14 days after intervention).  Patients with symptomatic pleural 
effusion are excluded unless the patient undergoes a therapeutic thoracentesis or has had 
pleurodesis (> 14 days before randomization/enrollment) with subsequent stable 
effusions. 
12. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc.  All patients must 
undergo an assessment of pulmonary function at screening. 
13. Infection (including tuberculosis infection, etc) requiring systemic (oral or intravenous) 
antibacterial, antifungal, or antiviral therapy ≤ 14 days before the first dose of study 
drug(s), or patients with symptomatic COVID-19 infection.  Patients that have recovered 
from symptomatic COVID-19 infection can be rescreened on this study.   
Note: Antiviral therapy is permitted for patients with chronic infection with hepatitis B 
virus (HBV) or infection with hepatitis C virus (HCV).  Patients receiving prophylactic 
antibiotics (eg, for the prevention of urinary tract infection, chronic obstructive 
pulmonary disease, or for dental extraction) are eligible.  
14. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/mL (or 
≥ 2500 copies/mL) at screening. 
Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B 
(HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled.  Patients with detectable 
HBsAg or detectable HBV DNA should be managed per treatment guidelines.  Patients 
receiving antivirals at screening should have been treated for > 2 weeks before 
randomization/enrollment.  
15. With active hepatitis C. 
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody 
test followed by a negative HCV RNA test at screening are eligible.  The HCV RNA test 
will be performed only for patients testing positive for HCV antibody.  Patients receiving 
antivirals at screening should have been treated for > 2 weeks before 
randomization/enrollment. 
16. Known a history of HIV infection. 
17. Any major surgical procedure ≤ 28 days before randomization.  Patients must have 
adequately recovered from the toxicity and/or complications from the intervention before 
randomization/enrollment. 
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18. Immunodeficiency as assessed by the investigator not suitable for treatment by 
immune-modulating anticancer agents (Appendix 6), prior allogeneic stem cell 
transplantation, or organ transplantation. 
19. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization 
b. Symptomatic pulmonary embolism ≤ 28 days before randomization 
c. Any history of acute myocardial infarction ≤ 6 months before randomization 
d. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV (Appendix 7) ≤ 6 months before randomization 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization 
f. Any history of cerebrovascular accident ≤ 6 months before randomization  
g. Patients with inadequately controlled hypertension (defined as average systolic blood 
pressure [BP] ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) ≤ 28 days before 
randomization  
Note: Antihypertensive therapy to achieve these parameters is allowable. 
h. Any prior history of hypertensive crisis 
i. Any episode of syncope or seizure ≤ 28 days before randomization 
20. With a history of severe hypersensitivity reactions to other monoclonal antibodies or has 
experienced a severe imAE with prior immunotherapy. 
21. Has received any immunotherapy (eg, interleukin, interferon, thymosin, etc) or any 
investigational therapies ≤ 14 days or ≤ 5 half-lives (whichever is shorter) before the first 
dose of study drug.  
22. Was administered a live vaccine ≤ 28 days before randomization. 
Note: Seasonal vaccines for influenza or COVID-19 are generally inactivated vaccines 
and are allowed.  Live intranasal vaccines are not allowed. 
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, will 
affect the explanation of drug toxicity or AEs, or will result in insufficient or impaired 
compliance with study conduct. 
24. Women who are pregnant or are breastfeeding. 
25. Concurrent participation in another therapeutic clinical study. 
Note: Concurrent participation in observational or noninterventional studies is allowed.  
In addition, patients who have completed active treatment in a clinical study and are in 
the follow-up period can be enrolled in this study. 
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26. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to 
baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy, and specific laboratory abnormalities). 
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5. 
STUDY TREATMENT  
The specific stipulations of the study treatment for experimental cohorts including formulation, 
packaging, handling dosage, administration, dose modification, and overdose are provided in 
each investigational agent-specific appendix.  Only common requirements for study treatment 
are presented in this section, unless otherwise specified. 
5.1. 
Formulation, Packaging, Labeling, and Handling  
5.1.1. 
BGB-A445  
BGB-A445 is provided as a sterile, nonpyrogenic injectable solution for intravenous 
administration.  It is formulated in the 
 at pH 
, consisting of 
 mg/mL BGB-A445, 
, 
, 
 
, and 
. 
The drug product is fill-finished in 20 mL glass vials (United States Pharmacopeia Type I 20 mm 
finishing neutral borosilicate glass) stoppered with ethylene-tetra-fluoro-ethylene-coated butyl 
rubber stoppers and aluminum flip-off seal caps. 
Each single-use vial contains 
 mL (
 mg) of BGB-A445 monoclonal antibody at a 
concentration of 
 mg/mL. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition specified on the label.  Shaking should 
be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous study drug preparation, 
administration, accountability, and disposal.  Refer to the BGB-A445 Investigator’s Brochure for 
other details regarding BGB-A445. 
5.1.2. 
Docetaxel  
Docetaxel will be provided in vials for infusion.  The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
Docetaxel must be kept at the temperature condition specified on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.1.3. 
Ramucirumab  
Ramucirumab will be provided in vials for infusion.  The contents of the label will be in 
accordance with all applicable local regulatory requirements. 
Ramucirumab must be kept at the temperature condition specified on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.1.4. 
Investigational Agents  
Refer to the respective appendices for details. 
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5.2. 
Dosage, Administration, and Compliance  
The first dose of study drug is to be administered ≤ 2 business days after randomization.  All 
patients will be monitored during the study for AEs. 
Accurate records of all study drugs received, dispensed, returned, and disposed of should be 
maintained in the site’s Drug Inventory Log.  Refer to the Pharmacy Manual for details of study 
drug management. 
5.2.1. 
BGB-A445 Administration  
BGB-A445 
 will be administered as an intravenous infusion once every 3 weeks 
(1 cycle) in combination with investigational agents.   
The administration of BGB-A445 in different combination treatments is presented in Table 4.   
Table 4: 
Administration of BGB-A445  
Cycle 
BGB-A445 Infusion Duration 
C1D1, C2D1, and C3D1   
BGB-A445 
 infusion 60 (± 5) minutes 
C4D1 onwards 
BGB-A445 
 infusion 30 (± 5) minutes 
Abbreviations: C, cycle; D, day. 
Note: The infusion rate may be decreased, or the infusion may be stopped in the event of an infusion-related 
reaction.  See Section 8.7.1 for details. 
For the administration schedule of combination treatment, the dose, frequency, administration 
duration, and patient monitoring duration of BGB-A445 and investigational agents are detailed 
in the respective section and/or appendices: 
• Refer to Section 5.2.2 for the administration of BGB-A445 in combination with 
docetaxel. 
• Refer to Appendix 14 for the administration of BGB-A445 in combination with 
BGB-15025. 
BGB-A445 will be administered separately by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter.  BGB-A445 must be prepared and administered as separate infusions and may not be 
infused simultaneously with any other investigational agents.   
5.2.2. 
Docetaxel Administration  
Docetaxel 75 mg/m2 will be administered as an intravenous infusion over 1 hour once every 3 
weeks until disease progression, intolerable toxicity, or withdrawal of consent.   
Additional premedications should be administered as per standard practice.  Please refer to the 
label of docetaxel for additional information. 
Stage 1: BGB-A445 + docetaxel 
For the administration of BGB-A445 in combination of docetaxel in Stage 1, the infusion and 
post-infusion rules are outlined in Table 5. 
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Table 5: 
Administration of BGB-A445 and Docetaxel and Monitoring Time  
Cycle 
BGB-A445 and Docetaxel 
C1D1, C2D1, and C3D1 a    BGB-A445 
 infusion 60 (± 5) minutes 
Docetaxel 75 mg/m2 infusion over 1 hour (refer to the label of docetaxel 
for details) 
Patient monitoring for ≥ 120 minutes 
 C4D1 onwards 
BGB-A445 
 infusion 30 (± 5) minutes 
Docetaxel 75 mg/m2 infusion over 1 hour (refer to the label of docetaxel 
for details) 
Patient monitoring for ≥ 30 minutes 
Abbreviations: C, cycle; D, day. 
Note: The infusion rate may be decreased, or the infusion may be stopped in the event of an infusion-related 
reaction.  See Section 8.7.1 for details. 
a Subsequent decrease(s) in study drug infusion time and/or post-infusion monitoring time is contingent upon the 
tolerability of prior study drug administrations.  If a cycle is missed, the equivalent number of study drug infusions 
must be met before a decrease in time can occur.  
Stage 2: Docetaxel + ramucirumab 
For the administration of the reference cohort in Stage 2 (ie, docetaxel in combination with 
ramucirumab), please refer to Section 5.2.3 for more details.  
5.2.3. 
Ramucirumab Administration  
Ramucirumab 10 mg/kg will be administered as an intravenous infusion over 1 hour once every 3 
weeks until disease progression, intolerable toxicity, or withdrawal of consent.  Ramucirumab 
will be administered before the administration of docetaxel. 
Additional premedications should be administered as per standard practice.  Please refer to the 
label of ramucirumab for additional information. 
5.2.4. 
Investigational Agents Administration  
For the administration of investigational agents in combination with BGB-A445, refer to the 
respective appendices for details. 
5.3. 
Overdose  
AEs associated with an overdose or incorrect administration of study drug will be recorded in the 
AE eCRF. Any SAEs associated with an overdose or incorrect administration must be reported 
≤ 24 hours after awareness via the SAE reporting process described in Section 8.6.2.  Supportive 
care measures should be administered as appropriate. 
Refer to each investigational agent-specific appendix for details. 
5.4. 
Dose Delay and Modification  
Every effort should be made to administer the study drugs according to the planned dose and 
schedule.  In the event of significant toxicities, dose modification may be taken.  Reasons for 
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dose modification, the supportive measures taken, and the outcome will be documented in the 
patient’s source documents and recorded in the eCRF.  
The dose modification guidelines in the protocol are not intended to be a substitute for clinical 
judgment.  Investigators may delay doses for other reasons (eg, AEs or laboratory findings) as 
appropriate. 
5.4.1. 
Dose Delay  
In general, dose delays for reasons other than management of AEs are prohibited.  A dose delay 
of ≤ 12 weeks after the last dose of study drug(s) is allowed for the combination treatment at the 
discretion of the investigator after consultation with the medical monitor or designee.  If the 
patient is unable to resume the combination treatment ≤ 12 weeks of total delay duration, then 
the patient should be discontinued from the combination treatment.  If the patient is not able to 
resume study treatment ≤ 12 weeks of total delay duration for unforeseen nondrug related 
reasons, continued treatment may be allowed after consultation and approval by the medical 
monitor.    
Study treatment(s) may be temporarily suspended if the patient experiences a toxicity that is 
suspected to be related to the treatment and requires a dose to be withheld.  If study treatment is 
delayed because of TEAEs, study treatment may resume only after the AEs 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 because of worsening of 
laboratory results, eg, hematologic or biochemical parameters, the frequency of relevant blood 
tests should be increased, as clinically indicated.   
The total durations of dose delay allowed for the management of AEs suspected to be related to 
each study drug are specified in the following sections and agent-specific appendix.  If the 
patient is unable to resume a certain study drug within the allowed time frame, the treatment of 
study drug should be discontinued.  However, if a patient is benefiting from study treatment(s) 
while meeting the discontinuation criteria, resumption of study treatment(s) may occur after 
discussion and agreement with the medical monitor.   
When treatment is delayed, the next cycle, including assessments scheduled for that cycle, will be 
delayed until the treatment commences.  The counting of the next cycle (eg, C2D1) for the 
combination treatment is detailed in each agent-specific appendix. 
In cases of prolonged study treatment delays, consult the medical monitor regarding modification 
(eg, frequency, types of assessments, etc) of the unscheduled assessments.  When the patient 
receives study treatment, all of the scheduled assessments for that cycle (including PK and 
biomarkers) and each subsequent cycle (assuming no dose delays) should be performed according 
to the Appendix 1.  For example, if a patient’s C2D1 was delayed, the patient should continue to 
undergo safety assessments as outlined for Cycle 1 in the Schedule of Assessments 
(Appendix 1), which means the patient will undergo weekly assessments.  Once a patient 
resumes study treatment, the Schedule of Assessments for Cycle 2 should be followed.   
Tumor assessments should continue as scheduled, which is every 6 weeks (± 7 days) from 
randomization for the first 9 months, and every 12 weeks (± 7 days) thereafter.   
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5.4.1.1. 
Dose Delay for BGB-A445  
BGB-A445 treatment may be temporarily suspended if the patient experiences a toxicity that is 
suspected to be related to BGB-A445 and requires a dose to be withheld.  Study treatment of 
BGB-A445 should resume as soon as possible after the AEs recover to baseline or Grade 1 
(whichever is more severe) after the last dose of BGB-A445.    
Additional dose modification details for BGB-A445 when administered in combination with 
investigational agent(s) in experimental cohorts are provided in the investigational agent-specific 
appendix.   
Specific treatment modifications to manage study treatment-related toxicities, such as 
infusion-related reactions and imAEs, are described in Section 8.7, Appendix 8, and Appendix 9. 
5.4.1.2. 
Dose Delay for Docetaxel  
Stage 1: BGB-A445 + docetaxel 
Please refer to Section 5.4.1.1 for the details of BGB-A445 dose delay. 
Docetaxel treatment may be temporarily suspended if the patient experiences a toxicity that is 
suspected to be related to docetaxel and requires a dose to be withheld.  Study treatment of 
docetaxel should resume as soon as possible after the AEs recover to baseline or Grade 1 
(whichever is more severe) after the last dose of docetaxel. 
If a dose delay of either BGB-A445 or docetaxel (because of the causes mentioned above) is 
≤ 10 days for a planned dosing cycle (eg, C2D1), the delayed treatment(s) in this cycle (eg, 
Cycle 2) should be administered, and the combination treatment in the next cycle (eg, C2D1) 
will not be delayed and will be administered as scheduled. 
If the dose delay of either BGB-A445 or docetaxel (because of the causes mentioned above) is 
> 10 days for a planned dosing cycle (eg, C2D1), then the patient should skip the delayed 
treatment in the delayed cycle (eg, C2), and the combination treatment should be administered on 
Day 1 of the next planned cycle (eg, C3D1). 
Exceptions may be considered following consultation between the investigator and the medical 
monitor.    
Specific treatment modifications to manage study treatment-related toxicities, such as 
infusion-related reactions are described in Section 8.7. 
Stage 2: Docetaxel + ramucirumab 
For the administration of the reference cohort in Stage 2 (ie, docetaxel in combination with 
ramucirumab), please refer to Section 5.4.1.3 for more details. 
5.4.1.3. 
Dose Delay for Ramucirumab  
In Stage 2, ramucirumab is administered in combination with docetaxel as the reference 
treatment.  The guidance of dose delay for ramucirumab and docetaxel is to be followed per the 
local guideline and the investigator’s discretion. 
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5.4.1.4. 
Dose Delay for Investigational Agents  
Dose delay for the investigational agent(s) is provided in the investigational agent-specific 
appendix. 
5.4.2. 
Dose Modification  
In the event of significant toxicity, dosing may be interrupted and/or dose(s) modified in 
accordance with Table 6.   
Table 6: 
Management of Nonimmune-Mediated Adverse Events  
System 
Adverse event 
Toxicity 
management 
Study drug management 
Hematologic 
Anemia 
Grade 3 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment until resolved 
to Hgb ≥ 9 g/dL. 
If resolved ≤ 7 days, then maintain 
current dosage. 
If resolved > 7 days, decrease 
A445 treatment by 1 dose level. 
If blood transfusion is required, 
consider decreasing A445 
treatment by 1 dose level if 
clinically indicated. 
Anemia 
Grade 4 
Maximize supportive 
therapy until 
Hgb ≥ 9 g/dL. 
Hold study treatment until resolved 
to Hgb ≥ 9 g/dL.  After resolution, 
decrease A445 by 1 dose level. 
Neutropenia 
(ANC decrease) 
Grade 3 
Treat with appropriate 
supportive care as 
medically indicated 
until 
ANC ≥ 1000/mm3. 
Hold study treatment until resolved 
to ANC ≥ 1000/mm3 or baseline. 
If resolved in ≤ 7 days, then 
maintain current dosage. 
If resolved in > 7 days, then 
decrease A445 by 1 dose level. 
Neutropenia 
(ANC decrease) 
Grade 4 
Maximize appropriate 
supportive therapy 
until 
ANC ≥ 1000/mm3. 
Hold study treatment until resolved 
to ANC ≥ 1000/mm3 or baseline.  
After resolution, decrease A445 by 
1 dose level. 
Febrile 
neutropenia 
≥ Grade 3 
Maximize appropriate 
supportive therapy.  
Rule out other 
etiologies of fever. 
Hold study treatment until 
neutrophil count ≥ 1000/mm3.  
After resolution, decrease A445 by 
1 dose level. 
For Grade 4 event, discontinue 
therapy. 
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System 
Adverse event 
Toxicity 
management 
Study drug management 
Thrombocytopenia 
(platelet count 
decrease) 
Grade 2 
Monitor and treat with 
appropriate supportive 
care as medically 
indicated. 
Maintain current dosage if no 
concerns of clinically significant 
risk of bleeding; continue to 
monitor using additional 
hematology assessments as 
required. 
Thrombocytopenia 
(platelet count 
decrease) 
Grade 3 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment until resolved 
to ≤ Grade 1 or baseline.  After 
resolution, decrease A445 by 
1 dose level.  
Thrombocytopenia 
(platelet count 
decrease) 
Grade 4 
Treat with appropriate 
supportive care as 
medically indicated.  
Hold study treatment until resolved 
to ≤ Grade 1 or baseline.  After 
resolution, decrease A445 by 
1 dose level.  
 
Other hematologic 
event 
Grade 3 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment. 
If improved to ≤ Grade 1 or 
baseline, decrease A445 treatment 
by 1 dose level. 
If event recurs at the reduced dose 
after receiving optimal supportive 
care, permanently discontinue 
study treatment. 
 
First occurrence of 
other hematologic 
Grade 4 event  
 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment until 
improved to ≤ Grade 1 or baseline.  
After resolution, decrease A445 by 
1 dose level, or permanently 
discontinue study treatment. 
 
Recurrent other 
hematologic 
Grade 4 event 
Treat with appropriate 
supportive care as 
medically indicated. 
Permanently discontinue study 
treatment. 
Nonhematologic Nonhematologic 
event 
Grade 3 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment. 
If improved to ≤ Grade 1 or 
baseline, decrease A445 treatment 
by 1 dose level. 
If event recurs at the reduced dose 
after receiving optimal supportive 
care, permanently discontinue 
study treatment. 
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System 
Adverse event 
Toxicity 
management 
Study drug management 
First occurrence of 
nonhematologic 
Grade 4 event 
Treat with appropriate 
supportive care as 
medically indicated. 
Hold study treatment until 
improved to ≤ Grade 1 or baseline.  
After resolution, decrease A445 by 
1 dose level, or permanently 
discontinue study treatment. 
Recurrent 
nonhematologic 
Grade 4 event 
Treat with appropriate 
supportive care as 
medically indicated. 
Permanently discontinue study 
treatment. 
Abbreviations: A445, BGB-A445; ANC, absolute neutrophil count; Hgb, hemoglobin. 
5.4.2.1. 
Dose Modification for BGB-A445  
After any interruption because of toxicity, BGB-A445 may be resumed at the same dose or at a 
reduced dose, depending on the toxicity, grade, prior events, and number of dose reductions. 
In general, a dose should be reduced to the next immediate lower dose level that was previously 
determined to be tolerable (Table 7).  A patient must discontinue BGB-A445 if, after BGB-A445 
is resumed at a lower dose, the toxicity recurs with the same or worse severity. 
A patient may have a maximum of 2 dose reductions.  Patients requiring > 2 dose reductions 
must discontinue study treatment except when, in the opinion of the investigator, the patient is 
benefiting from treatment.  For these patients, treatment may be continued after consultation and 
approval by the sponsor. 
Table 7: 
BGB-A445 Dose Reduction Levels  
 
