Conditions: Advanced Hepatocellular Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 94
Healthy volunteers: no

Brief summary:
This was a Phase 2, randomized, multicenter, open-label, 2-arm study to investigate the efficacy and safety of ociperlimab in combination with tislelizumab plus BAT1706, and tislelizumab plus BAT1706, as first-line treatment in participants with advanced Hepatocellular Carcinoma (HCC).

Detailed description:

Arms:
arm 1: Participants received tislelizumab 200 milligrams (mg) intravenously once every 3 weeks followed by BAT1706 15 milligrams per kilogram (mg/kg) intravenously once every 3 weeks followed by ociperlimab 900 mg intravenously once every 3 weeks in 21-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first. arm 2: Participants received tislelizumab 200 mg intravenously once every 3 weeks followed by BAT1706 15 mg/kg intravenously once every 3 weeks in 21-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first.

Interventions: intervention 1: Ociperlimab intervention 2: Tislelizumab intervention 3: BAT1706
Intervention descriptions: intervention 1: 900 mg intravenously once every 3 weeks (dosed in 21-day cycles) intervention 2: 200 mg intravenously once every 3 weeks (dosed in 21-day cycles) intervention 3: 15 mg/kg intravenously once every 3 weeks (dosed in 21-day cycles)

Protocol document:
Prot_000.pdf: 
NCT Number:
 NCT04948697




AdvanTIG-206 
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CONFIDENTIAL 
Page 3 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
A Phase 2, Randomized, Open-labeled Clinical Study Investigating the 
Efficacy and Safety of Ociperlimab in Combination With Tislelizumab 
Plus BAT1706 and of Tislelizumab Plus BAT1706 as First-line 
Treatment in Patients With Advanced Hepatocellular Carcinoma 
Protocol Identifier: 
AdvanTIG-206 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries.  I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page.  PRINT your 
name, title, and the name and address of the center in which the study will be conducted.  
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................22 
1. 
INTRODUCTION AND RATIONALES ..................................................................25 
1.1. 
Background Information on Hepatocellular Carcinoma .............................................25 
1.2. 
Current Treatment of Hepatocellular Carcinoma .......................................................25 
1.2.1. 
Anti-PD-1/Anti-PD L1 or Anti-PD-1/Anti-PD L1-Combination Therapy for 
Advanced Hepatocellular Carcinoma .........................................................................27 
1.3. 
Background Information on Ociperlimab ...................................................................27 
1.3.1. 
Nonclinical Experience ...............................................................................................30 
1.3.1.1. 
Pharmacology .............................................................................................................30 
1.3.1.2. 
Toxicology ..................................................................................................................30 
1.3.2. 
Clinical Experience .....................................................................................................32 
1.3.2.1. 
Clinical Pharmacology ................................................................................................32 
1.3.2.2. 
Preliminary Safety Profile ..........................................................................................32 
1.3.2.3. 
Preliminary Efficacy Profile .......................................................................................38 
1.3.2.4. 
Clinical Experience With Other TIGIT Inhibitors ......................................................38 
1.4. 
Background Information on Tislelizumab as a PD-1 Inhibitor ..................................40 
1.4.1. 
Pharmacology .............................................................................................................40 
1.4.2. 
Toxicology ..................................................................................................................40 
1.4.3. 
Clinical Pharmacology ................................................................................................40 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................41 
1.4.4.1. 
Treatment-Emergent Adverse Events Assessed as Related to Tislelizumab ..............41 
1.4.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................43 
1.5. 
Background Information on BAT1706, a Bevacizumab Biosimilar ..........................44 
1.5.1. 
Nonclinical Experience ...............................................................................................44 
1.5.1.1. 
Pharmacology .............................................................................................................44 


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1.5.1.2. 
Toxicology ..................................................................................................................45 
1.5.2. 
Clinical Experience .....................................................................................................45 
1.5.2.1. 
Clinical Pharmacology ................................................................................................45 
1.5.2.2. 
Clinical Safety ............................................................................................................46 
1.6. 
Study Rationale ...........................................................................................................47 
1.6.1. 
Rationale for Dose Selection ......................................................................................48 
1.6.1.1. 
Rationale for the Selection of Ociperlimab Dose in Combination with 
Tislelizumab and BAT1706 ........................................................................................48 
1.6.1.2. 
Rationale for the Selection of Tislelizumab Dose ......................................................49 
1.6.1.3. 
Rationale for the Selection of BAT1706 Dose in Combination with 
Tislelizumab ...............................................................................................................49 
1.6.2. 
Rationale for Combination of Ociperlimab With Tislelizumab and BAT1706 
in the First-Line Treatment of Advanced Hepatocellular Carcinoma ........................50 
1.6.3. 
Biomarker Strategy Rationale.....................................................................................51 
1.7. 
Benefit-Risk Assessment ............................................................................................52 
1.8. 
Study Conduct ............................................................................................................53 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................54 
2.1. 
Study Objectives .........................................................................................................54 
2.1.1. 
Primary Objectives .....................................................................................................54 
2.1.2. 
Secondary Objectives .................................................................................................54 
2.1.3. 
Exploratory Objectives ...............................................................................................54 
2.2. 
Study Endpoints ..........................................................................................................54 
2.2.1. 
Primary Endpoints ......................................................................................................54 
2.2.2. 
Secondary Endpoints ..................................................