Dose 
Frequency of Administration 
Initial dose level a 
 
Day 1 of each cycle (3 weeks) 
Dose Reduction 1 
 
Dose Reduction 2 b 
 
Dose Reduction 3 c 
Discontinue BGB-A445 
a The initial dose level of BGB-445 should be deemed as safe in the combination treatments during the safety 
lead-in.  
b BGB-A445 must be discontinued if, after it is resumed at a lower dose, the toxicity recurs with the same or worse 
severity. 
c If > 2 dose reductions are required for a patient, BGB-A445 must be discontinued unless, in the opinion of the 
investigator, the patient is benefiting from BGB-A445 treatment.  In this case, BGB-A445 may be continued after 
consultation with and approval by the sponsor. 
5.4.2.2. 
Dose Modification for Docetaxel  
Guidelines for docetaxel dose modifications presented in the US labeling to manage general 
toxicities are shown in Table 8. 
After any interruption because of toxicity, docetaxel may be resumed at the same dose or at a 
reduced dose, depending on the toxicity, grade, prior events, and number of dose reductions. 
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In general, a dose should be reduced to the next immediate lower dose level per the US labeling 
(Table 8).  A patient must discontinue docetaxel if, after docetaxel is resumed at a lower dose, 
the toxicity recurs with the same or worse severity. 
Table 8: 
Guidelines for Docetaxel Dose Modifications  
Adverse Event 
(Worst Grade in Previous Cycle) 
Action to Be Taken 
Febrile neutropenia/Grade 4 neutropenia ≥ 7 days 
Severe or cumulative cutaneous reactions 
Grade 3 or 4 nonhematologic toxicity 
Withhold docetaxel until resolution of toxicity 
and then resumed at 55 mg/m2. a 
Peripheral neuropathy ≥ Grade 3 
Recurrence of ≥ Grade 3 toxicity after prior dose 
reduction 
Discontinue docetaxel treatment. 
a Docetaxel 75 mg/m2 should be deemed as safe first during the safety lead-in. 
Do not treat or discontinue treatment, if started, in patients: 1) with bilirubin above upper limit of 
normal (ULN), or 2) with AST and/or ALT elevation above 1.5 x ULN concomitant with 
alkaline phosphatase above 2.5 x ULN. 
5.4.2.3. 
Dose Modification for Ramucirumab  
Guidelines for ramucirumab dose modifications presented in the US labeling to manage general 
toxicities are shown below. 
Infusion-Related Reactions (IRR) 
• Reduce the infusion rate of ramucirumab by 50% for Grade 1 or 2 IRRs. 
• Permanently discontinue ramucirumab for Grade 3 or 4 IRRs. 
Hypertension 
• Interrupt ramucirumab for severe hypertension until controlled with medical 
management. 
• Permanently discontinue ramucirumab for severe hypertension that cannot be 
controlled with antihypertensive therapy 
Proteinuria 
• Interrupt ramucirumab for urine protein levels ≥ 2 g/24 hours. Reinitiate treatment at 
a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to 
< 2 g/24 hours. If the protein level ≥ 2 g/24 hours reoccurs, interrupt ramucirumab 
and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to 
< 2 g/24 hours. 
• Permanently discontinue ramucirumab for urine protein level > 3 g/24 hours or in the 
setting of nephrotic syndrome. 
Wound Healing Complications 
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• Interrupt ramucirumab before scheduled surgery until the wound is fully healed. 
Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding 
• Permanently discontinue ramucirumab. 
Please refer to the label for additional information of the dose modification for ramucirumab. 
5.4.2.4. 
Dose Modification for Investigational Agents  
Dose modification for the investigational agent(s) is provided in the investigational 
agent-specific appendix. 
5.5. 
Continued Access to Study Drug After the End of the Study  
At the end of the study as determined by the sponsor, any patient who is still on treatment and, in 
the opinion of the investigator, continues to benefit from study treatment will continue treatment 
via being kept in the study for continuous access to study drugs. Continuous access could be 
terminated in case of a decision to stop manufacturing investigational agents used in the study. 
Patients will still be monitored by assessments as described in Section 7.3 and Section 8. No 
further data will be collected in EDC system for patients in continuous access to study drugs, 
SAE reports should be submitted through paper forms per requirements and timelines described 
in Section 8.6.2.  The blood and tissue samples for PK/ADA and biomarker analysis are not 
required to be collected. The continuous treatment access would be discontinued for reasons 
listed in Section 3.5 or when the total duration reaches 36 cycles (ie, approximately 2 years) as 
described in Section 3.3. During the continuous study treatment, patient visits should be 
dependent on investigator’s discretion. Other assessments, including but not limited to tumor 
assessment and adverse events collection, continue to follow the Appendix 1. These assessment 
data will be kept in study sites.  
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
The exclusion criteria specify that patients must not have received prior therapy for current lung 
cancer targeting OX40 or any other T-cell agonists including, but not limited to, 4-1BB and 
GITR (Section 4.2).  All prior cancer-related treatments, treatments for underlying active medical 
conditions, and all medications (eg, prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, and nutritional supplements) used by the patient ≤ 30 days before 
randomization must be recorded in the appropriate eCRF. 
Information on prior and concomitant therapies that are permitted, prohibited, and/or restricted in 
relation to a specific investigational agent is provided in each appendix. 
6.2. 
Concomitant Therapy  
If applicable, additional requirements with respect to concomitant therapy for a particular 
experimental cohort will be presented in the investigational agent-specific appendix. In addition 
to the common stipulations stated this section in the protocol body, investigational agent-specific 
requirements for concomitant therapy should be met based on patient assignment. 
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with the local 
standards of medical care at the discretion of the investigator for the supportive care (eg, 
antiemetics, antidiarrheals, pain medications, and nutritional support) and for a patient’s 
wellbeing are allowed. All concomitant medications will be recorded in the eCRF, including all 
prescriptions, over-the-counter drugs, herbal supplements, and intravenous medications and 
fluids. 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 in the 
eCRF. Medications received ≤ 30 days before the first dose or infusion of study drug and after 
the last dose or infusion of study drug are considered as concomitant medications and should be 
recorded. 
6.2.1.1. 
Systemic Corticosteroids  
Systemic corticosteroids for management of imAEs must be tapered gradually (see Appendix 8) 
and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the 
next study treatment administration. The short-term use of steroids as prophylactic treatments 
(eg, for patients with allergies to diagnostic imaging contrast dyes) is permitted. 
6.2.1.2. 
Hepatitis B Treatment  
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, as aligned with 
local guidance. Such medications must be documented in the patient’s chart and recorded in the 
eCRF. Patients receiving antivirals at screening should be treated for > 2 weeks before 
enrollment. Once initiated, antiviral treatment should continue until 6 months after the last dose 
of study treatment or as permitted by local guidance. 
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6.2.1.3. 
Hepatitis C Treatment  
Patients with detectable HCV RNA who are receiving treatment at screening must meet the 
criterion of negative HCV RNA to be eligible. If the patients are treated and eligible, they should 
remain on continuous, effective antiviral therapy during the study. Investigators can consider 
treatment with antivirals following the international or local guidelines as appropriate. Patients 
who are given antiviral therapy must initiate treatment > 14 days before enrollment and continue 
treatment during the study and for 6 months after study treatment discontinuation. 
6.2.1.4. 
Radiation Therapy  
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline provided 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 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if clinically indicated per investigators’ discretion and after consultation with 
the medical monitor.  Whenever possible, these patients should have a tumor assessment of the 
lesion(s) before receiving the radiotherapy in order to rule out progression of disease. 
It is not required to withhold study treatment during palliative radiotherapy. 
6.2.1.5. 
COVID-19 Vaccines  
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 ≤ 72 hours before or 
after study drug administration during the first 2 treatment cycles.  Vaccinations are considered a 
concomitant medication and hence should be entered in the eCRF.  The specific COVID-19 
vaccine should be recorded instead of generic language, eg, mRNA-1273 vaccine (Moderna), 
BioNTech vaccine (Pfizer), etc. 
6.2.2. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited from screening to the EOT/Safety Follow-up Visit: 
• Except for study treatment(s), any concurrent antineoplastic therapy(ies) (eg, any 
systemic anticancer therapy including chemotherapy, targeted therapies, hormonal 
therapy, immunotherapy, standard anticancer agents, and investigational anticancer 
agents, or any local antineoplastic treatment including radiotherapy, ablation, and 
other resection surgery for any cancer) are prohibited. 
• Live vaccines ≤ 28 days before randomization and ≤ 60 days after the last dose of 
study treatment(s) are prohibited. 
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• Herbal remedies for the treatment of cancer or Chinese patent medicines as anticancer 
treatment (regardless of cancer type) ≤ 14 days before the first dose of study drug(s) 
and during the treatment and EOT/Safety Follow-up Visit are prohibited 
(Appendix 13). 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with the liver or other major organ functions 
(eg, hypericin) are prohibited (Appendix 13). 
Patients must notify the investigator of all herbal remedies used during the study. 
6.2.3. 
Restricted Concomitant Medications/Procedures  
The following medications/procedures are 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 (per protocol) or for short-term use as prophylactic 
treatment. 
• Patients should not abuse alcohol or other drugs during the study. 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored. 
• Opiates and other medications required for palliative management of patients are 
allowed. Patients must notify the investigator of all concurrent medications used 
during the study. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Information on potential interactions between study drug and concomitant medications are 
provided in each investigational agent-specific appendix.  
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7. 
STUDY ASSESSMENTS AND PROCEDURES  
A table of scheduled study assessments for screening is provided in Appendix 1.  The 
assessments required for the treatment period, EOT Visit, Safety Follow-up, and Survival 
Follow-up are provided.  Patients will be closely monitored for safety and tolerability throughout 
the study.  All assessments must be performed and documented in the medical record for each 
patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (which must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Screening  
Screening evaluations will be performed ≤ 28 days before randomization.  Patients who agree to 
participate will sign the ICF before undergoing any screening procedure.  The screening period 
begins on the date the ICF is signed.  Screening evaluations may be repeated as needed within 
the screening period; the investigator will assess patient eligibility according to the latest 
screening assessment results. 
Results of standard-of-care tests or examinations performed before obtaining informed consent 
and ≤ 28 days before randomization may be used for the purposes of screening rather than 
repeating the standard-of-care tests unless otherwise indicated. 
For descriptions of assessments conducted during screening, see Section 7.3, Section 7.4, and 
Section 7.6. 
EGFR, ALK, BRAF V600E, RET, and ROS1 mutational status or other actionable alterations, if 
known, will be collected at screening.  Patients with known actionable alterations for which a 
targeted therapy has been approved by the local health authority will not be eligible.   
Rescreening under limited conditions may be allowed after consultation with the sponsor.  For 
example, rescreening may be considered when a patient narrowly misses a laboratory criterion 
that is correctable and not because of a rapidly deteriorating condition or disease progression.  
Rescreening is allowed only once.  Rescreened patients must provide new informed consent, as 
described in Section 7.1.1.  A new patient number will be assigned as described in Section 7.1.2. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before any 
study-specific procedures are performed.  ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization/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. 
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7.1.2. 
Patient Numbering  
After obtaining informed consent, study site personnel will access the interactive response 
technology (IRT) system to assign a unique patient number to a potential study participant. 
Patients who are rescreened (see Section 7.1) will be assigned a new patient number.  Screening 
numbers that are assigned to the same patient within the IRT system will be linked. 
7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply.  
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined.  No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
7.2.2. 
Enrollment and Randomization  
Patients enrolled in the study for safety lead-in will receive treatment for the appropriate 
experimental cohort.  All other patients will be randomized/enrolled to a treatment cohort 
according to the randomization ratios specified in Section 3.1 and Section 9.1.1 after enrollment.  
Site personnel will access the IRT system to enroll patients to perform randomization/enrollment 
and to enable study drug dispensation.  
Study treatment must commence ≤ 2 business days after randomization. 
7.3. 
Safety Assessments  
7.3.1. 
Vital Signs  
See Appendix 1 for vital signs to be collected at screening.  Vital signs collected during the 
treatment period and at the EOT Visit are described in the Schedule of Assessments 
(Appendix 1). 
7.3.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of the head, eyes, ears, nose, and throat, as well as the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
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At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed.  New or worsened clinically significant abnormalities are to be 
recorded as AEs on the eCRF.  Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements. 
7.3.3. 
Ophthalmologic Examination  
Because CPIs may be associated with imAEs, an eye exam, including a visual acuity test, 
captured before obtaining written informed consent and within 28 days of first dose of study 
drug may be used for the screening evaluation. 
Patients should be solicited before obtaining written informed consent and within 28 days of the 
first dose of study drug during screening for signs of uveitis, such as changes in visual acuity or 
intraocular inflammation (ex, blurred/distorted vision, blind spots, change in color vision, 
photophobia, tenderness/pain, and eyelid swelling), and referred to an ophthalmologist where slit 
lamp biomicroscopy should be considered, if warranted, for further evaluation if visual changes 
are reported.  For patients with symptomatic vision changes, dosing of study drug should be held 
until uveitis can be ruled out by an ophthalmologist.  For further management guidance see 
Appendix 8. 
7.3.4. 
Pulmonary Function Tests  
Pulmonary function tests including spirometry and assessment of oxygenation are required.  For 
the assessment of oxygenation, pulse oximetry at rest and with exercise is required at a 
minimum.  Moreover, the diffusion capacity could be tested alternatively for the assessment of 
oxygenation.  Pulmonary function tests are to be performed for all patients during the screening 
period to assist the determination of suitability on the study.  Respective test results need to be 
submitted to the sponsor.  For test results indicative of significantly impaired pulmonary function 
(eg, resting pulse oximetry < 90% on room air and further desaturation upon exercise, forced 
expiratory volume [FEV1] < 60% or diffusing capacity of the lungs for carbon monoxide 
[DLCO] [if performed] <  60% of age- and sex-adjusted predicted performance levels 
[Pellegrino et al 2005]), the medical monitor needs to be consulted to confirm eligibility. 
Tests may be repeated as clinically indicated while on study. 
7.3.5. 
Eastern Cooperative Oncology Group Performance Status  
The ECOG Performance Status (Appendix 4) will be assessed during the study. 
7.3.6. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of serum chemistry, hematology, coagulation, 
urinalysis, and thyroid function will be conducted as described in Appendix 1.  
If clinical chemistry, hematology, and coagulation at screening are not performed ≤ 7 days 
before study drug administration on Day 1 of Cycle 1, these tests should be repeated and 
reviewed within 48 hours before each study drug administration. 
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The following tests will also be conducted in this study at the timepoints shown in Appendix 1: 
• Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) must be performed and documented as negative ≤ 7 days 
before the randomization.  Furthermore, a negative urine or serum pregnancy test 
must be completed and recorded ≤ 72 hours before the administration of study drug(s) 
at each cycle.  A serum pregnancy test must be performed if the urine pregnancy test 
is positive or equivocal. 
• Thyroid function testing (ie, thyroid stimulating hormone, free triiodothyronine [T3], 
and free thyroxine [T4]).  Note: Total T3 [TT3] is acceptable in case free 
triiodothyronine analysis is not available). 
7.3.6.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatine kinase (CK) and CK cardiac isoenzyme (CK-MB) are monitored in all 
BGB-A445 studies to protect study participants and to quantify the risk of muscle inflammation 
(see Appendix 1 for the blood collection schedule and Appendix 8 for guidelines for the 
management of suspected immune-mediated myocarditis).  Serum troponins may be substituted 
per local guidelines if used consistently throughout the study. 
7.3.7. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all 
electrocardiogram (ECG) tracings.  Paper or electronic copies of ECG tracings will be kept as 
part of the patient’s permanent study file at the site. 
All ECGs are to be obtained predose on Day 1 of every cycle before other assessments scheduled 
at that same time (eg, vital sign measurements, blood draws, etc) and as clinically indicated.  The 
patient should rest in a semirecumbent supine position for ≥ 10 minutes in the absence of 
environmental distractions that may induce changes in heart rate (eg, television, radio, 
conversation, etc) before each ECG collection. 
On Day 1 of Cycle 1 and Cycle 5, ECGs must be performed predose and between 4 to 6 hours 
after study drug(s) infusion. 
Three consecutive 12-lead ECGs will be performed approximately 2 to 3 minutes apart to 
determine the mean QT interval corrected for heart rate using the Fridericia formula (QTcF) 
interval (see Appendix 1 for the schedule of ECG).  
7.3.8. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0.  
Characterization of toxicities will include frequency, severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.3.9. 
Hepatitis B and C Testing  
Testing will be performed by the local laboratory at screening (and as clinically indicated) and 
will include HBV/HCV serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B 
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core antibody [HBcAb], and HCV antibody).  In the case of active HBV or HCV infection, these 
tests will be followed by viral load assessment (HBV DNA and HCV RNA).  Patients who have 
detectable HBV DNA at screening regardless of screening results will undergo the respective 
viral load test every 4 cycles starting at Cycle 5. 
7.4. 
Tumor and Response Evaluations  
Tumor imaging will be performed ≤ 28 days before randomization.  Radiological images 
captured as standard of care before obtaining informed consent and ≤ 28 days before 
randomization may be used for the purposes of screening rather than repeating the 
standard-of-care tests.  During the study, tumor imaging will be performed every 6 weeks 
(± 7 days) from randomization for the first 9 months, and every 12 weeks (± 7 days) thereafter 
based on RECIST v1.1.  If a tumor assessment is missed or conducted outside of the specified 
assessment window, all subsequent scans should be conducted on the planned schedule. 
Screening assessments and each subsequent assessment of the tumor must include computed 
tomography (CT) scans (with oral and/or intravenous contrast, unless contraindicated) or a 
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis.  Other known or 
suspected sites of disease must be included in the imaging assessments. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation.  The same radiographic procedure used to 
assess disease sites at screening is required to be used throughout the study (eg, the same contrast 
protocol for CT scans or MRIs). 
• Imaging of the brain (preferably MRI) at baseline is required for all screened patients.  
Screening evaluations will be performed ≤ 28 days before randomization. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards of a 
diagnostic CT scan. 
• Bone scans (technetium-99m) or PET should be performed at screening if clinically 
indicated.  If bone metastases are present at screening and cannot be seen on CT or 
MRI scans, technetium-99m or PET bone scans should be repeated when a complete 
response (CR) is suspected in the target lesion or when progression in bone is 
suspected. 
− If bone metastases are visualized on the bone scan or PET scan at screening, a 
confirmatory CT/MRI scan should be performed.  If the metastases are confirmed 
by CT/MRI, then evaluation by CT/MRI should be given preference for 
subsequent assessments.  If the metastases are not confirmed by CT/MRI, then the 
use of bone scan or CT/MRI for subsequent assessments is at the investigator’s 
discretion. 
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− If an increase in the uptake of existing lesions is seen on a bone scan, or the 
appearance of new osteoblastic bone lesions is seen on an x-ray, CT, or MRI, this 
should not automatically be considered evidence of progression in an otherwise 
stable or responding subject.  It may in fact be indicative of response to therapy. 
− New areas of uptake seen on a bone scan should not automatically result in 
diagnosis of progressive disease but should be correlated with other available 
imaging (eg, CT, MRI, or x-ray). 
• CT scans of the neck or extremities should be performed at screening only if 
clinically indicated and should be repeated throughout the study if there is evidence 
of metastatic disease in these regions at screening. 
• At the investigator’s discretion, other methods of assessing target lesions and 
nontarget lesions per RECIST v1.1 may be used.  However, CT or MRI should be 
given preference for assessment of target lesions. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 5).  The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits. 
After initial documentation of response (CR or PR), confirmation of tumor response should 
occur ≥ 4 weeks after the first response or at the next scheduled assessment timepoint. 
At the investigator’s discretion, patients may continue their assigned treatment after progressive 
disease has been confirmed by the investigator per RECIST v1.1.  To continue treatment, the 
criteria for treatment beyond disease progression in Section 3.3 must be met. 
Tumor assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression.  Tumor assessment in such patients should continue until 
study treatment discontinuation. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original plan until the patient 
experiences disease progression, withdraws consent, is lost to follow-up, dies, or until the study 
terminates, whichever occurs first. 
Tumor assessments are required to be performed on schedule, regardless of whether study 
treatment has been administered or held.  That is, assessments should not be adjusted for delays 
in cycles. 
7.5. 
Pharmacokinetic and Antidrug Antibody Testing  
Blood samples will be collected for PK characterization of BGB-A445 and investigational 
agents.  The serum or plasma (as appropriate) samples will be assayed for BGB-A445 and/or 
investigational agent concentrations using validated bioanalytical methods.  Validated screening 
and confirmatory assays will be employed to detect ADAs for BGB-A445 and other 
investigational agents, as appropriate.  The immunogenicity evaluation will utilize a risk-based 
immunogenicity strategy (Koren et al 2008; Rosenberg and Worobec 2004a; Rosenberg and 
Worobec 2004b) to characterize ADA responses to BGB-A445 and investigational agents in 
support of the clinical development program.  
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The timing for blood sample collection for PK assessment and ADA testing is specified in 
Appendix 1. 
Shipping, storage, and handling of samples for the assessment of PK and ADA will be managed 
through the central laboratory.  Refer to the laboratory manual for instructions.  
7.6. 
Biomarkers  
Blood and tumor tissue samples will be collected at specified times as described in Appendix 2 
for the evaluation of biomarkers, including, but not limited to, soluble OX40 levels, 
concentrations of cytokine and soluble proteins in serum, circulating tumor DNA mutation 
analysis, investigational agent-specific protein expression, gene expression profiling, tumor 
infiltrating immune cells in tumor tissue, genomic alterations, and tumor mutation 
burden/microsatellite instability/genetic mutation and profiles.  Other assessments may be 
conducted as indicated and as allowed by local regulations. 
During the screening period, patients are required to provide archival tumor tissues (FFPE blocks 
containing tumor [preferred] or approximately 15 [at least 10] freshly cut unstained slides).  The 
most recently collected tissue is preferred.  
Optional biopsy after 2 cycles of treatment is recommended if the patient is medically fit and it is 
clinically feasible (within 3-day window before Cycle 3 Day 1 is recommended).   
Optional biopsies are also recommended from patients who have confirmed disease progression 
and at the EOT or Safety Follow-up Visit for evaluation of pharmacodynamic effects and 
resistance mechanism(s).  If feasible, post treatment biopsy samples should be taken from the 
same tumor lesion as the baseline biopsy or archival tissue. 
Tumor tissues will be sent to the designated laboratory for evaluation of the expression level of 
PD-L1, OX40, and other investigational agent-specific proteins.  In addition, other tumor 
tissue-based exploratory biomarkers, such as, but not limited to, tumor-infiltrating lymphocytes 
assessment, tumor mutation analysis, and gene expression profiling, may be tested and studied 
retrospectively in correlation with clinical response/benefit to treatments. 
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. 
Shipping, storage, and handling of blood as well as archival tumor and/or fresh tumor tissue 
samples for the assessment of biomarkers will be managed through a central laboratory.  Refer to 
the laboratory manual for details of sample handling and Appendix 2 for timepoints. 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drug  
8.1.1. 
Risks Associated With BGB-A445  
BGB-A445 is an investigational agent currently in clinical development.  Limited clinical 
information is available for BGB-A445.  OX40 is an immune costimulatory receptor involved in 
innate and adaptive immune tolerance and therefore imAEs are a potential risk for BGB-A445.  
Although most imAEs observed with CPIs have been mild and self-limiting, such events should 
be recognized early and treated promptly to avoid potential major complications.  Suggested 
evaluation and management guidelines for suspected imAEs are provided in Appendix 8.   
BGB-A445 is a monoclonal antibody drug formulated for intravenous infusion and, therefore, 
infusion-related reactions are a potential risk.  Symptoms of infusion-related reactions include 
angioedema, bronchospasm, chills/rigor, dizziness, fever, headache, hypertension, hypotension, 
myalgia, nausea, pruritus, rash, urticaria, and vomiting.  Severe reactions may include acute 
respiratory distress syndrome, cardiogenic shock, myocardial infarction, and ventricular 
fibrillation.  Patients should be closely monitored for such reactions.  The management for 
infusion-related reactions is outlined in Section 8.7.1. 
No animal reproductive and developmental toxicity studies have been conducted at this time.  
However, there were no gross lesions or histopathological changes noted in male or female 
reproductive organs of cynomolgus monkeys following 13 weeks of repeated doses. 
Refer to the BGB-A445 Investigator’s Brochure for more details.  
8.1.2. 
Risks Associated With Docetaxel  
Please refer to the Table 9 for the reported toxicity for docetaxel.  Because of the ethanol content 
in the docetaxel formulation, some patients may experience intoxication during and after 
treatment that should be monitored (and infusion rate decreased if appropriate).   
The investigator should refer to the package insert for a complete list of potential side effects. 
Table 9: 
A Summary of the Commonly Reported Toxicities of Docetaxel  
Most Common Side Effects 
Less Common Side Effects (but May Be Severe 
or Life Threatening) 
Myelosuppression ± infection or bleeding (may be 
severe) 
Hypersensitivity (may be severe) 
Fluid retention (may be severe) 
Neuropathy (may be severe) 
Cutaneous effects (including nails, may be severe) 
Alopecia 
Secondary malignancy/leukemia 
Cardiotoxicity, arrhythmia 
Pneumonitis 
Gastrointestinal obstruction, perforation, 
hemorrhage 
Venous thromboembolism 
Arterial thromboembolism 
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Gastrointestinal (anorexia, nausea, vomiting, 
stomatitis, diarrhea, constipation) 
Asthenia (may be severe) 
Disseminated intravascular coagulation 
Seizures 
Hepatotoxicity 
8.1.3. 
Risks Associated With Ramucirumab   
Please refer to the Table 10 for the reported adverse drug reactions (ADRs) for ramucirumab 
when given in combination with chemotherapies in some Phase 3 studies.   
Besides the ADRs mentioned in Table 10, serious and occasionally fatal arterial thromboembolic 
events occur when ramucirumab is given as a single agent.  Additionally, impaired wound 
healing is also likely to occur as ramucirumab is an antiangiogenic therapy with the potential to 
adversely affect wound healing.  
The investigator should refer to the package insert for a complete list of potential side effects. 
Table 10: 
A Summary of Adverse Drug Reactions Reported in Patients Treated With 
Ramucirumab in Combination With Chemotherapy or Erlotinib In Phase 3 
Clinical Trials   
Very Common Adverse Drug Reactions 
Common Adverse Drug Reactions 
Infections  
Neutropenia 
Leukopenia 
Thrombocytopenia 
Anemia 
Headache  
Hypertension 
Epistaxis 
Stomatitis  
Diarrhea 
Alopecia 
Proteinuria 
Fatigue 
Mucosal inflammation  
Peripheral edema 
Sepsis  
Febrile neutropenia 
Hypoalbuminemia 
Hyponatremia 
Pulmonary hemorrhage 
Gastrointestinal hemorrhage events 
Gastrointestinal perforation 
Gingival bleeding 
Palmar-plantar erythyrodysesthesia syndrome 
 
8.1.4. 
Risks Associated With Investigational Agent  
The information on the risks associated with the investigational agent(s) is provided in the 
respective appendix. 
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8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study.  Results from the 
nonclinical toxicology studies and clinical data with BGB-A445, as well as the 
nonclinical/clinical data from other OX40 inhibitors, were considered.  Specifically, patients at 
risk for developing study-emergent active autoimmune diseases or who have a history of 
autoimmune diseases that may relapse, patients who have undergone allogeneic stem cell or 
organ transplantation, and patients who have received a live vaccine ≤ 28 days before 
randomization are excluded from the study. 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0 (except as noted in Section 8.6.4).  All enrolled patients will be 
evaluated clinically and with standard laboratory tests at regular intervals during their 
participation in this study.  Safety evaluations will consist of medical interviews, physical 
examinations, vital signs, laboratory measurements (hematology, chemistry, etc), imaging, 
consultations (as needed), and other assessments including those listed in Appendix 1.  In 
addition, patients will be closely monitored for the development of any signs or symptoms of 
infections or autoimmune conditions. 
At the start of each cycle, study drug(s) will only be administered after clinical laboratory results 
have been reviewed.  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. 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in Section 8.7. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, or duration, and/or an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug administration, even 
though the condition may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
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• 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 must be blinded or 
redacted on the copies of the medical records before submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study.  AEs and 
SAEs should be assessed and graded based upon NCI-CTCAE v5.0. 
Toxicities that are not specified in NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
selfcare ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions.  Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment.  Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the administration of study drug should be considered and investigated.  The 
investigator should consult the investigator’s brochure of BGB-A445, investigator’s brochure of 
each investigational agent, and prescribing information of the marketed study drug in making his 
or her assessment. 
There may be situations when an SAE has occurred and the investigator has only limited 
information to include in the initial report to the sponsor.  However, it is very important that the 
investigator always assess causality for every SAE before transmitting the SAE report to the 
sponsor, because the causality assessment is one of the criteria used in determining regulatory 
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reporting requirements.  After considering follow-up information, the investigator may 
subsequently change his or her opinion of causality and may amend the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on all information available at the time of reporting.  An AE is considered 
related if there is “a reasonable possibility” that the AE may have been caused by the study drug 
(ie, there are facts, evidence, or arguments to suggest possible causation).  A number of factors 
should be considered in making this assessment, including the following: 
• Temporal relationship of the AE to the administration of study treatment or study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
• Biological plausibility 
• An AE should be considered “related” to study drug if any of the following criteria 
are met.  Otherwise, the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
8.3.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide the sponsor with further information on the patient’s condition. 
All AEs and SAEs that were documented at a previous visit/contact and designated as ongoing 
will be reviewed at subsequent visits/contacts.  
All AEs and SAEs will be followed until resolution, the condition stabilizes, or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultations with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
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New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs.  This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and significantly worsen during the study.  The definition of clinically significant is 
left to the judgment of the investigator.  In general, these are the laboratory test abnormalities or 
other abnormal assessments that meet the following criteria:  
• are associated with clinical signs or symptoms, or 
• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF.  Clinically associated events can be 
reported as a single event (eg, simultaneous occurrence of anemia, thrombocytopenia, and 
leukopenia may be reported as myelosuppression).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L (or mmol/L) 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF unless the etiology or grade changes.  
The initial grade of the event should be recorded, and the grade and seriousness should be 
updated any time the event changes. 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose, meet any of the following criteria: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE.  It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency department for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
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• 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 with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator or the sponsor based on 
medical judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are not considered to be SAEs: 
• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the investigator’s brochure of BGB-A445, investigator’s 
brochure of each investigational agent, and prescribing information of the marketed study drug. 
The assessment of SUSARs will be performed by the sponsor. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events  
8.6.1. 
Adverse Event Recording Period  
After informed consent has been signed but before the administration of the study drug, only 
SAEs associated with protocol-defined procedures should be reported to the sponsor. 
After the initiation of study drug, all AEs and SAEs, regardless of their relationship to the study 
drug, will be reported until either 30 days after the last dose of study drug(s) or the initiation of a 
new anticancer therapy, whichever occurs first.  Immune-mediated AEs (serious but not 
treatment-related or nonserious regardless of relationship to study drug[s]) should be recorded 
until 90 days after the last dose of study drugs (whichever occurs later), regardless of the 
initiation of a new anticancer therapy.  SAEs considered related to the study drug(s) that are 
brought to the attention of the investigator should be reported regardless of time since the last 
dose of treatment. 
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AEs and SAEs should be recorded according to the details in Table 11.  For the follow-up period 
for AEs, see Section 8.3.4.  For the definition of TEAEs, see Section 9.3.2. 
Table 11: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Cohorts 
Event type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEs associated with 
protocol-defined procedure 
Signing of informed 
consent 
First dose of study drug 
Non-serious AEs, AESIs, and 
SAEs a  
First dose of study drug 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs  
First dose of study drug 
Up to 90 days after last dose of BGB-A445 
or investigational agent(s) (whichever 
occurs later, regardless of initiation of new 
anticancer therapy), death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; SAE, serious adverse event. 
a All SAEs considered related to the study treatment(s) that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (≤ 24 hours after determination) to the sponsor or designee as 
described in Table 12. 
Table 12: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for sending 
initial/follow-up report a    
Documentation 
method 
Reporting method 
All SAEs 
≤ 24 hours after first 
knowledge of the SAE 
SAE report 
Electronic submission of 
SAE form to safety 
database b                        
Abbreviations: SAE, serious adverse event. 
a Report follow-up information that is clinically relevant and pertains to the SAE, which includes but is not limited 
to the following: update to the SAE, new additional SAE, outcome, seriousness criteria, investigator causality, event 
start date/date of onset, date of death, and relationship to each study drug.  Follow-up information will also be 
reported as per the discretion of the investigator if the new or updated information changes the medical assessment 
of the case.  
 b SAE reports should be submitted to the sponsor safety database electronically from within the electronic data 
capture system.  If the electronic submission is not available for any reason, a paper SAE form should be submitted 
by email or fax.  
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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, the investigator 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, the investigator must not wait 
to receive additional information before notifying the sponsor or designee of the SAE and 
completing the form.  The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.6.2.1.  The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
The investigator, or person responsible according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5) will be submitted to all applicable regulatory authorities 
and investigators for BGB-A445 and investigational agent 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 or her IRB/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 patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.6.4. 
Progressive Disease  
Progression of an underlying malignancy and related symptoms (including fatal outcomes) are 
not reported as an AE if it is clearly consistent with the expected pattern of progression of the 
underlying cancer.  In most cases, the expected pattern of progression will be based on RECIST 
criteria.  In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through the use of 
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objective criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an AE during the AE recording period on the Adverse Event eCRF, and 
immediately reported to the sponsor if assessed as a SAE.  
8.6.5. 
Deaths  
For this study, mortality is an efficacy endpoint.  Deaths that occur during the protocol-specified 
AE reporting period (see Section 8.6.1) that are attributed by the investigator solely to 
progression of underlying disease should be recorded on the end of study (EOS)/Death eCRF 
only. 
For all other deaths which occurred during the study safety reporting period (refer to 
Section 8.6.1 ), regardless of relationship to the study drug, the primary cause of death must be 
recorded as a fatal SAE on the Adverse Event eCRF and be immediately reported to the sponsor. 
Death should be considered an outcome and not a distinct event.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF.  Generally, only one such event should be reported.  If the cause of 
death is unknown or if it is a sudden death, then the death could be recorded as an AE as 
“unknown cause of death” or “sudden death.” 
8.6.6. 
Adverse Events of Special Interest  
An AE of special interest (serious or nonserious) is an AE of scientific and medical concern 
specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor could be appropriate.  Such an event might 
require further investigation to characterize and understand it.  Depending on the nature of the 
event, rapid communication by the study sponsor to other parties (eg, regulators) might also be 
warranted.  
AEs of special interest may warrant collection of additional information across the entire study 
population to better characterize these events (eg, particular laboratory parameters, vital signs, 
risk factors, concomitant therapies, and/or concomitant illnesses).  
AEs of special interest (no matter nonserious or serious) are required to be reported by the 
investigator to the sponsor immediately (ie, no more than 24 hours after learning of the event). 
AEs of special interest for this study are as follows:  
• The finding of a concurrent elevated ALT or AST (> 3 x ULN or > 3 x baseline if 
baseline was abnormal) in combination with an elevated bilirubin (> 2 x ULN or 
> 2 x baseline if baseline was abnormal). The most appropriate diagnosis or (if a 
diagnosis cannot be established) the abnormal laboratory values should be recorded 
on the eCRF. 
• Potential imAE  
• Grade ≥ 2 Immune-mediated hepatitis.  
• Grade ≥ 2 Immune-mediated pneumonitis.  
• Grade ≥ 2 Immune-mediated colitis.  
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• Grade ≥ 2 Immune-mediated myositis/rhabdomyolysis.  
• Grade ≥ 2 Immune-mediated myocarditis/pericarditis.  
• Grade ≥ 2 Immune-mediated reactions (ocular).  
• Grade ≥ 2 Immune-mediated reactions (CNS).  
• Grade ≥ 3 Immune-mediated skin adverse reaction. 
• Grade ≥ 3 Infusion-related Reaction. 
8.6.7. 
Pregnancies  
If a female patient or the female partner of a male patient becomes pregnant within 120 days 
after the last dose of study drug(s), a pregnancy report form must be submitted to the sponsor.   
If the patient receives docetaxel-containing combination treatment, a pregnancy report form must 
be submitted to the sponsor when the female patient or the female partner of the male patient 
becomes pregnant within 180 days after the last dose of study drug(s).   
The pregnancy report is a type of SAE report and must follow the same prompt reporting 
guidelines described in Section 8.6.2.1.  The outcome of the pregnancy, including any premature 
termination of the pregnancy, will also be reported to the sponsor. 
While pregnancy itself is not considered an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  An abortion, 
whether accidental, therapeutic, or spontaneous, should always be reported as an SAE.  
Similarly, any congenital anomaly or birth defect in a child born to a patient exposed to the study 
drug should be recorded and reported as an SAE. 
Patients who become pregnant must immediately discontinue treatment (see Section 3.5).  For 
patients who are no longer pregnant, resumption of treatment may be discussed with the medical 
monitor. 
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 RSI documents in the investigator’s brochure of BGB-A445, 
investigator’s brochure of each investigational agent, and prescribing information of the 
marketed study drug. 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events  
Treatment with anti-OX40 therapy or immune checkpoint inhibitors can cause autoimmune 
disorders.  All AEs considered by the investigator to be immune mediated (see Section 8.7.2) 
should be classified as imAEs and identified as such on the eCRF AE page. 
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8.6.10. 
Recording Infusion-Related Reactions  
Most anticancer treatments carry a risk for infusion reactions; the incidence may increase when 
different agents are administered concomitantly.  The majority of infusion-related reactions are 
characterized by nonspecific symptoms including headache, nausea, fever or chills, dizziness, 
flush, pruritus, and chest or back pain.  These may occur more frequently on initial exposure 
with less frequent, or less severe reactions observed on re-exposure.  Severe reactions are 
uncommon but may be fatal without appropriate intervention.  Any signs or symptoms 
experienced by patients during the infusion of pharmacologic or biologic agents or any event 
occurring on the first day of drug administration should be evaluated accordingly.  
Any event occurring during or within 24 hours of study drug administration and considered 
related to the infusion of study treatment should be recorded as a diagnosis (infusion-related 
reaction) on the Adverse Event eCRF.  Associated signs and symptoms, associated drug cycles, 
onset time, duration, etc should be recorded in the case narrative if the event meets the criteria of 
AESIs or SAEs.  
8.6.11. 
Recording Anaphylaxis  
Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may 
cause death.  It is characterized by the rapid development of airway and/or breathing and/or 
circulation problems.  Intramuscular adrenaline is the most important treatment.  Rechallenge is 
contraindicated.  The definition currently accepted by the EMA relies on clinical diagnostic 
criteria and does not specify a particular immunologic mechanism (Sampson et al 2006). 
It is acknowledged that the distinction between an infusion reaction and anaphylaxis (refer to 
Section 8.6.10) can be challenging, but nevertheless such distinction is necessary due to the 
different clinical consequences and the potential option of being rechallenged. 
To capture all potential AEs, it is recommended to report all cases meeting the clinical diagnostic 
criteria of anaphylaxis as a diagnosis of “Anaphylaxis” with appropriate NCI-CTCAE grading 
(only Grade 3 through 5 is applicable). 
8.7. 
Management of Events to be Monitored  
Infusion-related reactions, anaphylaxis, and imAEs according to the NCI-CTCAE criteria are 
outlined below.  In addition to the common statements with respect to AEs of special interest 
presented in this section, additional requirements regarding AEs of special interest for each agent 
are provided in the investigational agent-specific appendix, if applicable. 
8.7.1. 
Infusion-Related Reactions  
As a routine precaution after infusion of the study treatments, patients must be monitored.  Refer 
to Section 5.2 for the administration of the study treatments and monitoring time. 
Patients should be closely monitored during and after study drug administration for 
infusion-related reactions and anaphylaxis.  Immediate access to an intensive care unit (ICU) or 
equivalent environment and appropriate medical therapy (including epinephrine, corticosteroids, 
antihistamines, bronchodilators, and oxygen) must be available to treat infusion-related reactions 
and anaphylaxis. 
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See Appendix 8 and Appendix 10 for management of infusion-related reactions and anaphylaxis 
as well as treatment modifications. 
8.7.2. 
Immune-Mediated Adverse Events  
In this study, imAEs are of special interest.  Potential imAEs are listed in Table 13 below.  All 
AEs similar to those listed in the table should be evaluated in patients receiving BGB-A445 with 
investigational agent(s) to determine whether the AE is immune mediated.  The investigator 
should exclude alternative explanations (eg, combination drugs, infectious disease, metabolic 
causes, toxins, disease progression, or other neoplastic causes) with appropriate diagnostic tests 
that may include, but are not limited to, serologic, immunologic, and histologic (biopsy) data 
(see Appendix 8).  If alternative causes have been ruled out and the AE required the use of 
systemic corticosteroids, other immunosuppressants, or endocrine therapy, and it is consistent 
with an immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should 
be checked. 
The recommendations for diagnostic evaluation and management of imAEs are based on 
European Society for Medical Oncology and American Society of Clinical Oncology guidelines 
(Haanen et al 2017; Brahmer et al 2018), and common immune-mediated toxicities are detailed 
in Appendix 8.  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 on 
diagnostic evaluation and management of immune-mediated toxicities. 
Recommendations for managing imAEs are detailed in Appendix 8. 
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Table 13: 
Examples of Immune-Mediated Adverse Events 
Body System Affected 
Events 
Skin  
rash; vitiligo; follicular or urticarial dermatitis; erythematous/lichenoid 
rash; Sweet syndrome; full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis  
Endocrine 
thyroiditis; hypothyroidism; hyperthyroidism; hypophysitis with features of 
hypopituitarism; insulin-dependent diabetes mellitus; diabetic ketoacidosis; 
adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Musculoskeletal 
arthritis; arthralgia; myalgia; myasthenic syndrome/myasthenia gravis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis  
Cardiac 
pericarditis; myocarditis  
Neurologic 
encephalitis; meningitis; meningoradiculitis; meningoencephalitis; 
Guillain-Barré syndrome; neuropathy 
Recommendations for managing imAEs are detailed in Appendix 8. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade after restart of the study drug should permanently discontinue 
treatment. 
8.7.3. 
Hepatic Function Abnormalities  
When liver function laboratory abnormalities are observed, the investigator must evaluate for 
reactivation of viral hepatitis, consider other drug-related toxicities, and exclude progressive 
disease involving the liver.  Findings of an elevated ALT or AST (> 3 × ULN) in combination 
with either an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia are indicators of severe liver injury (potential 
Hy’s law case).  Investigators must report the occurrence as an SAE to the sponsor.  For 
diagnosis and management of patients with abnormal ALT or AST, please see Section 8.6.6 and 
refer to Appendix 8. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
9.1. 
Statistical Analysis  
9.1.1. 
Randomization  
As discussed in Section 7.2.2, once eligibility is determined, patients will be randomly assigned 
to a cohort using the IRT system.  For either stage, an equal randomization is initially applied to 
each cohort, and approximately 20 patients per cohort may be enrolled or randomized. 
9.1.2. 
Analysis Sets  
The Intent-to-Treat (ITT) Analysis Set consists of all the patients who were enrolled or 
randomized to a treatment cohort.  
The Safety Analysis Set consists of all the patients who were enrolled or randomized and 
received any dose of any study drug. 
The Efficacy Evaluable Analysis Set consists of all patients who were enrolled or randomized 
and received any dose of any study drug, have evaluable disease at baseline, and have 
≥ 1 evaluable postbaseline tumor response assessment unless any clinical progressive disease or 
death occurred before the first postbaseline tumor assessment. 
The PK Analysis Set consists of all the patients who received any dose of the study drug and for 
whom the valid study drug PK parameters can be estimated. 
The Biomarker Analysis Set consists of all the patients who received any dose of study drug(s) 
and have ≥ 1 derivable biomarker parameter. 
9.1.3. 
Patient Disposition  
The number of patients enrolled, randomized, treated, and discontinued from the study drug(s) 
and/or the study will be counted.  The primary reason for study drug(s) and/or study 
discontinuation will be summarized according to the categories in the eCRF.   
Important protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized using descriptive statistics.   
9.1.5. 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of the first dose of 
any 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 the EOT/Safety Follow-up Visit).  In addition, concomitant medication associated 
with an imAE or a new anticancer therapy at 60 and 90 days (± 14 days) after the last dose of 
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study drug(s), regardless of whether the patient starts a new anticancer therapy, may also be 
included as part of the analysis, where applicable. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary drug codes and will be further coded to the appropriate Anatomical Therapeutic 
Chemical (ATC) code indicating therapeutic classification.  Prior and concomitant medications 
will be summarized and listed by drug and drug class in the clinical study report for this study.   
9.2. 
Efficacy Analyses  
The efficacy endpoints will be based upon investigators’ tumor assessments per RECIST v1.1 
and will be summarized as follows to evaluate the anticancer activities of BGB-A445 combined 
with investigational agent(s): 
• ORR is defined as the proportion of patients with best overall response (BOR) of a 
CR or PR. 
• Duration of response (DOR) is defined as the time from the first determination of an 
objective response per RECIST v1.1 until the first documentation of progression or 
death, whichever comes first.  
• Disease control rate (DCR) is defined as the proportion of patients with BOR of a CR, 
PR, or stable disease.  
• Clinical benefit rate (CBR) is defined as the proportion of patients with BOR of a CR, 
PR, or stable disease lasting ≥ 24 weeks. 
• PFS is defined as the time from the date of randomization to the date of the first 
documentation of progressive disease or death due to any cause, whichever occurs 
first. 
• OS is defined as the time from the date of randomization to the date of death due to 
any cause. 
9.2.1. 
Primary Efficacy Analysis  
ORR assessed by the investigator will be reported.  The corresponding 95% CIs will be reported 
using the Clopper-Pearson method (Clopper and Pearson 1934).  
9.2.1.1. 
Stage 1 Primary Efficacy Analysis  
Confirmed ORR assessed by the investigator will be reported for each cohort.  The 
corresponding 95% CIs will be reported using the Clopper-Pearson method (Clopper and 
Pearson 1934).   
9.2.1.2. 
Stage 2 Primary Efficacy Analysis  
In Stage 2, the ORR difference between any experimental cohort and the concurrent reference 
cohort (ΔORR) and the corresponding 95% CIs will be reported.  For investigational agents 
evaluated in both stages, an analysis by combing the data from two stages will be conducted if 
deemed necessary. 
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9.2.2. 
Secondary Efficacy Analysis  
The DOR, CBR, and DCR will be summarized. The DOR will be estimated using the 
Kaplan-Meier method in the responders.  The CBR and DCR will be analyzed similarly to ORR. 
In addition, the difference between any experimental cohort and the reference cohort will be 
reported in Stage 2.   
Waterfall plots of maximum tumor shrinkage per patient will be presented. 
9.2.3. 
Exploratory Efficacy Analysis  
The PFS will be estimated using the Kaplan-Meier method.  The median PFS and the cumulative 
probability of PFS at every 3 months will be calculated for each cohort and presented with 
2-sided 95% CIs.  The PFS censoring rule will follow United States Food and Drug 
Administration Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics (US FDA 2018). 
OS will be analyzed similarly to PFS.  
9.3. 
Safety Analyses  
The safety profile will be determined by the AEs observed 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 NCI-CTCAE v5.0.  The incidence of DLT events and TEAEs will be 
reported as the number (percentage) of patients with TEAEs by Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and Preferred Term.  Descriptive 
summary statistics (eg, n, mean, standard deviation, median, minimum, and 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 using the 
Safety Analysis Set. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient, dose intensity, and relative dose intensity.  The number (percentage) of 
patients requiring dose modification and drug discontinuation because of AEs will be 
summarized. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation because of AEs will be summarized for each study drug.  Reasons for dose 
modifications will be summarized as well. 
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 
MedDRA.  AEs will be coded to MedDRA by the Lowest Level Term, Preferred Term, and 
primary System Organ Class. 
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A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug(s) and up to 30 days after the last dose of 
study drug(s) or initiation of new anticancer therapy, whichever occurs first.  Only those AEs 
that are treatment emergent will be included in summary tables of TEAEs.   
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(s).  
Treatment-related TEAEs include those events considered by the investigator to be related to a 
study drug or with a missing assessment of the causal relationship.  SAEs, deaths, TEAEs 
≥ Grade 3, imAEs, treatment-related TEAEs, and TEAEs that led to treatment discontinuation, 
dose interruption, dose reduction, or dose delay will be summarized. 
Immune-mediated AEs will be identified from all AEs that had an onset date or a worsening in 
severity from baseline (pretreatment) on or after the first dose of BGB-A445 and/or the 
investigational agent(s) and up to 90 days after the last dose of BGB-A445 or the investigational 
agent(s) (whichever occurs later), regardless of whether the patient starts a new anticancer 
therapy.  All AEs, treatment-emergent or otherwise, will be presented in patient data listings. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, and urinalysis) values will be evaluated 
for each laboratory parameter as appropriate.  Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range.  Reference (normal) ranges for 
laboratory parameters will be provided.  Descriptive summary statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables) for laboratory parameters and their changes from baseline will be calculated.  
Laboratory values will be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 will be summarized by 
NCI-CTCAE grade.  In the summary of laboratory parameters by NCI-CTCAE grade, 
parameters with NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, 
and sodium) will be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (body temperature, pulse rate, and systolic and 
diastolic blood pressure) and changes from baseline will be presented by visit for all visits.  Vital 
signs will be listed by patient and visit. 
9.4. 
Pharmacokinetic Analysis  
Serum/plasma concentration data will be tabulated and summarized by the visit/cycle at which 
these samples are collected.  Descriptive statistics will include means, medians, ranges, and 
standard deviations, as appropriate.  Additional PK analyses, such as population PK, may be 
conducted as appropriate.  Exposure-response (efficacy or safety endpoints) analysis may be 
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conducted if supported by data.  The results from these analyses will be reported separately from 
the main study report. 
9.5. 
Immunogenicity Analyses  
ADA samples will be collected for BGB-A445 and relevant investigational agents in this study 
as outlined in Appendix 1.  The immunogenicity results will be summarized using descriptive 
statistics by the number and percentage of patients who develop detectable ADAs.  The 
incidence of positive ADAs and neutralizing ADAs will be reported for evaluable patients.  The 
effect of immunogenicity on PK, efficacy, and safety may be evaluated if data allow and 
reported separately from the main clinical study report. 
9.6. 
Other Exploratory Analyses  
Summary statistics will be provided for pharmacodynamic biomarkers.  An exploratory analysis 
on a potential correlation of these pharmacodynamic biomarkers with the dose, safety, and 
preliminary anticancer 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(s) response, such as efficacy. 
9.7. 
Sample Size Consideration  
This study is designed to obtain efficacy, safety, PK, and immunogenicity data on BGB-A445 in 
combination with novel agents.  No formal hypothesis testing will be performed in the efficacy 
evaluation because the study is not designed to make explicit power and Type I error 
considerations for a hypothesis test.  In both Stage 1 and Stage 2, approximately 20 patients will 
be enrolled or randomized into each treatment cohort; approximately 6 patients will be enrolled 
first if a safety lead-in is planned. 
9.8. 
Interim Monitoring  
A futility analysis will be conducted when approximately 20 patients are enrolled or randomized 
in any of the experimental cohorts at the end of Stage 1 and when these patients have been 
followed up for ≥ 2 postbaseline tumor assessments.  Bayesian posterior probability will be used 
to evaluate clinical antitumor activity in Stage 1 for BGB-A445 in combination with 
investigational agents in each cohort.  An experimental cohort will be considered futile and not 
proceed to Stage 2 if the ORR in this group is unlikely to exceed a historical benchmark (eg, 
Posterior Probability [true ORR ≥ 23%] ≤ 20%).  The historical benchmark will be assessed 
periodically and may be updated based on the emergent data during the cause of the study. 
This section also provides the safety monitoring process with safety stopping rules that will be 
performed during the course of the study to evaluate the safety of any treatment cohort.    
To control the number of patients at risk in the event of a major safety concern, a pause in 
enrollment will be triggered by unacceptable conditions such as any death because of reasons 
other than disease progression and at least possibly related to the study treatment.  
The safety stopping boundaries for TR-Deaths (deaths possibly related to the study treatment) 
are listed in Table 14, which is derived based on the Bayesian posterior probability that the 
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number of patients with deaths possibly related to the study treatment is > 5% with 90% 
confidence and a weak prior distribution Beta (0.005, 0.095).  
Following the stopping boundaries, if the accumulating data in a cohort suggest that the 
incidence rate of TR-Deaths is likely to exceed 5% with 90% probability, the enrollment to that 
specific cohort will be paused, and a comprehensive evaluation of the safety data will be 
performed by the SMC and the sponsor.  Based on the totality of the data, recommendations 
from the SMC, and benefit-risk evaluation, the sponsor will take appropriate safety actions to 
continue or terminate enrollment in the relevant treatment cohort(s). 
Table 14: 
Safety Stopping Boundaries for Number of Patients With TR-Deaths  
Abbreviation: TR-Deaths, deaths possibly related to the study treatment. 
 
 
Number of Patients in a Cohort 
Number of Patients With TR-Deaths That Will 
Trigger Pause in Enrollment 
1-2 
≥ 1  
3-11 
≥ 2  
12-23 
≥ 3  
24-36 
≥ 4  
37-40 
≥ 5  
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10. 
STUDY COMMITTEES AND COMMUNICATION  
An SMC will be established to review safety data for patients enrolled in the safety lead-in and 
for regular safety monitoring during the randomization phase.  The SMC will include both 
investigators and the sponsor (including the medical monitor and study team members from 
Pharmacovigilance/Drug Safety, Clinical Pharmacology, and Biostatistics, with other members, 
as appropriate).  The SMC will review available safety and other relevant data as appropriate to 
make recommendations regarding dose selection, modification, and further enrollment.  The 
SMC may also be called upon by the sponsor to advise on the conduct of the study on an ad hoc 
basis where applicable.  The detailed scope and meeting frequency of the SMC is defined in the 
SMC charter. 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study can be fully documented.  Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals.  In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits any 
time during or after completion of this clinical study.  If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to provide the representatives of a regulatory agency or 
representatives of the sponsor with access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements.  Alternatively, the 
sponsor will file the protocol to the appropriate regulatory agency before the study is initiated at 
a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit.  Regulatory agencies may also conduct a regulatory inspection 
of this study.  Such audits/inspections can occur at any time during or after completion of the 
study.  If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his or her time and the 
time of his or 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(s).  This includes acknowledging receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product.  Dispensation records will document quantities received from the 
sponsor’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, and the initials of the person 
dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with the sponsor’s requirements specified in 
the Pharmacy Manual.  At appropriate times during the conduct of the study or at the end of the 
study after final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet the sponsor’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and the sponsor or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be reviewed periodically and verified by the 
study monitor over the course of the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the investigator and the study center in full conformance with 
the guidelines for Good Clinical Practice (ICH E6) and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the patient.  The study will also comply with the Definitions and 
Standards for Expedited Reporting (ICH E2A). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB/IEC.  
Copies of the IRB/IEC correspondence and approval of the amended ICF or other information 
and the approved amended ICF or other information must be forwarded to the sponsor promptly. 
The investigator is responsible for providing written summaries of the status of the study to the 
IRB/IEC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC.  Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments.  In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and the IRB/IEC.  Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor.  Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor.  All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements.  Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The final IRB/IEC-approved ICFs must be provided 
to the sponsor for health authority submission purposes according to local requirements. 
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The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate.  The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must reconsent to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study.  For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality  
The principal 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: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
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• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law.  In limited circumstances, such as in connection with insurance 
purposes or patient support services ancillary to certain study sites (eg, for patient travel or 
reimbursement), the 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 laboratory). 
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 US FDA, the China NMPA, and all other national and local health 
authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including, but not limited 
to, the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter.  This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor.  The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
13.5. 
Financial Disclosure  
Investigators (including any sub-investigators and coinvestigators) are required to provide the 
sponsor with sufficient accurate financial information in accordance with regulations to allow the 
sponsor to submit complete disclosure or certification to the absence of certain financial interest 
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of the clinical investigators, and/or disclose those financial interests, as required, to the 
appropriate health authorities.  This is intended to ensure financial interests and arrangements of 
the clinical investigators with the sponsor that could affect reliability of data submitted to health 
authorities are identified and disclosed by the sponsor.  Investigators are responsible for 
providing information about their financial interests before participation in the study and to 
update this information if any relevant changes occur during the study and for 1 year after 
completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs.  In no event should the entry of the study data into the eCRF be later 
than what is stipulated in the site contract after the data are collected or received by the 
investigator or study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an EDC system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor or appropriate regulatory authorities. 
14.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol will be stored by the sponsor at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.  Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study.  Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA.  AEs will be coded to MedDRA by the Lowest Level Term, Preferred Term, and 
primary System Organ Class.  Concomitant medications will be coded using the WHO Drug 
Dictionary.  Concomitant diseases/medical history will be coded using MedDRA. 
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14.2. 
Data Integrity and In-House Blinding  
Functions/persons with access to the EDC system shall be prohibited from using the EDC system 
to generate unnecessary listings or summaries that may introduce unwanted bias or to share such 
outputs from the EDC system with other functions or persons who do not have access to the 
EDC.  Although the study is open-label, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least 1 of the following categories: 1) investigator’s study file, and/or 
2) patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECGs, electroencephalograms, x-rays, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, etc. 
After closure of the study, the investigator must maintain all study records in a safe and secure 
location.  The records must be maintained to allow easy and timely retrieval when needed (eg, 
audit or inspection) and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel.  Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, or electronic); however, caution needs to 
be exercised before such action is taken.  The investigator must ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required.  Furthermore, the investigator must 
ensure that there is an acceptable backup of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to ≥ 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers away from the site so that they can be returned sealed to the 
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investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage away from the site. 
Subject to patient consent, or as otherwise allowed under applicable law, biological samples at 
the conclusion of this study may be retained for ≤ 10 years or as allowed by your IRB/IEC, 
whichever is shorter. 
14.4. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  Investigators assert that they will apply 
due diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol.  Any 
major deviations that might impact patient safety and/or data integrity must be promptly reported 
by the investigator to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
14.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies).  The sponsor 
will ensure that the report meets the standards set out in the Guideline for Structure and Content 
of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study.  The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential.  As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor.  Thereafter, any secondary publications will reference the original publication(s).  
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement.  This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy.  The 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 and/or protection in advance of the 
publication/presentation. 
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14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including but not limited to those for PK, ADA, and 
biomarkers) to the assay laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason.  
Potential reasons for suspension or discontinuation include, but are not limited to, safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations.  If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time.  When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons.  The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action.  If required by applicable regulations, the investigator must inform the IRB/IEC promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor.  In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to the following: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 14.5 
If a written contract for the conduct of the study is executed and it includes provisions 
inconsistent with this statement, that contract’s provisions shall apply rather than this statement. 
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15. 
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United States Food and Drug Administration Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics. December 2018. Accessed February 20, 2023. 
https://www.fda.gov/media/71195/download  
Voo KS, Bover L, Harline ML, et al. Antibodies targeting human OX40 expand effector T cells 
and block inducible and natural regulatory T cell function. J Immunol. 2013;191(7):3641-50.  
Walsh RJ, Soo RA. Resistance to immune checkpoint inhibitors in non-small cell lung cancer: 
biomarkers and therapeutic strategies. Ther Adv Med Oncol. 2020, 12: 1758835920937902.  
Wang R, Yan F, Hilt E, et al. Exploring OX40 receptor modulation in Phase 1/2a study of OX40 
costimulatory agonist BMS-986178+/- Nivo or IPI in patients with advanced solid tumors 
[AACR Abstract LB-127]. Cancer Res. 2018;78(13 Suppl):LB-127-LB-127.  
Willoughby J, Griffiths J, Tews I, et al. OX40: Structure and function - What questions remain? 
Mol Immunol. 2017;83:13-22.
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APPENDIX 1.  SCHEDULE OF ASSESSMENTS  
Screening 
a     
Treatment cycles 
Follow-up 
 
 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
≥ Cycle 3 
(every 
21 days) 
EOT/SFU Visit b 
60/90 Day SFU c 
Efficacy 
Follow-up 
Visit d 
Survival 
Follow-up 
Visit d 
Visit day 
 
1 8 
15 
1 
8 
15 
1 
+ 30 days 
(EOT/SFU 
Visit) 
+ 60 days 
(phone 
call SFU) 
+ 90 days 
(phone 
call SFU) 
Visit window 
-28 to -1 
 ± 1 ± 2 ± 2 ± 2 ± 2 
± 3 
± 7 
± 14 
± 14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history e  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications/procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/height f  
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical examination g  
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECOG PS 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
12-lead ECG h  
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Ophthalmologic examination 
i  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events j 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications/ 
procedures 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology k 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
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Screening 
a     
Treatment cycles 
Follow-up 
 
 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
≥ Cycle 3 
(every 
21 days) 
EOT/SFU Visit b 
60/90 Day SFU c 
Efficacy 
Follow-up 
Visit d 
Survival 
Follow-up 
Visit d 
Visit day 
 
1 8 
15 
1 
8 
15 
1 
+ 30 days 
(EOT/SFU 
Visit) 
+ 60 days 
(phone 
call SFU) 
+ 90 days 
(phone 
call SFU) 
Visit window 
-28 to -1 
 ± 1 ± 2 ± 2 ± 2 ± 2 
± 3 
± 7 
± 14 
± 14 
Clinical chemistry k 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Coagulation parameters k 
X 
X 
As clinically indicated 
X 
 
 
 
 
Urinalysis k 
X 
As clinically indicated 
 
 
 
 
Cardiac enzyme monitoring l 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy test m 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Thyroid function n 
X 
 
 
 
X 
 
 
Even-
numbere
d cycles 
X 
 
 
 
 
If applicable: HBV/HCV 
tests o 
X 
Every 4 cycles starting at Cycle 5 in patients with 
detectable HBV DNA or HCV RNA at screening 
or as clinically indicated in all patients 
 
 
 
 
If applicable: 
Pulmonary function tests p 
X 
As clinically indicated 
 
 
 
 
Blood biomarkers q 
 
See Appendix 2 
 
 
 
 
Tumor assessment r 
X 
Every 6 weeks (± 7 days) for the 
first 9 months after randomization, 
then every 12 weeks (± 7 days) 
thereafter 
X 
 
 
X 
 
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Screening 
a     
Treatment cycles 
Follow-up 
 
 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
≥ Cycle 3 
(every 
21 days) 
EOT/SFU Visit b 
60/90 Day SFU c 
Efficacy 
Follow-up 
Visit d 
Survival 
Follow-up 
Visit d 
Visit day 
 
1 8 
15 
1 
8 
15 
1 
+ 30 days 
(EOT/SFU 
Visit) 
+ 60 days 
(phone 
call SFU) 
+ 90 days 
(phone 
call SFU) 
Visit window 
-28 to -1 
 ± 1 ± 2 ± 2 ± 2 ± 2 
± 3 
± 7 
± 14 
± 14 
Archival or fresh tumor 
tissue s 
X 
See Appendix 2 
 
 
 
 
 
BGB-A445 administration t 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Investigational agents 
administration u 
 
Refer to Section 5.2 and respective 
appendix  
 
 
 
 
 
PK sampling of BGB-A445 v 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
PK sampling of BGB-15025 
and BGB-21958 w 
 
X X 
X 
X 
 
 
X 
 
 
 
 
 
Sampling of 
Anti-BGB-A445 x 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Survival status 
 
 
 
 
 
 
X 
Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-myocardial band; CT, computed tomography; ECG, electrocardiogram; ECOG 
PS, Eastern Cooperative Oncology Group Performance Status; EOT, End-of-Treatment (Visit); FFPE, formalin-fixed paraffin-embedded; HBcAb, hepatitis B 
core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IEC, Independent 
Ethics Committee; IRB, Institutional Review Board; imAE, immune-mediated AE; MRI, magnetic resonance imaging; MUGA, multigated acquisition; 
NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; PK, Pharmacokinetics; RECIST, Response Evaluation Criteria in 
Solid Tumors; SFU, Safety Follow-up; T3, triiodothyronine; T4, thyroxine; TT3, total T3. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
a Written informed consent is required before performing any study-specific procedure.  Results of standard-of-care tests or examinations performed before 
obtaining informed consent and ≤ 28 days before randomization may be used for screening assessments rather than repeating such tests, unless otherwise 
indicated. 
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b The EOT Visit will be conducted ≤ 7 days after the investigator determines that study treatment will no longer be administered or the patient discontinues the 
study treatment.  Patients will undergo the Safety Follow-up Visit at approximately 30 days [± 7 days] after the last dose or before the initiation of a new 
anticancer treatment, whichever occurs first.  If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT or 
Safety Follow-up Visit, these tests need not be repeated.  Tumor assessment is not required at the EOT or Safety Follow-up Visit if < 6 weeks have passed 
since the last assessment. 
c Sixty- and 90-day Telephone Safety Follow-up: Contacts with patients should be conducted to assess adverse events (AEs; serious or nonserious) and related 
concomitant medications, if appropriate, at 60 days (± 14 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 new or worsening AE at a telephone follow-up contact, the investigator should arrange 
an unscheduled visit if a further assessment is indicated. 
d Efficacy Follow-up Period: Patients who discontinue study drug(s) for reasons other than progressive disease will continue to undergo tumor assessments per 
the original plan until the patient experiences progressive disease, starts subsequent anticancer therapy, or for any other reason listed in Section 3.8, whichever 
occurs first; Survival Follow-up Period: Overall survival data will be collected via telephone calls approximately every 8 weeks (± 7 days) after the Safety 
Follow-up Visit or as directed by the sponsor until death, loss to follow-up, withdrawal of consent, or the end of the study. 
e Includes age or year of birth, gender, and self-reported race/ethnicity.  
f Height assessment is required only at screening.  Vital signs will include measurements of weight, temperature (˚C), pulse rate, and blood pressure (systolic and 
diastolic) while the patient is in a seated position after resting for 10 minutes.  If coinciding with study drug infusions, the patient’s vital signs (temperature 
[˚C], pulse rate, and blood pressure [systolic and diastolic]) are required to be recorded within 60 minutes before, during, and 30 (± 10) minutes after the first 
infusion of study drug(s).  For subsequent infusions, vital signs (temperature [˚C], pulse rate, and blood pressure [systolic and diastolic]) will be collected 
within 60 minutes before infusion of each study drug(s), and if clinically indicated, during and 30 (± 10) minutes after each study drug(s) infusion. 
g Complete physical examination is required at screening while subsequent visits entail limited, symptom-directed physical examinations (as detailed in 
Section 7.3.2).  In addition, investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study 
visit during study treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
h The ECG recording will be performed predose on Day 1 of each cycle at the same time and when clinically indicated. On Day 1 of Cycle 1 and Cycle 5, ECGs 
must be performed predose and between 4 to 6 hours after study drug(s) infusion.  During screening and at EOT Visit, 3 consecutive ECGs will be performed 
approximately 2 to 3 minutes apart.  All ECGs are to be obtained before other assessments scheduled at that same time (vital sign measurements, blood draws, 
etc).  The patient should rest in a semirecumbent or supine position for ≥ 10 minutes in the absence of environmental distractions that may induce changes in 
heart rate (television, radio, conversation, etc) before each ECG collection. 
i  Eye examinations, including a visual acuity test captured before obtaining written informed consent and within 28 days of the first dose of study drug, may be 
used for the screening evaluation rather than repeating tests.  Eye examinations, including a visual acuity test, will be assessed by an appropriate specialist at 
the Screening Visit. 
j AEs and laboratory abnormalities will be graded per NCI-CTCAE Version 5.0.  
k Local and/or central laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted.  If clinical chemistry, hematology, 
cardiac enzyme, and coagulation at screening are not performed ≤ 7 days before study drug(s) administration on Day 1 of Cycle 1, these tests should be 
repeated and reviewed within 48 hours before study drug administration.  After Day 1 of Cycle 1, results are to be reviewed within 48 hours before study drug 
administration.  See Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
l CK and CK-MB levels will be evaluated at the timepoints specified within the table and when clinically indicated.  All patients will have creatine kinase and 
CK-MB testing at screening, and testing is to be repeated at all scheduled visits during the first 3 treatment cycles, all predose assessments from Cycle 4 
onwards, and at the End-of -Treatment/Safety Follow-up visit.  If CK-MB fractionation is not available, assess troponin I and/or troponin T instead.  Refer to 
Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
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m A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
≤ 7 days before the randomization.  A negative urine or serum pregnancy test must be completed and recorded ≤ 72 hours before the administration of study 
drug(s) at each cycle.  A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
n Analysis of T3, T4, and thyroid stimulating hormone will be performed by the local study site laboratory at screening and even numbered cycles.  TT3 is 
acceptable in case T3 analysis is not available. 
o Testing will be performed (local laboratory) at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody).  In the case of 
active HBV or HCV infection, these tests will be followed by viral load assessment (HBV DNA and HCV RNA).  Patients who have detectable HBV DNA or 
HCV RNA at screening regardless of screening results will undergo the respective viral load test every 4 cycles starting at Cycle 5. Patients who do not have 
active HBV/HCV infection or detectable HBV DNA or HCV RNA at screening will not be required to undergo the HBV/HCV tests at the EOT or Safety 
Follow-up Visit.  
p Pulmonary function tests including spirometry and assessment of oxygenation are required.  For the assessment of oxygenation, pulse oximetry at rest and with 
exercise is required at a minimum.  Moreover, the diffusion capacity could be tested alternatively for the assessment of oxygenation.  Pulmonary function tests 
are to be performed for all patients during the screening period to assist the determination of suitability on the study.  Respective test results need to be 
submitted to the sponsor. Refer to Section 7.3.4 for more details. 
q Blood biomarkers: See Appendix 2.  
r Tumor imaging will be performed ≤ 28 days before randomization. Results of standard-of-care tests or examinations performed before obtaining informed 
consent and ≤ 28 days before randomization may be used for the purposes of screening rather than repeating the standard-of-care tests.  During the study, tumor 
imaging will be performed approximately every 6 weeks (± 7 days) from randomization for the first 9 months, and every 12 weeks (± 7 days) thereafter, based 
on RECIST Version 1.1.  Tumor assessments must include CT scans (with oral and/or intravenous contrast, unless contraindicated) or MRI, with preference for 
CT, of the chest, abdomen, and pelvis.  All measurable and evaluable lesions should be assessed and documented at the Screening Visit and reassessed at each 
subsequent tumor evaluation.  The same radiographic procedure used to assess disease sites at screening must be used throughout the study (eg, the same 
contrast protocol for CT scans).   
s Archival or fresh tumor tissue: During the screening period, patients are required to provide archival tumor tissue (FFPE blocks containing tumor [preferred] or 
approximately 15 [at least 10] freshly cut unstained slides).  The most recently collected tissue is preferred. See Appendix 2. 
t BGB-A445 will be given intravenously on Day 1 of each 21-day cycle (once every 3 weeks) (see Section 5.2 5.2.1 for details).  Note: BGB-A445 must always 
be prepared and administered separately from any other systemic medication including investigational agents.   
u Investigational agents including docetaxel will be given intravenously on Day 1 of each 21-day cycle (every 3 weeks), while investigational agents including 
BGB-15025 will be received orally on a daily basis for each 21-day cycle (every 3 weeks) before the infusion.  Refer to the respective appendix for details. 
v Predose serum samples for BGB-A445 (≤ 60 minutes before starting infusion) are required to be collected on Day 1 of Cycles 1, 2, 5, 9, and 17.  Postdose 
serum samples (≤ approximately 30 minutes after completing study drug infusion) are required to be collected on Day 1 of Cycles 1 and 5.  An additional PK 
sample is required to be collected at the Safety Follow-up Visit.  Should a patient present with any ≥ Grade 3 immune-mediated adverse event (imAE), an 
additional blood PK sample may be taken.  These tests are required when it is allowed by local regulations/Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs). 
w Predose blood samples for BGB-15025 and its metabolite BGB-21958 (≤ 30 minutes before dose) are required to be collected on Day 1 of Cycles 1, 2, and 3, 
and Days 8 and 15 of Cycle 1.  Postdose blood samples at 2 hours (± 10 minutes) and 4-6 hours (± 20 minutes) after dosing are required to be collected on Day 
1 of Cycles 1 and 2.  Should a patient present with any ≥ Grade 3 imAE, an additional blood PK sample may be taken.  These tests are required when it is 
allowed by local regulations/IRBs/IECs. 
x Blood samples to test for anti-BGB-A445 antibody will be collected ≤ 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 5, 9, and 17 and at the 
Safety Follow-up Visit.  All samples should be drawn at the same time as blood collection for the predose PK analysis.  These tests are required when it is 
allowed by local regulations/IRBs/IECs. 
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APPENDIX 2. BLOOD AND TUMOR TISSUE BIOMARKER ANALYSIS  
Screening 
Treatment cycles 
Follow-up 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
≥ Cycle 3 
(every 
21 days) 
EOT/SFU Visit  
60/90 Day SFU 
Efficacy 
Follow-up 
Visit 
Survival 
Follow-up 
Visit 
Visit day 
-28 to -1 
1 
8 15 
1 
8 15 
1 
+ 30 days 
(EOT/SFU 
Visit) 
+ 60 
days 
(phone 
call 
SFU) 
+ 90 
days 
(phone 
call 
SFU) 
Visit window 
 
 
± 
1 
± 
2 
± 2 
± 
2 
± 
2 
± 3 
± 7 
± 14 
± 14 
Archival or fresh tumor 
tissue a  
X 
 
 
 
 
 
 
X (Cycle 3 
only) 
X 
 
 
 
 
Blood collection for 
biomarker analysis 
(Soluble OX40) b 
X 
(predose) 
X 
 
X 
(predose)  
 
  
 
 
 
 
 
 
Blood collection for 
biomarker analysis 
(cytokine/chemokine or 
soluble proteins) c 
 
X 
(predose) 
X 
 
X 
(predose)   
 
 
 
 
 
 
 
Blood collection for 
biomarker analysis 
(ctDNA/TMB/ 
mutation profiling)s d 
 
X 
(predose)  
 
 
 
 
X (predose, 
same visit as 
every tumor 
assessment 
until 
progressive 
disease) 
X 
(confirmed 
progressive 
disease) 
 
 
 
 
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Abbreviations: ctDNA, circulating tumor DNA; EOT, End-of-Treatment (Visit); FFPE, formalin-fixed paraffin-embedded; MSI, microsatellite instability; SFU, 
Safety Follow-up; TMB, tumor mutation burden. 
a Patients are required to provide an archived FFPE tumor tissue sample (block or approximately 15 [at least 10] freshly unstained FFPE slides). The most 
recently collected tissue is preferred. Optional biopsy after 2 cycles of treatment is recommended if the patient is medically fit and it is clinically feasible 
(within 3-day window before Day 1 of Cycle 3 is recommended). Patients who have progressive disease will be asked to provide an optional biopsy sample at 
the EOT Visit (or at a clinically feasible visit and as deemed appropriate by the treating physician) for the assessment of mechanisms of resistance.  
b Blood collection for biomarker analysis (Soluble OX40): Blood will be collected at Day 1 of Cycle 1 (predose), Day 8 of Cycle 1, and Day 1 of Cycle 2 
(predose). 
c Blood collection for biomarker analysis (cytokine/chemokine or soluble proteins): Blood samples for cytokine and soluble protein analysis will be collected at 
Day 1 of Cycle 1 (predose), Day 8 of Cycle 1, and Day 1 of Cycle 2 (predose). 
d Blood collection for biomarker analysis (ctDNA/TMB/mutation profiling): Blood samples will be taken predose on Day 1 of Cycle 1, then at every tumor 
assessment schedule until progressive disease, and at the EOT Visit after disease progression to evaluate TMB, MSI, mutational profiles, as well as other 
biomarkers in blood.  
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS  
Serum chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
function 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Potassium 
Sodium 
Calcium a  
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
Lipase 
Amylase 
Red blood cell 
count 
Hematocrit 
Hemoglobin 
Platelet counts 
WBC count 
Lymphocyte 
count 
Neutrophil count 
Prothrombin time 
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
International 
normalized ratio 
Glucose 
Protein 
Blood 
Ketones 
24-hour protein  
  
Free 
triiodothyronine 
Free thyroxine 
Thyroid 
stimulating 
hormone 
Abbreviations: WBC, white blood cell. 
a Calcium values will be corrected for patients with hypoproteinemia.  
  
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APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: Oken et al 1982.  Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 
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APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
Source: Eisenhauer et al 2009 
Definitions  
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1).  Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no 
less than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
• The concept of cystic metastases also applies to metastatic lesions with a necrotic 
component. Hence, measurable lesions with a necrotic component may be selected as 
target lesions. However, if non-necrotic lesions are present, these are preferred for 
selection as target lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  A maximum of 2 measurable 
lymph nodes, inclusive of all lymphatic chains involved, may be chosen as target lesions (ie, the 
lymphatic system is considered one organ).  Target lesions should be selected based on size 
(lesions with the longest diameter), how representative they are of all involved organs, and 
whether they lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures, which may be 
visible by imaging even if not involved by tumor.  Pathological nodes, which are defined as 
measurable and may be identified as target lesions, must meet the criterion of a short axis of 
≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as 2 perpendicular dimensions in the 
plane in which the image is obtained (for a CT scan, this is almost always the axial plane; for 
MRI, the plane of acquisition may be axial, sagittal, or coronal, but the axial plane is 
recommended for measurements).  The smaller of these measures is the short axis.  For example, 
an abdominal node that is reported as being 20 mm by 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with a short axis ≥ 10 mm but < 15 mm) 
should be considered nontarget lesions.  Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as a reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
nontarget lesions and should also be recorded at baseline.  Measurements are not required, and 
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these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”).  If a nontarget lymph node normalizes 
(< 10 mm in short axis) after baseline, the respective evaluation should be “absent.” 
Guidelines for Evaluation of Measurable Disease  
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  An imaging-based evaluation 
should always be done rather than a clinical examination, unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than x-ray, particularly in 
identifying new lesions.  However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: Target lesion measurements should be performed in the axial plane.  CT is 
the best currently available and reproducible method to measure lesions selected for 
response assessment.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  When CT scans 
have a slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (eg, 
for body scans).  If there is a change from CT to MRI or the reverse, target lesions 
should continue to be measured provided the imaging parameters do not render 
measurements incomparable. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
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• 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 studies 
where recurrence after complete response (CR) or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.   
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain).  When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
Response Criteria 
Evaluation of Target Lesions 
• CR: Disappearance of all target lesions.  Any pathological lymph nodes must have 
reduction in short axis to < 10 mm. 
• PR: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
• Progressive Disease : 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 progressive disease, taking as reference the smallest sum diameters 
while on study. 
• Both PR and progressive disease: If the change in sum of diameters is consistent with 
both PR and progressive disease at a tumor assessment visit, progressive disease 
should take precedence. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  The case report form may be designed to have target 
nodal lesions recorded in a separate section where, to qualify for CR, each node must 
achieve a short axis < 10 mm.  For PR, stable disease, and progressive disease, the 
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actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 
• Target lesions that become “too small to measure”: While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.”  When this 
occurs, it is important that a value be recorded on the electronic case report form 
(eCRF).  If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.  If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat, such 
as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in 
this circumstance as well).  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially nonreproducible; therefore, providing this 
default value will prevent false responses or progressions based upon measurement 
error.  To reiterate, however, if the radiologist is able to provide an actual measure, 
that measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (< 10 mm short axis). 
• Non-CR/Non-progressive disease: Persistence of 1 or more nontarget lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
• Progressive disease: Unequivocal progression (as detailed below) of existing 
nontarget lesions.  (Note: The appearance of 1 or more new lesions is also considered 
progression.) 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of stable 
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disease or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.  A modest “increase” in the size of 1 or more 
nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
nontarget disease in the face of stable disease or PR of target disease will therefore be 
extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
Phase 3 studies when it is not a criterion of study entry to have measurable disease.  
The same general concept applies here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition: if all lesions are truly nonmeasurable), a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in nonmeasurable 
disease is comparable in magnitude to the increase that would be required to declare 
progressive disease for measurable disease: ie, an increase in tumor burden 
representing an additional 73% increase in “volume” (which is equivalent to a 20% 
increase diameter in a measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large,” an 
increase in lymphangitic disease from localized to widespread, or it may be described 
in protocols as “sufficient to require a change in therapy.”  If “unequivocal 
progression” is seen, the patient should be considered to have had overall progressive 
disease 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 preexisting lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is a 
patient who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered that reveals metastases.  The patient’s brain metastases are considered evidence of 
progressive disease even if he or she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents a truly new disease.  If repeat scans confirm 
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there is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in the assessment of progression (particularly possible “new” disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
progressive disease 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 
progressive disease.  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 progressive disease 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 progressive disease. 
• 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-progressive disease 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-progressive disease or not all 
evaluated 
No 
PR 
Stable disease 
Non-progressive disease or not all 
evaluated 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
NE 
Progressive 
disease 
Any 
Yes or No 
Progressive 
disease 
Any 
progressive disease 
Yes or No 
Progressive 
disease 
Any 
Any 
Yes 
Progressive 
disease 
Abbreviations: CR, complete response; NE, not evaluable; PR, partial response. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
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Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-progressive disease 
No 
Stable disease (Non-CR/non-progressive 
disease) 
Not all evaluated 
No 
NE 
Unequivocal progressive disease 
Yes or No 
Progressive disease 
Any 
Yes 
Progressive disease 
Abbreviations: CR, complete response; NE, not evaluable. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment 
until the end of treatment considering any requirement for confirmation.  On occasion, a 
response may not be documented until after the end of therapy, so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response.  
Protocols must specify how any new therapy introduced before progression will affect best 
response designation.  The patient’s best overall response assignment will depend on the findings 
of both target and nontarget disease and will also take into consideration the appearance of new 
lesions.  Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement.  Specifically, in nonrandomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response.” 
The best overall response is determined once all the data for the patient are known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these studies is defined as the best response across all timepoints 
(for example, a patient who has stable disease at first assessment, PR at second assessment, and 
progressive disease on last assessment has a best overall response of PR).  When stable disease is 
believed to be the best response, it must also meet the protocol-specified minimum time from 
baseline.  If the minimum time is not met when stable disease is otherwise the best timepoint 
response, the patient’s best response depends on the subsequent assessments.  For example, a 
patient who has stable disease at first assessment, progressive disease at second, and does not 
meet minimum duration for stable disease, will have a best response of progressive disease.  The 
same patient lost to follow-up after the first stable disease assessment would be considered 
inevaluable. 
Best response determination in studies where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order to not to overstate progression should it 
be based on increase in the size of the nodes.  As noted earlier, this means that patients with CR 
may not have a total sum of “zero.” 
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In studies where confirmation of response is required, repeated "NE" (not evaluable) timepoint 
assessments may complicate best response determination.  The analysis plan for the study must 
address how missing data/assessments will be addressed in determination of the response and 
progression.  For example, in most studies it is reasonable to consider a patient with timepoint 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and inevaluability” are study specific and 
should be clearly described in each protocol (depending on treatment duration, and treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease-specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to a false positive CR because of limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions. cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response 
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies.  However, in all other circumstances, ie, in 
randomized studies (Phase 2 or 3) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of study results.  However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies that are not blinded. 
In the case of stable disease, measurements must have met the stable disease criteria at least once 
after study entry at a minimum interval (in general, not less than 6 weeks). 
Duration of Overall Response 
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The duration of overall response is measured from the time measurement criteria are the first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR 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 (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for the calculation of progressive 
disease). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular study, the protocol should specify the minimal time interval 
required between 2 measurements for the determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between studies are to be made. 
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APPENDIX 6. PREEXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves disease 
Guillain-Barre syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome 
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Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Koyanagi-Harada disease 
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APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure 
at rest.  If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
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APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated 
adverse event (imAE) are intended as guidance.  This document should be used in conjunction 
with expert clinical judgement (by specialist physicians experienced in the treatment of cancer 
using immunological agents), and individual institutional guidelines or policies. 
The recommendations for diagnostic evaluation and management of imAEs are based on 
European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology 
(ASCO) guidelines (Haanen et al 2017; Brahmer et al 2018).  For any adverse events (AEs) not 
included in the tables below, refer to the ASCO Clinical Practice Guideline (Brahmer et al 2018) 
for further guidance on diagnostic evaluation and management of immune-mediated toxicities. 
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 treatment and the AE? 
• How did the patient respond to withdrawal of study treatment? 
• Did the event recur when study treatment was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the electronic case report form (eCRF) should be checked.  If further 
diagnostic evaluations change the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse 
Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid disorders 
Scheduled and repeated thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  
Perform pituitary and whole brain MRI in patients with headache, visual 
disturbance, unexplained fatigue, asthenia, weight loss, and unexplained 
constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is 
detected. 
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Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
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. 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive 
testing, including the following: FBC, UEC, LFTs, CRP, TFTs, stool 
microscopy and culture, viral PCR, Clostridium difficile toxin, and 
cryptosporidia (drug-resistant organism). 
In case of abdominal discomfort, consider imaging (eg, x-ray, CT scan).  If 
a patient experiences bleeding, pain, or distension, consider colonoscopy 
with biopsy and surgical intervention as appropriate. 
Eye disorders 
If a patient experiences acute, new onset, or worsening of eye 
inflammation; blurred vision; or other visual disturbances, refer the patient 
urgently to an ophthalmologist for evaluation and management. 
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend 
on severity of the AE (eg, daily if Grade 3 to 4; every 2 to 3 days if 
Grade 2, until recovering).  Review medications (eg, statins, antibiotics) 
and alcohol history.  Perform liver screen including Hepatitis A/B/C 
serology, Hepatitis E PCR and assess anti-ANA/SMA/LKM/SLA/LP/LCI, 
iron studies.  Consider imaging (eg, ultrasound scan for metastases or 
thromboembolism).  Consult with a hepatologist and consider liver biopsy. 
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  
Consider renal ultrasound scan, protein assessment, or phase-contrast 
microscopy.  Refer to a nephrologist for further management assistance. 
Dermatology 
Consider other causes by conducting a physical examination.  Consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint x-ray and other imaging as required to 
exclude metastatic disease.  Perform autoimmune serology and refer to a 
rheumatologist for further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include CK, ESR, 
CRP, troponin, and consider a muscle biopsy. 
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Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
Management of Immune-Mediated Adverse Events 
Immune-mediated AEs can escalate quickly.  Study treatment interruption, close monitoring, 
timely diagnostic work-up, and treatment intervention as appropriate are 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 study medical monitor. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade after the restart of study drug should permanently discontinue 
treatment. 
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be considered 
if there is evidence of a clinical response to study treatment, after consultation with the study 
medical monitor. 
Corticosteroid 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. 
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Management of Immune-Mediated Adverse Events 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Thyroid 
disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to 
normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat 
with a beta blocker, and consider 
oral prednisolone 0.5 mg/kg/day 
for thyroid pain. 
Taper corticosteroids over 2-4 
weeks.  Monitor thyroid function 
regarding the need for hormone 
replacement. 
Continue study 
treatment or 
withhold treatment 
in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization 
required 
Refer patient to an 
endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for 
the elderly or those with 
comorbidities, the suggested 
starting dose is 0.5 µg/kg/day).  
Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker and 
may require carbimazole until 
thyroiditis resolves. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1.  
Hypophysitis 
1-2 
Mild-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for patients with 
pituitary inflammation.  Taper 
corticosteroids over at least 
1 month. 
If there is no improvement in 
48 hours, treat as Grade 3-4. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or life-
threatening 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. 
Initiate pulse intravenous 
methylprednisolone 1 mg/kg for 
patients with headache/visual 
disturbance due to pituitary 
inflammation.  Convert to oral 
prednisolone and taper over at 
least 1 month. 
Maintain hormone replacement 
according to endocrinologist’s 
advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary 
inflammation until 
resolved/improved 
to ≤ Grade 2.  
Discontinuation is 
usually not 
necessary.  
Pneumonitis 
1 
Radiographic 
changes only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: 
exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if 
symptoms/appearance persist for 
48 hours or worsen. 
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study 
treatment.  
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or 
life-threatening 
symptoms: 
breathless at rest 
Admit to a hospital and initiate 
treatment with intravenous 
methylprednisolone 
2-4 mg/kg/day.  If there is no 
improvement, or worsening after 
48 hours, add infliximab 5 mg/kg 
(if no hepatic involvement). 
Convert to oral prednisolone and 
taper over at least 2 months. 
Cover with empiric antibiotics and 
consider prophylaxis for 
Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
toxicity 
1 
Mild symptoms 
N/A 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 
0.5-1 mg/kg/day.  Taper over at 
least 4 weeks. 
Obtain neurology consultation. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grade 0-1. 
3-4 
Severe/life-threateni
ng symptoms 
Initiate treatment with oral 
prednisolone or intravenous 
methylprednisolone 
1-2 mg/kg/day, depending on 
symptoms.  Taper corticosteroids 
over at least 4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
≤ 4 liquid stools per 
day over baseline 
and feeling well 
Symptomatic management: fluids, 
loperamide, avoid high 
fiber/lactose diet. 
If Grade 1 persists for > 14 days, 
manage as a Grade 2 event. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Moderate symptoms: 
4-6 liquid stools per 
day over baseline, or 
abdominal pain, or 
blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic 
tests to start treatment.  Taper 
corticosteroids over 2-4 weeks. 
Consider endoscopy if symptoms 
are recurring. 
Hold study 
treatment; resume 
when 
resolved/improved 
to baseline grade. 
3 
Severe symptoms: 
≥ 7 liquid stools per 
day over baseline, or 
if episodic within 
1 hour of eating 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  
Consider prophylaxis for adverse 
steroid effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, hepatitis, 
NYHA Class III/IV CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study 
treatment; 
retreatment may be 
considered when 
resolved/improved 
to baseline grade and 
after discussion with 
the study medical 
monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10%-
30% of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical corticosteroids (moderate 
strength cream once a day or 
potent cream twice a day) ± oral or 
topical antihistamines for itch.  
Consider a short course of oral 
corticosteroids. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3 
Rash covers > 30% 
BSA or Grade 2 with 
substantial 
symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate corticosteroids as follows 
based on clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 
3 days then taper over 2-4 weeks. 
For severe symptoms: intravenous 
methylprednisolone 
0.5-1 mg/kg/day; convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Hold study 
treatment. 
Re-treat when AE is 
resolved or 
improved to mild 
rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
4 
Skin 
sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal 
detachment) 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Admit to a hospital and seek 
urgent dermatology consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN 
to 3 x ULN 
Check LFTs within 1 week and 
before the next dose to verify that 
there has been no worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs 
are unchanged or 
improving. 
Hold study treatment 
if LFTs are 
worsening until 
improvement is 
seen. 
2 
ALT or AST > 3 x to 
5 x ULN 
Recheck LFTs every 48-72 hours. 
For persistent ALT/AST elevation: 
consider oral prednisolone 
0.5-1 mg/kg/day for 3 days, then 
taper over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and 
taper over 2-4 weeks; re-escalate 
dose if LFTs worsen, depending 
on clinical judgement.  
Hold study 
treatment; treatment 
may be resumed 
when 
resolved/improved 
to baseline grade and 
prednisolone tapered 
to ≤ 10 mg. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3 
ALT or AST > 5 x to 
20 x ULN 
 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate 
oral prednisolone 1 mg/kg and 
taper over at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day. 
When LFTs improve to Grade 2 or 
lower, convert to oral prednisolone 
and taper over at least 4 weeks. 
If ALT and AST 
≤ 10 x ULN: Hold 
study treatment until 
improved to baseline 
grade; reintroduce 
only after discussion 
with the medical 
monitor. 
If ALT or 
AST > 10 x ULN: 
Discontinue study 
treatment. 
 
4 
ALT or 
AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 2 mg/kg/day.  
Convert to oral prednisolone and 
taper over at least 6 weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite corticosteroids: 
If on oral prednisolone, change to pulsed intravenous methylprednisolone. 
If on intravenous methylprednisolone, add mycophenolate mofetil (MMF) 
500 to 1000 mg twice a day. 
If worsens on MMF, consider addition of tacrolimus. 
Duration and dose of corticosteroid required will depend on severity of event. 
Nephritis 
1 
Creatinine 
1.5 x baseline 
or > ULN to 
1.5 x ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as 
per criteria below. 
Continue study 
treatment. 
2 
Creatinine > 1.5-3 x 
baseline 
or > 1.5-3 x ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. 
Discuss with nephrologist the need 
for kidney biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-
72 hours. 
Hold study 
treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved 
to baseline grade: 
Restart study drug if 
tapered to < 10 mg 
prednisolone. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3 
Creatinine > 3 x base
line or > 3-6 x ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat 
creatinine every 24 hours; refer to 
a nephrologist and discuss need 
for biopsy. 
If worsening, initiate intravenous 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 
4 weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug 
suspected: 
Discontinue study 
treatment. 
 
4 
Creatinine > 6 x UL
N 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose 
value ULN to 
160 mg/dL; ULN to 
8.9 mmol/L 
Monitor closely and treat 
according to local guideline.  
Check for C-peptide and 
antibodies against glutamic acid 
decarboxylase and islet cells are 
recommended. 
Continue study 
treatment. 
2 
Fasting glucose 
value 
160-250 mg/dL; 8.9-
13.9 mmol/L 
Obtain a repeat blood glucose 
level at least every week.  Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when 
blood glucose is 
stabilized at baseline 
or Grade 0-1. 
3 
Fasting glucose 
value 
250-500 mg/dL; 
13.9-27.8 mmol/L 
Admit patient to hospital and refer 
to a diabetologist for 
hyperglycemia management.  
Corticosteroids may exacerbate 
hyperglycemia and should be 
avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or 
Grade 0-1. 
4 
Fasting glucose 
value > 500 mg/dL; 
> 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. 
Refer the patient to a diabetologist 
for insulin maintenance and 
monitoring. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or 
Grade 0-1. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Ocular toxicity 
1 
Asymptomatic eye 
examination/test 
abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or 
mild symptoms 
Refer patient to an 
ophthalmologist for assessment 
and topical corticosteroid 
treatment. 
Consider a course of oral 
corticosteroids. 
Continue study 
treatment or hold 
treatment if 
symptoms worsen or 
if there are 
symptoms of visual 
disturbance. 
3 
Posterior 
uveitis/panuveitis or 
significant 
symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
4 
Blindness (at least 
20/200) in the 
affected eyes 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, 
blood test 
abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, 
nausea and vomiting 
Admit to hospital for urgent 
management.  Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day.  Convert to oral 
prednisolone when amylase/lipase 
improved to Grade 2 and taper 
over at least 4 weeks. 
Hold study 
treatment; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
 
4 
Acute abdominal 
pain, surgical 
emergency 
Admit to hospital for emergency 
management and appropriate 
referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, 
swelling 
Management per local guideline.  
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Moderate pain with 
inflammation, 
swelling, limited 
instrumental (fine 
motor) activities 
Management as per local 
guideline.  Consider referring 
patient to a rheumatologist. 
If symptoms worsen on treatment, 
manage as a Grade 3 event. 
Continue treatment 
or, if symptoms 
continue to worsen, 
hold study treatment 
until symptoms 
improve to baseline 
or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint 
damage, daily living 
activity limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. 
Initiate oral prednisolone 
0.5-1 mg/kg and taper over at least 
4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; 
reintroduce only 
after discussion with 
the study medical 
monitor. 
 
Mucositis/ 
Stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, 
reduced oral intake, 
limited instrumental 
activities 
As per local guidelines, treat with 
analgesics, topical treatments, and 
oral hygiene care. 
Ensure adequate hydration. 
If symptoms worsen or there is 
sepsis or bleeding, manage as a 
Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid 
intake, daily living 
activity limited 
Admit to hospital for appropriate 
management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improve to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care.  Consider intravenous 
corticosteroids if not 
contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider 
oral corticosteroids and treat as 
Grade 2. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Moderate weakness 
with/without pain 
If CK is 3 x ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus intravenous 
(methyl)prednisolone and 1-
2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. 
If symptoms do not improve, add 
immunosuppressant therapy. 
Taper oral corticosteroids over at 
least 4 weeks. 
For Grade 3: Hold 
study treatment until 
improved to 
Grade 0-1. 
Discontinue upon 
any evidence of 
myocardial 
involvement. 
 
Myocarditis a 
< 2 
Asymptomatic but 
significantly 
increased CK-MB or 
increased troponin 
OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat 
serum testing and including ECG, 
cardiac echo/MUGA, and/or other 
interventions per institutional 
guidelines; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2. 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered immune 
mediated, 
permanently 
discontinue study 
treatment in patients 
with moderate or 
severe symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart study 
treatment unless 
cardiac parameters 
have returned to 
baseline and after 
discussion with the 
study medical 
monitor. 
 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or intravenous 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage 
symptoms of cardiac failure 
according to local guidelines. 
If no immediate response, change 
to pulsed doses of 
(methyl)prednisolone 1 g/day and 
add MMF, infliximab, or 
anti-thymocyte globulin. 
3 
Severe symptoms 
with mild exertion 
4 
Life-threatening 
≤ 2 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Other 
immune-mediate
d adverse events 
3 
Clinical management per local 
guideline based on adverse event 
type and severity. 
Hold study treatment 
until improved to 
Grade 0-1. 
For recurrent 
Grade 3: 
Discontinue study 
treatment. 
4 
Discontinue study 
treatment. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; N/A, not applicable; NYHA, New York Heart Association; T4, thyroxine; TB, 
tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, 
upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 9. MANAGEMENT OF INFUSION-RELATED REACTIONS  
Patients should be closely monitored during and after study drug administration for 
infusion-related reactions and anaphylaxis.  See Section 5.2.1 for the monitoring periods 
required.  Immediate access to an intensive care unit (ICU) or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 
Management of infusion-related reactions is provided in the table below (Rosello et al 2017). 
NCI-CTCAE Grade v5.0 
Management 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
Decrease infusion rate by 50%.   
Closely monitor for worsening signs or symptoms.   
Medical management as needed. 
Subsequent infusions should be given after appropriate 
premedication and at the reduced infusion rate. 
Grade 2  
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs [NSAIDS], 
narcotics, intravenous [IV] fluids); prophylactic 
medications indicated for ≤ 24 hours 
Temporarily stop infusion.   
Treatment may include but is not limited to H1/H2 
antagonists or corticosteroids.  
Restart infusion at 50% rate once infusion-related 
reaction has resolved or decreased to Grade 1 in 
severity and titrate to tolerance 
Closely monitor for worsening signs or symptoms.   
Appropriate medical management should be instituted. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3  
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms after initial improvement; 
hospitalization indicated for clinical sequelae 
Immediately stop the infusion.   
Treatment includes but not limited to H1/H2 
antagonists or corticosteroids.  
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4  
Life-threatening consequences; urgent intervention 
indicated 
Immediately stop the infusion.  
Treatment includes but not limited to H1/H2 
antagonists or corticosteroids.  
Proper medical management should be instituted. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
For the prophylaxis of mild events (eg, nasal congestion or flu-like symptoms), a dose of 25 mg 
indomethacin or a comparable dose of nonsteroidal anti-inflammatory drugs (eg, 600 mg 
ibuprofen or 500 mg naproxen sodium) may be administered 2 hours before and 8 hours after the 
start of each dose of study drugs(s) infusion.  Alternative treatments for fever (eg, paracetamol) 
may be given to patients at the discretion of the investigator. 
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 the treatment.  
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APPENDIX 10. MANAGEMENT OF ANAPHYLAXIS  
If anaphylaxis occurs, the patient must be managed according to the best available medical 
practice, as described in the guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008).  Patients 
should be instructed to report any delayed reactions to the investigator immediately.  
The National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
grading of anaphylaxis starts from Grade 3.  
Management and treatment modifications for symptoms of anaphylaxis associated with study 
drug(s) administration are provided in the table below. 
 
NCI-CTCAE Grade v5.0 
Management 
Grade 3  
Symptomatic bronchospasm, with or without urticaria; 
parenteral intervention indicated; allergy-related 
edema/angioedema; hypotension 
 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated 
Immediately stop the infusion. 
Proper medical management should be instituted. 
Treatment may include but is not limited to oral or 
intravenous antihistamines, antipyretics, 
glucocorticoids, epinephrine, bronchodilators, and 
oxygen. 
The patient should be withdrawn from study drug(s) 
treatment. 
Rechallenge is prohibited. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Event. 
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APPENDIX 11. FORMULAE FOR ESTIMATING RENAL FUNCTION  
The Cockcroft-Gault Formula: 
 
Source: Cockcroft and Gault 1976  
Abbreviation: Clcr/CLcr, creatinine clearance; SCr, serum creatinine. 
Note: The ideal body weight is determined by the local practice and/or guideline. 
 
 
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APPENDIX 12. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical studies include the use of highly effective forms of birth control (Clinical 
Trials Facilitation 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, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patients’ usual and preferred lifestyle.  Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
Definitions of “Women of Childbearing Potential” AND “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
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Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 mIU/mL 
and all alternative medical causes for the lack of spontaneous menses for ≥ 
12 months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG) 2014. 
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APPENDIX 13. LIST OF PROHIBITED CHINESE HERBAL AND PATENT 
MEDICINES  
The following table provides examples of Chinese herbal and patent medications that may be 
used to treat cancer or that have immune-stimulating properties.  This list is not intended to be 
all-inclusive.  These medications require a 14-day washout period 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 
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Drug Name (Chinese)  
Drug Name (English) 
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 
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: Jiao Nang/Jiaonang, capsule; Ke Li/Keli, granules; Kou Fu Ye/koufuye, oral liquid; Pian, tablet; 
Wan, pill/bolus; Zhue She ye/Zhusheye, injections 
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APPENDIX 14. BGB-15025  
1. INTRODUCTION - BGB-15025  
BGB-15025 is developed as a potent and selective inhibitor of hematopoietic progenitor kinase 1 
(HPK1), a hematopoietic cell-restricted serine/threonine protein kinase, which has been reported 
to serve as a critical negative feedback regulator of T lymphocytes and dendritic cells (DC) 
activation (Alzabin et al 2009; Shui et al 2007) and appears to be a potential target for 
immune-oncology therapy.  HPK1 is prominently expressed in immune cells such as T cells, B 
cells, and DC (The Human Protein Atlas).  Notably, HPK1 is involved in the progression of a 
variety of malignant tumorigenesis and disease progression (Yang et al 2006; 
Alzabin et al 2010). 
Furthermore, it has been recently demonstrated that the kinase activity of HPK1 is essential for 
antitumor immune surveillance and HPK1 blockade as a potential combination with the immune 
checkpoint inhibitor therapy for effective cancer treatment (Hernandez et al 2018; 
Liu et al 2019).  HPK1 kinase-dead (KD) mice enhanced T-cell receptor (TCR) signaling and 
effector cytokine secretion with TCR stimulation.  Therapeutic co-blockade of HPK1 kinase and 
programmed death ligand 1 (PD-L1) enhanced T effector cell function, resulting in antiviral 
responses and tumor growth suppression.  Therefore, the kinase activity of HPK1 played a key 
role in the antitumor immune response and small molecule HPK1 inhibitors can be potentially 
combined with the immune checkpoint inhibitor therapy for effective cancer treatment. 
Refer to the BGB-15025 Investigator’s Brochure for additional background on BGB-15025. 
1.1. 
Background Information on BGB-15025  
1.1.1 Pharmacology  
BGB-15025 potently inhibited HPK1 kinase in biochemical assay, with 50% inhibitory 
concentration (IC50) of 1.04 nM under Km (Michaelis constant) concentration of adenosine 
triphosphate.  Consistently, BGB-15025 potently inhibited HPK1-mediated SH2 domain-
containing leukocyte protein of 76 kDa (SLP76) phosphorylation and increased downstream 
extracellular signal-regulated kinases (ERK) phosphorylation in Jurkat cells.  In consequence, 
BGB-15025 dose-dependently increased interleukin-2 (IL-2) production in both activated Jurkat 
cells and peripheral blood mononuclear cells (PBMCs).  BGB-15025 was screened against a 
panel of 57 human kinases in biochemical assays and a SafetyScreen87 panel (Eurofins Panlabs 
Discovery Services Taiwan, Ltd.) for 87 primary molecular targets including G protein-coupled 
receptors, transporters, ion channels, nuclear receptors, and other nonkinase enzymes. 
BGB-15025 was identified as a selective inhibitor of HPK1. 
In in vivo pharmacodynamic studies, oral administration of BGB-15025 demonstrated a 
dose-dependent phosphorylated SLP76 (pSLP76) inhibition in splenic T cells and serum IL-2 
level increase.  In vivo efficacy studies demonstrated that BGB-15025, in combination with an 
anti-programmed cell death protein-1 (anti-PD-1) antibody, induced potent antitumor effects 
against the syngeneic CT26 wild type (WT) tumors in mice at as low as 1 mg/kg.  In addition, 
BGB-15025 demonstrated dose-dependent antitumor effects in the syngeneic GL261 tumor 
model. 
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The inhibition of BGB-15025 on the human ether-à-go-go-related gene (hERG) channel 
appeared to be moderate with an IC50 of 8.9 μM.  No BGB-15025-related effects on the central 
nervous system or respiratory system were noted in Sprague Dawley rats following single oral 
doses up to 100 mg/kg.  No BGB-15025-related effects on blood pressure, heart rate, 
electrocardiogram (ECG) parameters, or qualitative ECG waveforms were noted in cynomolgus 
monkeys at doses up to 100 mg/kg via telemetry.  Moreover, no BGB-15025-related changes in 
ECG were noted in monkeys at repeated oral doses up to 100 mg/kg/day for 28 days.  Based on 
the ECG data from single and repeated-dose studies in monkeys, and the hERG assay result, the 
risk of corrected QT interval (QTc) prolongation is considered low. 
1.1.2. Toxicology  
Based on International Council for Harmonisation (ICH) S9, all the available toxicological 
studies and data are considered adequate to support the in-patient dosing and the clinical 
development of BGB-15025 for treatment of patients with advanced cancer.  All pivotal 
toxicology studies were conducted in compliance with Good Laboratory Practices (GLP) 
regulations/principles. 
In the single-dose studies in rats and in monkeys orally administered BGB-15025 at doses of 
1000 mg/kg, no test article-related adverse effects or apparent treatment-related toxicity were 
noted.  The maximum tolerance dose (MTD) was considered to be 1000 mg/kg. 
In the 14-day repeat-dose studies in rats and in monkeys orally administered BGB-15025 at 
doses of 30, 100, or 300/200 mg/kg/day, no test article-related adverse effects were noted at 
doses of ≤ 100 mg/kg/day.  The no observed adverse effect level (NOAEL)/MTD was 
considered to be 100 mg/kg/day. 
In the 28-day repeat-dose studies in rats and in monkeys orally administered BGB-15025 at 
doses of 10, 30, or 100 mg/kg/day, no mortality in rats was noted and one moribundity in 
monkeys was noted at the dose of 100 mg/kg/day.  The MTD was considered to be 
100 mg/kg/day and NOAEL was considered to be 30 mg/kg/day in rats, while the NOAEL/MTD 
was considered to be 30 mg/kg/day in monkeys. 
Because BGB-15025 absorbed wavelengths between 290 and 382 nm with a molar extinction 
coefficient (MEC) greater than 1000 L/mol/cm, according to the ICH S10 photosafety evaluation 
guideline, an in vitro phototoxicity study was conducted in 3T3 cells using the neutral red uptake 
phototoxicity test and demonstrated a positive result for BGB-15025.  A follow-up in a 
preclinical in vivo phototoxicity study is planned to verify the phototoxicity potential of 
BGB-15025 in vivo and its relevance to humans. 
In the human PBMC-based cytokine release assay, compared with the negative control (0.01% 
DMSO), 10 nM of BGB-15025 did not induce any increase of tested cytokines or chemokines, 
while 100 nM of BGB-15025 only slightly increased IL-8 production (1.6 fold).  The results 
suggested that BGB-15025 had a low risk for causing cytokine release syndrome because of 
peripheral immune stimulation. 
The systemic exposure (AUC0-24h and Cmax) increased slightly less than dose proportionally in 
rats and monkeys.  No marked sex differences or drug accumulation was noted. 
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Refer to the BGB-15025 Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.1.3 Clinical Pharmacology  
BGB-15025 is being studied in Study BGB-A317-15025-101 (referred to as Study 101 
hereafter).  This clinical study is being conducted in compliance with Good Clinical Practice.  
BGB-15025 was administered using capsule formulation containing free base drug substance in 
global ex-China cohorts 1A to 6A and 1B to 3B, and in China cohorts 3A to 5A.  BGB-15025 
was administered using tablet formulation containing citrate drug substance in global ex-China 
cohorts 7A and 4B.  The exposures of BGB-15025 tablets 
 
are generally comparable to those of BGB-15025 capsules 
, respectively. 
As of the data cutoff date of 10 January 2023, the preliminary pharmacokinetic (PK) data have 
shown that BGB-15025 (capsule formulation) is absorbed after oral administration with Cmax 
reaching approximately 4 hours after dosing.  Both the Cmax and AUC0-24 during BGB-15025 
monotherapy increased in an approximately dose-proportional manner 
once 
daily and in a less than dose proportional manner 
 once daily in global 
ex-China cohorts.  In contrast, BGB-15025 PK exposures increased approximately dose 
proportionally 
 after single doses in China cohorts.  These differences are 
likely because of PK variability and the small cohort sizes. Preliminary population PK analysis 
indicated no significant PK differences between the global ex-China and China cohorts.  The 
mean elimination half-life (t1/2) across the doses evaluated was approximately 13 hours.  
Consistent with its t1/2, minimal accumulation of plasma exposure was observed after repeated 
dosing once daily compared to that after a single dose.  In comparison, the steady-state AUC0-24hr 
following 
 is approximately 2.6-fold of that after a single 
dose.  The active metabolite BGB-21958 showed similar t1/2 to BGB-15025 with its mean 
exposure ranging from 18% to 40% of BGB-15025 across cohorts.  In addition, BGB-15025 
exposure and elimination half-life values across the China cohorts after single and multiple doses 
in general are comparable to those in the global ex-China cohorts, indicating that race may not 
impact BGB-15025 plasma exposure. 
Refer to the BGB-15025 Investigator’s Brochure for detailed information regarding clinical 
pharmacology studies. 
1.1.4. Prior Clinical Experience with BGB-15025  
Study 101 is an open-label, multicenter, and nonrandomized Phase 1a/1b clinical study to 
investigate the safety, tolerability, PK, and preliminary antitumor activity of BGB-15025 alone 
and in combination with tislelizumab in patients with advanced solid tumors. 
The study is designed to include 2 phases: 
• Phase 1a, a dose-escalation phase to assess the safety and tolerability and determine 
the MTD or maximum administered dose (MAD) and recommended dose(s) for 
expansion (RDFE[s]) of BGB-15025 alone and in combination with tislelizumab in 
patients with advanced solid tumors. 
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• Phase 1b, a dose-expansion phase to assess the overall response rate (ORR) per 
Response Evaluation Criteria in Solid Tumor Version 1.1 (RECIST v1.1) for 
BGB-15025 alone and in combination with tislelizumab with or without 
chemotherapy in patients with advanced solid tumors. 
1.1.4.1. 
Safety Assessment of BGB-15025  
As of 14 January 2023, 81 patients have been dosed in Australia, New Zealand, the United States 
of America, and China.  Fifty-five patients were dosed with BGB-15025 monotherapy and 
26 patients were dosed with BGB-15025 plus tislelizumab at enrollment.  Among the 55 patients 
who received BGB-15025 monotherapy, 14 patients switched to tislelizumab, 2 patients 
switched to BGB-15025 
 in combination with tislelizumab, and 4 patients switched to 
BGB-15025 
 in combination with tislelizumab. 
BGB-15025 monotherapy 
Of the 55 patients with BGB-15025 monotherapy, treatment-emergent adverse events (TEAEs) 
were reported in 53 patients (96.4%).  TEAEs identified in 37 patients (67.3%) were considered 
to be treatment related.  Grade 3 or higher TEAEs were reported in 23 patients (41.8%) and 4 
patients (7.3%) experienced a ≥ Grade 3 TEAE considered treatment related.  Serious TEAEs 
were reported in 24 patients (43.6%), and 4 patients (7.3%) experienced ≥ 1 serious TEAE 
considered treatment related.  
The Grade 3 or higher TEAEs occurring in ≥ 2 patients with BGB-15025 monotherapy by PT 
were Anaemia (4 patients, 7.3%), Abdominal pain (3 patients, 5.5%), Dyspnoea (2 patients, 
3.6%), Pleural effusion (2 patients, 3.6%), and Pneumonia (2 patients, 3.6%). 
Treatment-emergent immune-mediated AEs (imAEs) were reported in 9 patients (16.4%).  All 9 
treatment-emergent imAEs were considered to be treatment related.  As of the data cutoff date, 1 
Grade 3 or higher treatment-emergent imAE (1.8%) was observed and considered treatment 
related.  No serious treatment-emergent imAE was observed.  Two treatment-emergent imAEs 
(3.6%) were reported leading to treatment modification.  No treatment-emergent imAEs leading 
to death or treatment discontinuation were reported.  The reported treatment-emergent imAE 
occurring in ≥ 2 patients by PT was Pruritus (3 patients, 5.5%).   
TEAEs leading to death were reported in 4 patients (7.3%), but no treatment-related TEAE 
leading to death was reported.  TEAEs leading to treatment modification were reported in 23 
patients (41.8%).  No TEAE leading to treatment discontinuation was reported.  No dose-limiting 
toxicity (DLT) was observed as of the data cutoff date.    
BGB-15025 in combination with tislelizumab 
Of the 26 patients with BGB-15025 plus tislelizumab combination therapy, TEAEs were 
reported in 25 patients (96.2%).  TEAEs identified in 20 patients (76.9%) were considered to be 
treatment related.  Grade 3 or higher TEAEs were reported in 14 patients (53.8%), and 7 patients 
(26.9%) experienced a ≥ Grade 3 TEAE considered treatment related.  Serious TEAEs were 
reported in 13 patients (50.0%), and 6 patients (23.1%) experienced ≥ 1 serious TEAE 
considered treatment related. 
The Grade 3 or higher TEAEs occurring in ≥ 2 patients by PT were Alanine aminotransferase 
increased (3 patients, 11.5%), Aspartate aminotransferase increased (3 patients, 11.5%), 
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Diarrhoea (2 patients, 7.7%), Blood bilirubin increased (2 patients, 7.7%), Dyspnoea (2 patients, 
7.7%), and Rash (2 patients, 7.7%).   
Treatment-emergent imAEs were reported in 12 patients (46.2%).  All 12 treatment-emergent 
imAEs were considered to be treatment related.  As of the data cutoff date, 5 Grade 3 or higher 
treatment-emergent imAEs were observed and considered treatment related.  Five serious 
treatment-emergent imAEs were observed and considered treatment related.  Three patients 
experienced DLTs as of the data cutoff date. No treatment-emergent imAEs were reported 
leading to death.  The reported treatment-emergent imAEs occurring in ≥ 2 patients by PT were 
Alanine aminotransferase increased (4 patients, 15.4%), Aspartate aminotransferase increased (3 
patients, 11.5%), Uveitis (2 patients, 7.7%), Diarrhoea (2 patients, 7.7%), and Rash (2 patients, 
7.7%). 
TEAEs leading to death were reported in 4 patients (15.4%), but no treatment-related TEAE 
leading to death was reported.  TEAEs leading to treatment discontinuation were reported in 5 
patients (19.2%).  TEAEs leading to treatment modification were reported in 17 patients 
(65.4%).  Four patients experienced DLTs as of the data cutoff date.  One infusion-related 
reaction was reported.  
1.2. 
BGB-15025 Rationales  
1.2.1. Rationale for BGB-15025 in Combination With BGB-A445  
Half of the non-small cell lung cancer (NSCLC) patients receive primary or secondary 
checkpoint inhibitor (CPI)-based therapies and almost all of them inevitably develop disease 
progression or relapse after CPI-based therapies.  Two main mechanisms have been revealed for 
the CPI resistance in NSCLC, which include: 1) the lack of sufficient T-cell proliferation and 
activation, and 2) an immunosuppressive tumor microenvironment (TME) that is characterized 
by high levels of immune-suppressing cytokines and/or metabolites with high levels of immune-
suppressive cells.  
The kinase activity of HPK1 has been recently demonstrated to play an important role in 
antitumor immune surveillance, and the HPK1 blockade could be a potential modality in 
combination with CPI including anti-PD-(L)1 therapy for effective cancer treatment (Hernandez 
et al 2018; Liu et al 2019).  BGB-15025, as a highly potent and selective HPK1 kinase inhibitor, 
is hypothesized to modulate the TME by activating the CD4+ and CD8+ T cells; in vitro, 
BGB-A445 in combination with BGB-15025 has demonstrated a dual combo effect in human 
peripheral blood mononuclear cells activation assay in preclinical studies. 
Therefore, BGB-15025 may be potentially effective for anti-PD-(L)1-pretreated NSCLC in 
combination with BGB-A445, which can also modulate the TME by targeting the different signal 
pathway.   
1.2.2. Rationale for Selection of BGB-15025 Dose  
BGB-15025 will be administered at a dose no higher than the highest confirmed safe dose in the 
Phase 1 Study BGB-A317-15025-101.  The dose 
 was selected based on the acceptable 
safety and tolerability observed in patients in the ongoing Phase 1 Study 101.  Additional dose 
levels may be explored in Stage 2 if indicated based on emerging clinical data from the ongoing 
Study 101. 
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1.2.3. Rationale for Biomarker Strategy  
Biomarker analyses will be performed to study the following aspects of BGB-A445 in 
combination with BGB-15025: 1) treatment effects induced in patients, and 2) biomarkers 
predictive of or correlated with response or resistance (exploratory).  HPK1 inhibitors have been 
shown to enhance immune cell activation and increase pro-inflammatory cytokines secretion. 
Cytokines secreted by these immune cell subsets may be evaluated through cytokine analysis in 
blood.  Treatment effects may be evaluated by comparing cytokines, circulating tumor DNA 
(ctDNA), tumor mutation burden (TMB), microsatellite instability (MSI), and gene alterations in 
peripheral blood before, during, and post treatment.  Cluster of differentiation 8 (CD8), PD-L1, 
HPK1, and OX40 expression level at baseline and/or changed levels upon treatment in tumor 
tissue by immunohistochemistry may serve as predictive biomarkers. TMB, MSI, gene 
alterations, gene expression profiles, and tumor infiltrating lymphocytes may be explored in 
these tissues as possible predictive biomarkers. 
1.3. 
Benefit-Risk Assessment of BGB-15025  
Nonclinical experience with BGB-15025 suggests that patients may experience gastrointestinal 
toxicity, potential abnormal liver function based on minimal to mild multifocal centrilobular 
hepatocellular degeneration/necrosis, and potential skin phototoxicity.  Patients who are enrolled 
in this study must be closely monitored for these potential adverse events (AEs).  As of the data 
cutoff date (14 January 2023) for the most recent BGB-15025 Investigator’s Brochure, available 
clinical safety and tolerability data suggest that risks observed in patients treated with 
BGB-15025 as monotherapy or in combination with tislelizumab are manageable.  
Based upon the mechanism(s) of action, preclinical efficacy data suggest that BGB-15025 could 
inhibit the growth of solid tumors in combination with the anti-OX40 antibody.  BGB-15025 
administered in combination with BGB-A445 is unlikely to result in clinically relevant drug-drug 
interactions (DDI) based on absorption, metabolism, elimination, or protein binding.  The GLP 
toxicity studies demonstrated sufficient safety margins by comparing the exposures of tolerable 
doses in toxicity studies and the predicted human efficacious dose in solid tumors.  In summary, 
given the unmet medical need and limited treatment options for these patients, the anticipated 
benefit/risk of BGB-15025 in combination with BGB-A445 is considered favorable. 
2. STUDY OBJECTIVES AND ENDPOINTS  
No BGB-15025-specific content. 
3. STUDY DESIGN  
A safety lead-in is planned for the combination of BGB-A445 and BGB-15025. The details can 
be found in Section 3.4. 
During the safety lead-in, please refer to §Section 5.2 for the detailed schedule of administration. 
If the combination of BGB-A445 and BGB-15025 is deemed not tolerable, the dose of 
BGB-15025 will be reduced to 
 combined with 
 BGB-A445 for further 
evaluation.  The stopping rules described in Section 9.8 will be applied in the further evaluation. 
4. STUDY POPULATION  
No BGB-15025-specific content. 
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5. STUDY TREATMENT – BGB-15025  
5.1. Formulation, Packaging, Labeling, and Handling  
BGB-15025 will be provided as 
.  BGB-15025 tablets are 
packaged in high-density polyethylene bottles with induction-seals and child-resistant caps. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drugs must be stored at the condition specified on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
Please also refer to the BGB-15025 Investigator’s Brochure for other details regarding 
BGB-15025. 
5.2. Dosage, Administration, and Compliance  
BGB-15025 will be self-administered orally at the recommended dose 
 once a day.   
In this study, BGB-15025 will be self-administered in combination with BGB-A445. The dosing 
selection and timing for BGB-15025 in combination with BGB-A445 are provided in §Table 1. 
§Table 1: 
Selection and Timing of Dose for Study Drug 
Study Drug 
Dose 
Frequency and Sequence of 
Administration 
Route of 
Administration 
BGB-A445 
 
Day 1 of each cycle (3 weeks) 
Intravenous 
infusion 
BGB-15025 
 
Once daily in each cycle (3 weeks) 
Administer before BGB-A445 
Orally 
Specific instructions for product preparation, storage, and administration are provided in the 
Pharmacy Manual. 
On the day when the administration of BGB-A445 is scheduled, the patient will take the daily 
dose of BGB-15025 before receiving BGB-A445.  Dosing administration and monitoring times 
are provided in §Table 2.   
Monitoring must occur in an area where emergency medical equipment and appropriately trained 
staff are available. If the infusion of BGB-A445 is well tolerated in the first cycle, duration of 
infusion and monitoring time can be decreased in subsequent cycles, as outlined in §Table 2.  
§Table 2: 
Administration of BGB-15025 and BGB-A445 and Monitoring Time  
Cycle 
BGB-15025 and BGB-A445 Combination 
Cycle 1, Cycle 2, and 
Cycle 3 Day 1 
 
BGB-15025 oral administration 
BGB-A445 infusion 60 (± 5) minutes  
Patient monitoring for ≥ 120 minutes  
Cycle 4 Day 1 
Onwards 
BGB-15025 oral administration 
BGB-A445 infusion 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes  
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Note: The infusion rate of BGB-A445 may be decreased or the infusion may be stopped in the event of an 
infusion-related reaction. 
5.3. Overdose  
No BGB-15025-specific content. 
5.4. Dose Delay and Modification for BGB-15025  
Dose Delay for BGB-15025  
BGB-15025 is administered in combination with BGB-A445. 
Please refer to Section 5.4.1.1 for the details of BGB-A445 dose delay. 
BGB-15025 may be temporarily suspended if the patient experiences a toxicity that requires a 
dose to be withheld for toxicity deemed solely related to BGB-15025.  BGB-15025 should 
resume as soon as possible after AEs recover to baseline or Grade 1 (whichever is more severe) 
after the last dose of BGB-15025.  BGB-15025 may be resumed at the same dose or at a reduced 
dose, depending on the toxicity, grade, prior events, and number of dose reductions. 
If a dose delay for BGB-A445 is required, the treatment of BGB-15025 may continue.  
Resumption of BGB-A445 after dose interruption because of BGB-A445-related toxicity 
requires consultation with the medical monitor.  Study drug(s) may be resumed only after 
discussion with the medical monitor and approval by the sponsor. 
If a dose delay for BGB-15025 is required, BGB-A445 and tislelizumab treatment may continue. 
If, in the opinion of the investigator, the toxicity may be related to both study drugs (BGB-A445 
and BGB-15025), then the most conservative guidance should be followed until the toxicity is 
resolved to baseline level or Grade 1 (whichever is more severe). 
Exceptions may be considered following consultation between the investigator and the medical 
monitor. 
When treatment is delayed, the next cycle, including assessments scheduled for that cycle, will be 
delayed until the patient receives study treatment of BGB-A445.  For example, if a patient comes 
in for C2D1 but treatment of BGB-A445 is delayed, the counting of C2D1 will not commence 
until the patient resumes study treatment of BGB-A445.  Accordingly, the day study treatment of 
BGB-A445 is given will be considered C2D1.  In such cases, patients should continue with 
safety assessments (Appendix 1) according to the most recent cycle in which they received study 
treatment.  Such assessments should be entered into the electronic data capture system as 
unscheduled assessments. 
5.4.1. Dose Delay for BGB-15025  
In the event of significant toxicities, dosing may be modified based on the guidelines described 
in §Table 3. 
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§Table 3: 
Management of Non-Immune-Mediated Adverse Events 
System 
Adverse event 
Toxicity 
management 
Study treatment management 
Hematologic 
Anemia 
Grade 3 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment until resolved to 
Hgb ≥ 9 g/dL. 
If resolved ≤ 7 days, then maintain 
current dosage. 
If resolved > 7 days, decrease 
BGB-15025 treatment by 1 dose level. 
Anemia 
Grade 4 
Maximize 
supportive therapy 
until Hgb ≥ 9 g/dL. 
Hold study treatment until resolved to 
Hgb ≥ 9 g/dL. After resolution, 
decrease BGB-15025 by 1 dose level. 
Neutropenia 
(ANC decrease) 
Grade 3 
Treat with 
appropriate 
supportive care as 
medically indicated 
until 
ANC ≥ 1000/mm3. 
Hold study treatment until resolved to 
ANC ≥ 1000/mm3 or baseline. 
If resolved in ≤ 7 days, then maintain 
current dosage. 
If resolved in > 7 days, then decrease 
BGB-15025 by 1 dose level. 
Neutropenia 
(ANC decrease) 
Grade 4 
Maximize 
appropriate 
supportive therapy 
until 
ANC ≥ 1000/mm3. 
Hold study treatment until resolved to 
ANC ≥ 1000/mm3 or baseline. After 
resolution, decrease BGB-15025 by 1 
dose level. 
Febrile 
neutropenia 
≥ Grade 3 
Maximize 
appropriate 
supportive therapy. 
Rule out other 
etiologies of fever. 
Hold study treatment until neutrophil 
count ≥ 1000/mm3. After resolution, 
decrease BGB-15025 by 1 dose level. 
For Grade 4 event, discontinue 
treatment. 
Thrombocytopenia 
(platelet count 
decrease) 
Grade 2 
Monitor and treat 
with appropriate 
supportive care as 
medically indicated. 
Maintain current dosage if no concerns 
of clinically significant risk of 
bleeding; continue to monitor using 
additional hematology assessments as 
required. 
Thrombocytopenia 
(platelet count 
decrease) 
Grade 3 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment until resolved to 
≤ Grade 1 or baseline. After resolution, 
decrease BGB-15025 by 1 dose level.  
Thrombocytopenia 
(platelet count 
decrease) 
Grade 4 
Treat with 
appropriate 
supportive care as 
medically indicated.  
Hold study treatment until resolved to 
≤ Grade 1 or baseline. After resolution, 
decrease BGB-15025 by 1 dose level.  
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System 
Adverse event 
Toxicity 
management 
Study treatment management 
Other hematologic 
event 
Grade 3 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment. 
If improved to ≤ Grade 1 or baseline, 
decrease BGB-15025 treatment by 1 
dose level. 
If event recurs at the reduced dose after 
receiving optimal supportive care, 
permanently discontinue study 
treatment. 
First occurrence of 
other hematologic 
Grade 4 event  
 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment until improved to 
≤ Grade 1 or baseline. After resolution, 
decrease BGB-15025 by 1 dose level, 
or permanently discontinue study 
treatment. 
Other recurrent 
hematologic 
Grade 4 event 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Permanently discontinue study 
treatment. 
Nonhematologic Non-hematologic 
event 
Grade 3 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment. 
If improved to ≤ Grade 1 or baseline, 
decrease BGB-15025 treatment by 1 
dose level. 
If event recurs at the reduced dose after 
receiving optimal supportive care, 
permanently discontinue study 
treatment. 
First occurrence of 
non-hematologic 
Grade 4 event 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Hold study treatment until improved to 
≤ Grade 1 or baseline. After resolution, 
decrease BGB-15025 by 1 dose level, 
or permanently discontinue study 
treatment. 
Recurrent 
non-hematologic 
Grade 4 event 
Treat with 
appropriate 
supportive care as 
medically indicated. 
Permanently discontinue study 
treatment. 
Abbreviations: ANC, absolute neutrophil count; Hgb, hemoglobin. 
After any interruption, BGB-15025 may be resumed at the same dose or at a reduced dose, 
depending on the toxicity, grade, prior events, and number of dose reductions. 
In general, a dose should be reduced to the next immediate lower dose level that was previously 
determined to be tolerable (§Table 4).  A patient must discontinue BGB-15025 if the toxicity 
recurs with the same or worse severity after BGB-15025 is resumed at a lower dose.   
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A patient may have a maximum of 1 dose reduction for BGB-15025.  For these patients, 
treatment with BGB-15025 may be continued after consultation and approval by the sponsor. 
§Table 4: 
BGB-15025 Dose Reduction Levels 
 
Dose  
Frequency of 
Administration  
Initial dose level a 
  
 b 
Once daily every 3 weeks 
 
Dose Reduction 1 
 b 
Discontinue BGB-15025 
Dose Reduction 2 
Discontinue 
BGB-15025 
N/A 
N/A  
Abbreviations: N/A, not applicable. 
a The initial dose level of BGB-15025 depends on the evaluation in the safety lead-in.  
b BGB-15025 must be discontinued if, after it is resumed at a lower dose, the toxicity recurs with the same or worse 
severity. 
6. PRIOR AND CONCOMITANT THERAPY – BGB-15025  
6.1. 
Permitted Concomitant Medications, Prohibited Concomitant Medications, and 
Restricted Concomitant Medications  
Medications/Procedures Prohibited to be Used With BGB-15025 
• Any herbal or prescription medications known to be strong inhibitors or inducers of 
CYP3A enzymes should be avoided during the study (see §Appendix 1) 
• Any herbal or prescription medications known to be strong inhibitors of P-gp should 
be avoided during the study (see §Appendix 2) 
• Drugs known to prolong QT/QTc interval should be avoided in the study (see 
§Appendix 3). 
Medication to be Used with Caution 
• Any herbal or prescription medications known to be moderate inhibitors or inducers 
of CYP3A enzymes (see §Appendix 1) 
• Any herbal or prescription medications known to be moderate P-gp inhibitors (see 
§Appendix 2) 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant Medications  
The potential for drug-drug interaction between BGB-A445 and BGB-15025 is very low, given 
BGB-A445 is a therapeutic monoclonal antibody. BGB-A445 is unlikely to have an effect on 
drug metabolizing enzymes or transporters because it is expected to be degraded into amino 
acids and recycled into other proteins. 
7. STUDY ASSESSMENTS AND PROCEDURES  
No BGB-15025-specific content. 
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8. SAFETY MONITORING AND REPORTING - BGB-15025  
8.1. 
Risks Associated With BGB-15025  
BGB-15025 is being evaluated in the first-in-human study. According to the nonclinical data, 
gastrointestinal toxicity is the major finding. Gastrointestinal toxicities (including vomitus, 
diarrhea, depressed foci [focal erosion] in mucosa of the stomach, dilated cecum/colon, and 
mucosal single cell necrosis of cecum/colon/rectum) were noted in both species of rats and 
monkeys. Gastrointestinal toxicities should be closely monitored in clinical trials. Initial findings 
of gastrointestinal toxicity observed in the clinical trial have been mostly of low grade.  
Increases in liver weights and minimal to mild multifocal centrilobular hepatocellular 
degeneration/necrosis were noted in rats at 100 mg/kg/day, which had a 15- to 17-fold margin of 
predicted human exposure at the first-in-human starting dose of 20 mg. Although no obvious 
alterations in liver functional serum chemistry parameters were noted, close monitoring of 
changes in serum chemistry values and other liver toxicity signs in clinical studies is highly 
recommended. Initial findings of liver toxicity observed in the clinical trial have been mostly of 
low grade.  
BGB-15025 phototoxicity was evaluated in accordance with ICH S10. The initial evaluation was 
based on the photochemical properties of this product. The molar extinction coefficient of 
BGB-15025 was greater than 1000 L∙moL-1∙cm-1 between 290 nm and 382 nm; a potential 
phototoxicity risk in skin is considered based on ICH S10. Patients should be advised to 
minimize exposure to the sun and use sunscreen. Patients should be monitored for potential skin 
phototoxicity. 
8.2. 
Pregnancies – BGB-15025  
No BGB-15025-specific content. 
9. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION  
No BGB-15025-specific content. 
10. STUDY COMMITTEES AND COMMUNICATION  
No BGB-15025-specific content. 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS  
No BGB-15025-specific content. 
12. QUALITY ASSURANCE AND QUALITY CONTROL  
No BGB-15025-specific content. 
13. ETHICS/PROTECTION OF HUMAN PATIENTS  
No BGB-15025-specific content. 
14. DATA HANDLING AND RECORD KEEPING  
No BGB-15025-specific content. 
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15. REFERENCES  
Alzabin S, Bhardwaj N, Kiefer F, et al. Hematopoietic progenitor kinase 1 is a negative regulator 
of dendritic cell activation. J Immunol. 2009;182(10):6187-94.  
Alzabin S, Pyarajan S, Yee H, et al. Hematopoietic progenitor kinase 1 is a critical component of 
prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunol 
Immunother. 2010;59(3):419-29.  
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine. 2007. http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed 
02 May 2022.  
Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, 
Drug Development and Drug Interactions and Inducers. https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers. Accessed 02 May 2022.  
Hernandez S, Qing J, Thibodeau RH, et al. The kinase activity of hematopoietic progenitor 
kinase 1 is essential for the regulation of T cell function. Cell Rep. 2018;25(1):80-94.  
Liu J, Curtin J, You D, et al. Critical role of kinase activity of hematopoietic progenitor kinase 1 
in anti-tumor immune surveillance. PLoS One. 2019;14(3):e0212670.  
Shui JW, Boomer JS, Han J, et al. Hematopoietic progenitor kinase 1 negatively regulates T cell 
receptor signaling and T cell-mediated immune responses. Nat Immunol. 2007;8(1):84-91.  
Woosley RL, Heise CW, Gallo T, et al. QTdrugs List. 2013. www.CredibleMeds.org. Accessed 
01 December 2020.  
Yang HS, Matthews CP, Clair T, et al. Tumorigenesis suppressor Pdcd4 down-regulates 
mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma 
cell invasion. Mol Cell Biol. 2006;26(4):1297-306. 
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16. Appendices  
16.1. §Appendix 1: CYP3A Inhibitors and Inducers  
Strong CYP3A Inhibitors (To Be Avoided) 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat a, conivaptan, elvitegravir, idelalisib, nefazodone 
Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir a, saquinavir, tipranavir 
Moderate CYP3A Inhibitors (To Be Used With Caution) 
Antibiotics: ciprofloxacin, erythromycin b 
Antifungals: fluconazole, clotrimazole 
Protease inhibitors: amprenavir, atazanavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil b 
Tyrosine kinase inhibitors (anticancer): imatinib, crizotinib 
Others: amiodarone b, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone b, tofisopam  
Food products: grapefruit juice, Seville oranges or their juices 
Strong CYP3A Inducers (To Be Avoided) 
Carbamazepine, oxcarbazepine, enzalutamide, mitotane, phenytoin, phenobarbital, rifampin 
(rifampicin), St. John’s wort (Hypericum perforatum)  
Moderate CYP3A Inducers (To Be Used With Caution) 
Avasimibe, bosentan, efavirenz, etravirine, modafinil, rifabutin  
Source: FDA Drug Development and Drug Interactions.  
Abbreviations: CYP3A, cytochrome P450 family 3 subfamily A; P-gp, p-glycoprotein 
Note: For a more complete list, please refer to the Flockhart Table (Flockhart 2007). 
The list of drugs in this table is not exhaustive. Please refer to the prescribing information and Summary of Product 
Characteristics to check for CYP3A inhibition or induction risks or contact the medical monitor. 
a Ritonavir and cobicistat are usually given in combination with other antiviral drugs in clinical practice. 
b The drugs will be avoided due to the strong inhibition of P-gp during coadministration with BGB-15025. 
 
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16.2. §Appendix 2: P-glycoprotein Inhibitors  
Strong P-gp Inhibitors (To Be Avoided) 
Antibiotics: clarithromycin, tetracycline, gentamicin, erythromycin 
Antifungals: itraconazole, posaconazole 
Antivirals: telaprevir and cobicistat a 
Cardiovascular drugs: amiodarone, dronedarone, carvedilol, verapamil, captopril, quinidine, 
propafenone, ranolazine 
Protease inhibitors: ritonavir a, lopinavir and ritonavir, saquinavir and ritonavir, tipranavir and 
ritonavir  
Other: lapatinib, vemurafenib, flibanserin 
Moderate P-gp Inhibitors (To Be Used With Caution) 
Antibiotics: trimethoprim, telithromycin 
Antivirals: saquinavir, velpatasvir 
Cardiovascular drugs: diltiazem, tolvaptan, conivaptan, ticagrelor, atorvastatin 
Blood pressure: spironolactone, telmisartan, nifedipine 
Proton-pump inhibitor: rabeprazole 
Other: indomethacin, nefazodone, quinine, propantheline, mirabegron 
Source: University of Washington, drug-drug interaction database and FDA Drug Development and Drug 
Interactions.  
Abbreviation: P-gp, P-glycoprotein. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information and Summary of 
Product Characteristics to check for P-gp inhibition risks or contact the medical monitor. 
a Ritonavir and cobicistat are usually given in combination with other antiviral drugs in clinical practice.  
 
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16.3. §Appendix 3: Drugs With a Known Risk of QT Prolongation/Torsades de Pointes  
The text below was obtained from sources as follows: Woosley et al 2013 and Flockhart 2007.  
Bold font indicates medications or substances that might be relatively commonly used. 
• amiodarone 
• anagrelide 
• arsenic trioxide 
• astemizole (off United States [US] 
market) 
• azithromycin 
• bepridil (off US market) 
• chloroquine 
• chlorpromazine 
• cilostazol 
• ciprofloxacin 
• cisapride (off US market) 
• citalopram 
• clarithromycin 
• cocaine 
• disopyramide 
• dofetilide 
• domperidone (not on US market) 
• donepezil 
• dronedarone 
• droperidol 
• erythromycin 
• escitalopram 
• flecainide 
• fluconazole 
• gatifloxacin (off US market) 
• grepafloxacin (not on US market) 
• halofantrine (not on US market) 
• ibutilide 
• levofloxacin 
• levomepromazine/ 
methotrimeprazine (not on US 
market) 
• levomethadyl (off US market) 
• levosulpiride (not on US market) 
• mesoridazine (off US market) 
• methadone 
• moxifloxacin 
• ondansetron 
• oxaliplatin 
• pentamidine 
• pimozide 
• probucol (off US market) 
• procainamide 
• propofol 
• quinidine 
• roxithromycin (not on US 
market) 
• sevoflurane 
• sotalol 
• sparfloxacin (off US market) 
• sulpiride (not on US market) 
• sultopride (non on US market) 
• terfenadine (off US market) 
• terlipressin (not on US market) 
• terodiline (not on US market) 
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• haloperidol 
• ibogaine (not on US market) 
• thioridazine 
• vandetanib 
 
 
Approved Date
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BGB-LC-203 
PROTOCOL AMENDMENT 1.0 
SUMMARY OF CHANGES 
 
Study Title: A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination With Investigational Agents 
in Non-Small Cell Lung Cancer Patients Previously Treated With Anti-PD-(L)1 Antibody 
BeiGene, Ltd., has updated the BGB-LC-203 protocol from Original Protocol 0.0 (30 March 2023) to Protocol Amendment 1.0 
(15 May 2023).  The primary purposes for this update are as follows: 
• To revise the starting dose of sitravatinib in combination with BGB-A445 and tislelizumab 
• To specify the inclusion criteria and exclusion criteria related to sitravatinib 
• To clarify the details of some assessments  
Overall, editorial and format changes have been made throughout to enhance clarity and readability.   
Key changes made are summarized by protocol section in the table below.  Additions are in bold text and deletions are designated by 
strike through text. 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Cover Page 
Changed protocol version and dates 
To update the protocol 
version 
N 
N/A 

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Page 2 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 13 
SITRAVATINIB: 
Section 1.2.2 Rationale for 
Selection of Sitravatinib Dose 
Section 5.2 Dosage, 
Administration, and 
Compliance 
§Table 3 
Section 5.4.2 Dose 
Modification for Sitravatinib 
§Table 5 
Updated the starting dose of 
sitravatinib in combination with 
BGB-A445 and tislelizumab from 
100 mg to 70 mg 
To update the starting dose 
of sitravatinib in 
combination with 
BGB-A445 and 
tislelizumab for improved 
tolerability of the 
combination. 
Y 
Potential impact on the 
study conduct and on 
patient safety 
Appendix 13 
SITRAVATINIB: 
Section 1.2.2 Rationale for 
Selection of Sitravatinib Dose 
 
Given the low potential of 
pharmacokinetic and 
pharmacodynamic drug-drug 
interactions among sitravatinib, 
tislelizumab, and BGB-A445, and 
no critical safety findings observed 
in clinical studies where 
tislelizumab is combined with 
sitravatinib or BGB-A445, these 
doses will be adopted for the 
combination of three study drugs in 
this study. 
To update the rationale for 
selection of starting doses 
based on the latest 
information from ongoing 
studies 
N 
N/A 
Section 4.1 Inclusion Criteria 
#8 
c. Urinary protein < 2+ by urine 
dipstick.  If dipstick is ≥ 2+, then 
24-hour urinary protein must be 
< 1 g per 24 hours 
To update the inclusion 
criteria based on the 
proteinuria risk associated 
with sitravatinib 
Y 
Potential impact on the 
study conduct and on 
patient safety 

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Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 4.2 Exclusion Criteria 
#19 
g. Patients with inadequately 
controlled Uncontrolled 
hypertension (defined as average 
systolic blood pressure [BP] 
≥ 150 mmHg and/or diastolic BP 
≥ 100 mmHg) that cannot be 
managed by standard 
antihypertension medications 
≤ 28 days before randomization  
Note: Antihypertensive therapy 
to achieve these parameters is 
allowable. 
To provide more specific 
eligibility requirements for 
blood pressure condition  
Y 
Potential impact on the 
study conduct and on 
patient safety 
h. Any prior history of 
hypertensive crisis 
To provide more specific 
eligibility requirements for 
blood pressure condition 
Y 
Potential impact on the 
study conduct and on 
patient safety 
j. QT interval corrected by 
Fridericia’s method (QTcF) > 470 
450 msec 
Note: If a patient has QTcF interval 
> 470 450 msec on an initial ECG, 
a follow-up ECG will be performed 
to confirm the result. 
To update for consistency 
with CTCAE 
Y 
Potential impact on the 
study conduct and on 
patient safety 
Section 5.4.1 Dose Delay 
Tumor assessments should continue 
as scheduled, which is every 6 
weeks (± 7 days) from 
randomization for the first 9 
months, and every 12 weeks (± 7 
days) thereafter.   
To keep the contents 
consistent throughout the 
protocol 
N 
N/A 

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Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 7.3.7 
Electrocardiograms 
At each timepoint (see Appendix 
1), 3 Three consecutive 12-lead 
ECGs will be performed 
approximately 2 to 3 minutes apart 
to determine the mean QT interval 
corrected for heart rate using the 
Fridericia formula (QTcF) interval 
(see Appendix 1 for the schedule 
of ECG). 
To update for consistency 
with Appendix 1 
N 
N/A 
Section 8.1.3  
Risks Associated With 
Ramucirumab 
Besides the ADRs mentioned in 
Table 10, serious and occasionally 
fatal arterial thromboembolic 
events occur when ramucirumab 
is given as a single agent.  
Additionally, impaired wound 
healing is likely to occur as 
ramucirumab is an 
antiangiogenic therapy with the 
potential to adversely affect 
wound healing. 
To update the risks of 
ramucirumab per the 
prescribing information of 
ramucirumab 
N 
N/A 
Section 8.4 
Definition of a Serious 
Adverse Event 
An SAE is any untoward medical 
occurrence that, at any dose, meet 
any of the following criteria: 
 
Is considered a significant medical 
AE by the investigator or the 
sponsor based on medical 
judgement… 
To comply with US FDA 
regulation (final rule) 
N 
N/A 

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Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 8.6.1 
Adverse Event Recording 
Period 
 
Immune-mediated AEs (serious or 
nonserious serious but not 
treatment-related or nonserious 
regardless of relationship to 
study drug[s]) should be recorded 
until 90 days… 
To maintain consistency 
with the changes in table 11 
N 
N/A 
Table 11 
(First row) SAEs (not 
treatment-related) other than those 
due to progressive disease 
For clarity 
N 
N/A 
(Third row) Beginning of 
Treatment-related SAEs: 
First dose of study drug Signing of 
informed consent 
To align with sponsor’s 
template language 
N 
N/A 
(Forth row) Nonserious All AEs 
due to progressive disease 
To maintain consistency 
with the changes in section 
8.6.4 
N 
N/A 
(Sixth row) Immune-mediated AEs 
(serious or nonserious serious but 
not treatment-related or 
nonserious regardless of 
relationship to study drug[s]) 
To align with sponsor’s 
template language 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 1.0 Summary of Changes 
15 May 2023 
 
CONFIDENTIAL 
Page 6 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 8.6.4 
Disease Progression 
Similarly, nonserious AEs that are 
clearly consistent with the pattern 
of progression of the underlying 
disease and are considered 
unequivocally because of disease 
progression should not be recorded.  
However, if there is any uncertainty 
as to whether an nonserious AE is 
because of disease progression, it 
should be recorded as an AE.  All 
SAEs and deaths, regardless of 
relatedness to disease progression, 
should be recorded and reported 
(see Section 8.6.2). 
To maintain consistency 
with sponsor’s internal 
alignment 
N 
N/A 
Appendix 1 
SCHEDULE OF 
ASSESSMENTS 
Row  
Visit window for Visit day 1 of 
Cycle 2 (21 days): ± 2 
To clarify the visit window 
for Cycle 2 Day 1 for the 
clinical practice 
N 
N/A 
12-lead triplicate ECG  
 
To clarify the ECG 
performance requirement 
for clinical practice 
N 
N/A 
Tumor assessment  
Under Treatment Cycles column: 
Every 6 weeks (± 7 days) for the 
first 9 months after 
randomization, then every 12 
weeks (± 7 days) thereafter 
To clarify the start of tumor 
assessment 
 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 1.0 Summary of Changes 
15 May 2023 
 
CONFIDENTIAL 
Page 7 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Tumor assessment  
Under Efficacy Follow-up Visit 
column: X 
To add tumor assessment at 
Efficacy Follow-up Visit 
N 
NA 
Archival or fresh tumor tissue  
Under Efficacy Follow-up Visit 
column: 
X 
To remove the collection of 
archival or fresh tumor 
tissue during Efficacy 
Follow-up Visit 
N 
N/A 
PK sampling of BGB-15025 and 
BGB-21958  
Under + 30 days (EOT/SFU Visit) 
Column: X 
To remove PK sampling 
point at EOT/SFU Visit 
N 
N/A 
PK sampling of sitravatinib and 
M10  
Under + 30 days (EOT/SFU Visit) 
Column: X 
To remove PK sampling 
point at EOT/SFU Visit 
N 
N/A 
Echocardiogram (preferred) or 
MUGA  
To add a test for left 
ventricular ejection fraction 
Y 
Potential impact on the 
study conduct and on 
patient safety 
Survival status 
To maintain consistency 
with content of protocol 
body 
N 
N/A  
Appendix 1 
SCHEDULE OF 
ASSESSMENTS 
Column 
Survival Follow-up Visit  
To add a new column to 
maintain consistency with 
content of protocol body 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 1.0 Summary of Changes 
15 May 2023 
 
CONFIDENTIAL 
Page 8 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 1 
SCHEDULE OF 
ASSESSMENTS 
footnote 
Footnote d: Survival Follow-up 
Period: Overall survival data will 
be collected via telephone calls 
approximately every 8 weeks 
(± 7 days) after the Safety Follow-
up Visit or as directed by the 
sponsor until death, loss to follow-
up, withdrawal of consent, or the 
end of the study. 
To provide additional detail 
regarding the new column 
to maintain consistency 
with content of protocol 
body 
N 
N/A 
Footnote h: The triplicate ECG 
recordings will be performed 
predose on Day 1 of each cycle at 
the same time and when clinically 
indicated. … During screening 
and at EOT Visit, 3 consecutive 
ECGs will be performed 
approximately 2 to 3 minutes 
apart. 
To clarify the ECG 
performance requirement 
for clinical practice 
N 
N/A 
Footnote k: For patients receiving 
the combination treatment 
containing sitravatinib, urinalysis 
will be performed at each visit; if 
urine protein is ≥ 2+ by dipstick, 
then obtain a 24-hour urine 
sample for total protein analysis.   
To update the urinalysis 
requirement for patients 
receiving the combination 
treatment containing 
sitravatinib 
Y 
Potential impact on the 
study conduct and on 
patient safety 

BGB-LC-203 
BeiGene 
Protocol Amendment 1.0 Summary of Changes 
15 May 2023 
 
CONFIDENTIAL 
Page 9 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Footnote r: During the study, tumor 
imaging will be performed 
approximately every 6 weeks 
(± 7 days) from randomization for 
the first 9 months, and every 12 
weeks (± 7 days) thereafter … 
To clarify the start of tumor 
assessment 
N 
N/A 
Footnote Z: Only applicable for 
the patients receiving 
combination containing 
sitravatinib: Evaluations of 
cardiac function will be 
performed at screening and every 
12 weeks (± 7 days).  Evaluation 
by echocardiogram is preferred.  
Evaluation by MUGA scan is an 
acceptable alternative, if 
necessary.  The method used for 
individual patients should be 
consistent throughout study 
participation. 
To add footnote to clarify 
testing requirements for left 
ventricular ejection fraction 
for patients receiving the 
combination treatment 
containing sitravatinib. 
Y 
Potential impact on the 
study conduct and on 
patient safety 
Appendix 2 
BLOOD AND TUMOR 
TISSUE BIOMARKER 
ANALYSIS 
Row 
Visit window for Visit day 1 of 
Cycle 2 (21 days): ± 2 
To clarify the visit window 
for Cycle 2 Day 1 for the 
clinical practice 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 1.0 Summary of Changes 
15 May 2023 
 
CONFIDENTIAL 
Page 10 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 2 
BLOOD AND TUMOR 
TISSUE BIOMARKER 
ANALYSIS 
Column 
Survival Follow-up Visit  
To add a new column to 
maintain consistency with 
content of protocol body 
N 
N/A 
Abbreviations: ADR, adverse drug reactions; AE, adverse event; BP, blood pressure; CTCAE, Common Terminology Criteria for Adverse Events; ECG, 
electrocardiogram; EOT, End of Treatment; FDA, Food and Drug Administration; MUGA, multigated acquisition; N/A, not applicable; PK, pharmacokinetics; 
SAE, serious adverse events; SFU, Safety Follow-up; US, United States. 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 1 
BGB-LC-203 
PROTOCOL AMENDMENT 2.0 
SUMMARY OF CHANGES 
 
Study Title: A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination With Investigational Agents 
in Non-Small Cell Lung Cancer Patients Previously Treated With Anti-PD-(L)1 Antibody 
BeiGene, Ltd., has updated the BGB-LC-203 protocol from Protocol Amendment 1.0 (15 May 2023) to Protocol Amendment 2.0 
(13 November 2023).  The primary purposes for this update are as follows: 
• To remove the sitravatinib in combination with BGB-A445 and tislelizumab cohort 
• To update the inclusion criteria and exclusion criteria related to sitravatinib 
• To specify in the inclusion criteria that prior systemic therapy for patients must include platinum-based doublets 
chemotherapy, per China Center for Drug Evaluation (CDE) recommendation 
• To remove investigational agent information of sitravatinib and tislelizumab in the appendices  
Overall, editorial and formatting changes have been made throughout to enhance clarity and readability.   
Key changes made are summarized by protocol section in the table below.  Additions are in bold text and deletions are designated by 
strike through text. 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Cover Page 
Changed protocol version and 
date 
To update the protocol 
version. 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 2 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Synopsis 
Study Design 
Removed the sitravatinib in 
combination with BGB-A445 and 
tislelizumab cohort 
Due to sponsor’s decision to 
discontinue development of 
sitravatinib, relevant cohort 
will be removed from the 
protocol. Cohort specific 
content was deleted. 
Y 
Potential impact on the 
study conduct 
Synopsis 
Key Eligibility Criteria 
Patients who have received no 
more than 2 lines of prior 
systemic therapies which must 
include anti-PD-(L)1 treatment 
and a platinum-based 
chemotherapy administered in 
combination with, or 
sequentially before or after the 
anti-PD-(L)1 treatment.  
To clarify inclusion criteria 
for patients who had prior 
systemic therapies. 
Y 
Potential impact on the 
study conduct 
Synopsis 
Statistical Methods 
Update statistical analysis and 
interim monitoring 
For clarity. 
N 
N/A 
Section 1.2.3 Clinical 
Pharmacology 
 of BGB-A317, which is a 
BeiGene developed anti-PD-1 
monoclonal antibody, namely 
tislelizumab, 
For clarity. 
N 
N/A 
Section 3.1 Summary of Study 
Design, including Figure 1 
Removed the sitravatinib in 
combination with BGB-A445 and 
tislelizumab cohort 
Due to sponsor’s decision to 
discontinue development of 
sitravatinib, relevant cohort 
will be removed from the 
protocol. Cohort specific 
content was deleted. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 3 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 3.3 Treatment Period 
Study treatments in all cohorts 
will be administered up to 36 
cycles (approximately 2 years, 
everyone cycle consists of 
3 weeks based on the schedule 
of administration of BGB-A445) 
All patients will receive study 
drug(s) 
To clarify maximum 
treatment period.  
N 
N/A 
Section 3.4.2 Dose-Limiting 
Toxicity Definition 
Removed the sitravatinib specific 
DLT 
To remove sitravatinib from 
the study. 
N 
N/A 
Section 4.1 Inclusion Criteria 
#4 
Patients who have received no 
more than 2 lines of prior 
systemic therapies which must 
include anti-PD-(L)1 treatment 
and a platinum-based 
chemotherapy administered in 
combination with, or 
sequentially before or after the 
anti-PD-(L)1 treatment. 
To clarify inclusion criteria 
for patients who had prior 
systemic therapies. 
Y 
Potential impact on the 
study conduct 
Section 4.1 Inclusion Criteria 
#8 
c. Urinary protein < 2+ by urine 
dipstick.  If dipstick is ≥ 2+, then 
24-hour urinary protein must be < 
1 g per 24 hours 
Sitravatinib specific 
inclusion criteria; to remove 
sitravatinib from the study. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 4 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 4.1 Inclusion Criteria 
#9 
Note: If receiving the sitravatinib- 
or docetaxel-containing 
combination treatment, women of 
childbearing potential must be 
willing to use a highly effective 
method of birth control for the 
duration of the study and at least 
180 days after the last dose of 
study drug(s) 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Section 4.1 Inclusion Criteria 
#10 
Note: If receiving the sitravatinib- 
or docetaxel-containing 
combination treatment, nonsterile 
male patients must be willing to 
use a highly effective method of 
birth control for the duration of 
the study and at least 180 days 
after the last dose of study drug(s) 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Section 4.2 Exclusion Criteria 
#2 
With known actionable alterations 
(including, but not limited to, 
EGFR, ALK, BRAF, RET, and 
ROS1 mutations) for which 
targeted therapy has been 
approved in the second  and third 
line treatment setting by the 
respective local health authority. 
by the respective local health 
authority in the current 
treatment setting at the time of 
patient enrollment.     
To clarify the exclusion 
criteria. 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 5 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 4.2 Exclusion Criteria 
#19 
g. Patients with inadequately 
controlled hypertension (defined 
as average systolic blood pressure 
[BP] ≥ 150 140 mmHg and/or 
diastolic BP ≥ 100 90 mmHg) 
≤ 28 days before randomization 
To update the exclusion 
criteria for patient safety. 
Y 
Potential impact on the 
study conduct 
j. QT interval corrected by 
Fridericia’s method (QTcF) > 450 
msec 
Note: If a patient has QTcF 
interval > 450 msec on an initial 
ECG, a follow-up ECG will be 
performed to confirm the result. 
Sitravatinib specific 
inclusion criteria; to remove 
sitravatinib from the study. 
Y 
Potential impact on the 
study conduct 
k. Cardiac left ventricular ejection 
fraction < 50% or lower limit of 
normal as assessed by 
echocardiography or multigated 
acquisition (MUGA).  The same 
modality used at baseline must be 
applied for subsequent 
evaluations. 
Sitravatinib specific 
inclusion criteria; to remove 
sitravatinib from the study. 
Y 
Potential impact on the 
study conduct 
Section 5.2.1 BGB-A445 
Administration  
Table 4 
BGB-A445 
 infusion 
over 60 (± 5) minutes 
BGB-A445 
 infusion 
over 30 (± 5) minutes 
For clarity. 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 6 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 5.2.1 BGB-A445 
Administration  
Refer to Appendix 13 for the 
administration of BGB-A445 in 
combination with tislelizumab 
and sitravatinib. 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Section 5.2.2 Docetaxel 
Administration 
BGB-A445 
 infusion 
over 60 (± 5) minutes 
BGB-A445 
 infusion 
over 30 (± 5) minutes 
For clarity. 
N 
N/A 
Section 8.2.2 Abnormal Liver 
Function Tests 
Removed this section 
The content has been updated 
in Section 8.6.6 and 
Section 8.7.3. 
N 
N/A 
Section 8.6.1 Adverse Event 
Recording Period  
After informed consent has been 
signed but before the 
administration of the study drug, 
only serious adverse events 
associated with protocol-defined 
procedures should be reported 
to the sponsor. SAEs should be 
reported by the 
investigator/investigational site to 
the sponsor. 
To align with protocol 
template updates; to improve 
the reporting process. 
N 
N/A 
Section 8.6.1 Adverse Event 
Recording Period  
Table 11 
Streamlined Table 11 guidance on 
recording new or worsening AEs 
and included the changes in SAE 
reporting. 
To align with protocol 
template updates; to improve 
the reporting process. 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 7 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 8.6.4 Progressive 
Disease 
Updated disease 
progression-related AE reporting 
language 
To align with protocol 
template updates; to improve 
the reporting process; to 
avoid duplicate reporting. 
N 
N/A 
Section 8.6.5 Deaths 
Updated death-related AE 
reporting language for clarity 
To improve clarity. 
N 
N/A 
Section 8.6.6 Adverse Events 
of Special Interest 
Added adverse events of special 
interest section 
To align with protocol 
template updates; collecting 
AESI information to allow 
the sponsor to receive safety 
information in a timely 
manner.   
N 
N/A 
Section 8.6.7 Pregnancies 
If the patient receives the 
sitravatinib- or docetaxel-
containing combination treatment 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Section 8.6.10 Recording 
Infusion-Related Reactions 
Updated infusion-related reactions 
recording language. 
To align with protocol 
template updates; to improve 
the reporting process.  
N 
N/A 
Section 8.6.11 Recording 
Anaphylaxis 
Added Anaphylaxis recording 
language. 
To align with protocol 
template updates; to improve 
the reporting process.  
N 
N/A 
Section 8.7 Management of 
Events to be Monitored  
Changed the section heading from 
“Adverse Events of Special 
Interest” to “Management of 
Events to be Monitored”. 
For accuracy. 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 8 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Replace wording 
“hypersensitivity” by 
“anaphylaxis”  
For accuracy. 
N 
N/A 
Section 8.7.1 Infusion-Related 
Reactions 
Changed the section heading from 
“Infusion-Related Reactions and 
Hypersensitivity Reactions” to 
“Infusion-Related Reactions” 
For accuracy. 
N 
N/A 
Added language for monitoring 
patients after infusion of the study 
treatments 
For clarity. 
N 
N/A 
Replaced wording of 
“hypersensitivity” with 
“anaphylaxis”  
For accuracy. 
N 
N/A 
Section 8.7.2 
Immune-Mediated Adverse 
Events Table 13 
Updated Table 13 examples of 
imAEs. 
For clarity. 
N 
N/A 
Section 8.7.2 
Immune-Mediated Adverse 
Events  
Added discontinuation rule for 
patients with imAEs 
For clarity. 
N 
N/A 
Section 8.7.3 Hepatic Function 
Abnormalities  
Added a section titled “Hepatic 
Function Abnormalities” to 
provide guidance on diagnosis 
and management of patients with 
liver function laboratory 
abnormalities 
To align with Section 8.2.2 
due to reorganization of 
sections. 
Y 
Impact on safety reporting; 
ensure timely monitoring 
of patient safety 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 9 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 9.2.1 Primary Efficacy 
Analysis 
Updated primary efficacy analysis  For clarity. 
N 
N/A 
Section 9.8 Interim Monitoring Updated analysis method for 
interim monitoring 
For clarity. 
N 
N/A 
Section 15 References 
Added reference accordingly 
For consistency of content 
and reference.  
N 
N/A 
Appendix 1 
SCHEDULE OF 
ASSESSMENTS 
Row  
PK sampling of tislelizumab 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
PK sampling of sitravatinib and 
M10 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Sampling of anti-tislelizumab 
antibodies 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Echocardiogram (preferred) or 
MUGA 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 10 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 1 
SCHEDULE OF 
ASSESSMENTS 
footnote 
k. For patients receiving the 
combination treatment containing 
sitravatinib, urinalysis will be 
performed at each visit; if urine 
protein is ≥ 2+ by dipstick, then 
obtain a 24-hour urine sample for 
total protein analysis 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
u. Investigational agents including 
tislelizumab and docetaxel will be 
given intravenously on Day 1 of 
each 21-day cycle (every 3 
weeks), while investigational 
agents including BGB-15025 and 
sitravatinib will be received orally 
on a daily basis for each 21-day 
cycle (every 3 weeks) before the 
infusion.  Refer to the respective 
appendix for details 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 11 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
v. Predose serum samples for 
tislelizumab and/or BGB-A445 
(≤ 60 minutes before starting 
infusion) are required to be 
collected on Day 1 of Cycles 1, 2, 
5, 9, and 17.  Postdose serum 
samples (≤ approximately 30 
minutes after completing study 
drug infusion) are required to be 
collected on Day 1 of Cycles 1 
and 5.  An additional PK sample 
is required to be collected at the 
Safety Follow-up Visit.  Should a 
patient present with any ≥ Grade 3 
immune-mediated adverse event 
(imAE), an additional blood PK 
sample may be taken.  These tests 
are required when it is allowed by 
local regulations/Institutional 
Review Boards 
(IRBs)/Independent Ethics 
Committees (IECs) 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 12 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
w. Predose blood samples for 
BGB-15025 and its metabolite 
BGB-21958 (≤ 30 minutes before 
dose) are required to be collected 
on Day 1 of Cycles 1, 2, and 3, 
and Days 8 and 15 of Cycle 1.  
Postdose blood samples at 2 hours 
(± 10 minutes) and 4-6 hours (± 
20 minutes) after dosing are 
required to be collected on Day 1 
of Cycles 1 and 2.  Should a 
patient present with any ≥ Grade 3 
AE, an additional blood PK 
sample may be taken.  These tests 
are required when it is allowed by 
local regulations/IRBs/IECs. 
To clarify the window time. 
N 
N/A 
x. Predose blood samples for 
sitravatinib and its metabolite 
M10 (≤ 30 minutes before dose) 
are required to be collected on 
Day 1 of Cycles 1, 2, and 5.  
Postdose blood samples at 6 hours 
(± 1 hour) after dosing are 
required to be collected on Day 1 
of Cycles 1, 2, and 5.  Should a 
patient present with any ≥ Grade 3 
AE, an additional blood PK 
sample may be taken.  These tests 
are required when it is allowed by 
local regulations/IRBs/IECs 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 13 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
xy. Blood samples to test for 
anti-BGB-A445 and/or anti 
tislelizumab antibodies antibody 
will be collected ≤ 60 minutes 
before beginning the Day 1 
infusion of Cycles 1, 2, 5, 9, and 
17 and at the Safety Follow-up 
Visit.  All samples should be 
drawn at the same time as blood 
collection for the predose PK 
analysis.  These tests are required 
when it is allowed by local 
regulations/IRBs/IECs 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
z. Only applicable for the patients 
receiving combination containing 
sitravatinib: Evaluations of 
cardiac function will be 
performed at screening and every 
12 weeks (± 7 days).  Evaluation 
by echocardiogram is preferred.  
Evaluation by MUGA scan is an 
acceptable alternative, if 
necessary.  The method used for 
individual patients should be 
consistent throughout study 
participation. 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 14 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 3 
CLINICAL LABORATORY 
ASSESSMENTS 
footnote 
b On routine urinalysis, if urine 
protein is ≥ 2+ by dipstick, then 
obtain a 24-hour urine sample for 
total protein. 
Remove sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort; this 
is sitravatinib specific. 
Y 
Potential impact on the 
study conduct 
Appendix 8 
IMMUNE-MEDIATED 
ADVERSE EVENT 
EVALUATION AND 
MANAGEMENT 
 
Moved infusion-related reactions 
to Appendix 9 and anaphylaxis to 
Appendix 10 
To align with protocol 
template updates; to clarify. 
N 
N/A 
Appendix 9 MANAGEMENT 
OF INFUSION-RELATED 
REACTIONS 
 
Created new appendix for 
management of infusion-related 
reactions 
To align with protocol 
template updates; to clarify. 
N 
N/A 
Appendix 10 
MANAGEMENT OF 
ANAPHYLAXIS 
Created new appendix for 
management of anaphylaxis 
To align with protocol 
template updates; to clarify. 
N 
N/A 
Appendix 12 
TISLELIZUMAB 
Removed this appendix 
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 
Appendix 13 SITRAVATINIB 
Removed this appendix  
To remove the sitravatinib in 
combination with BGB-A445 
and tislelizumab cohort. 
Y 
Potential impact on the 
study conduct 

BGB-LC-203 
BeiGene 
Protocol Amendment 2.0 Summary of Changes 
13 November 2023 
 
CONFIDENTIAL 
Page 15 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Appendix 14 BGB-15025: 
Table 2 
BGB-A445 infusion over 
60 (± 5) minutes 
BGB-A445 infusion over 
30 (± 5) minutes 
For clarity. 
N 
N/A 
Appendix 14 BGB-15025: 
Section 8.3 Adverse Events of 
Special Interest – BGB-15025 
Removed this section 
Information mentioned in 
Section 8.6.6. 
N 
N/A 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; DLT, dose-limiting toxicity; ECG, electrocardiogram; IEC, Independent Ethics 
Committee; IRB, Institutional Review Board; imAE, immune-mediated AE; MUGA, multigated acquisition; N/A, not applicable; PD-(L)1, programmed cell 
death protein (ligand)-1; PK, pharmacokinetics; SAE, serious adverse event. 

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 Summary of Changes 
30 September 2024 
 
CONFIDENTIAL 
Page 1 
BGB-LC-203 
PROTOCOL AMENDMENT 3.0 
SUMMARY OF CHANGES 
 
Study Title: A Phase 2, Open-label, Randomized, Multi-arm Study of BGB-A445 in Combination With Investigational Agents 
in Non-Small Cell Lung Cancer Patients Previously Treated With Anti-PD-(L)1 Antibody 
BeiGene, Ltd., has updated the BGB-LC-203 protocol from Protocol Amendment 2.0 (13 November 2023) to Protocol Amendment 
3.0 (30 September 2024).  The primary purpose for this update is to add a description of patient continued access to study drug after 
the end of the study. 
Overall, editorial and formatting changes have been made throughout to enhance clarity and readability.   
Key changes made are summarized by protocol section in the table below.  Additions are in bold text and deletions are designated by 
strike through text. 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Cover Page 
Changed protocol version and 
date 
To update the protocol 
version. 
N 
N/A 
Final Protocol Approval Sheet 
Sponsor Development Core 
Team Lead Sponsor Medical 
Monitor 
Updated to reflect the 
approver of the protocol 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 Summary of Changes 
30 September 2024 
 
CONFIDENTIAL 
Page 2 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
Section 3.6 End of Treatment 
and Safety Follow-up; 
The End-of-Treatment (EOT) or 
Safety Follow-up Visit will be 
conducted ≤ 7 days after when 
the investigator determines that 
BGB-A445 in combination with 
investigational agents or 
reference treatments that study 
treatment will no longer be 
used administered or the patient 
withdraws from discontinues 
the study treatment.  Patients 
will be asked to return to the 
clinic for undergo the 
EOT/Safety Follow-up Visit 
which should occur at 
approximately 
30 days (± 7 days) after the last 
dose of study drug or the before 
initiation of any new anticancer 
therapy, whichever occurs first. 
Clarified the visit window of 
EOT and safety follow-up 
visit  
N 
N/A 
Section 5.2 Dosage, 
Administration, and 
Compliance 
The first dose of study drug is to 
be administered ≤ 2 calendar 
business days after 
randomization.   
Corrected typographical 
error 
N 
N/A 

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 Summary of Changes 
30 September 2024 
 
CONFIDENTIAL 
Page 3 
Section 5.5 Continued Access 
to Study Drug After the End 
of the Study 
At the end of the study as 
determined by the sponsor, 
any patient who is still on 
treatment and, in the opinion 
of the investigator, continues 
to benefit from study 
treatment will continue 
treatment via being kept in the 
study for continuous access to 
study drugs. Continuous 
access could be terminated in 
case of a decision to stop 
manufacturing investigational 
agents used in the study. 
Patients will still be monitored 
by assessments as described in 
Section 7.3 and Section 8. No 
further data will be collected 
in EDC system for patients in 
continuous access to study 
drugs, SAE reports should be 
submitted through paper 
forms per requirements and 
timelines described in 
Section 8.6.2.  The blood and 
tissue samples for PK/ADA 
and biomarker analysis are 
not required to be collected. 
The continuous treatment 
access would be discontinued 
for reasons listed in Section 3.5 
or when the total duration 
To provide continuous 
access of study drugs for 
patients who still benefit 
from the ongoing treatments 
after the end of study. 
N 
N 

BGB-LC-203 
BeiGene 
Protocol Amendment 3.0 Summary of Changes 
30 September 2024 
 
CONFIDENTIAL 
Page 4 
Section  
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on the 
Safety of Patients, Study 
Conduct, or Expectedness 
of Suspected Serious 
Adverse Effects 
reaches 36 cycles (ie, 
approximately 2 years) as 
described in Section 3.3. 
During the continuous study 
treatment, patient visits should 
be dependent on investigator’s 
discretion. Other assessments, 
including but not limited to 
tumor assessment and adverse 
events collection, continue to 
follow the Appendix 1. These 
assessment data will be kept in 
study sites. 
Appendix 1 Schedule of 
Assessments 
Corrected typographical errors in 
the Schedule of Assessments 
table, footnote #b, footnote #o, 
footnote #w 
Corrected typographical 
error 
N 
N/A 
Abbreviations: ADA: antidrug antibody; EDC: electronic data capture (system); N/A, not applicable; PK, pharmacokinetics; SAE, serious adverse event.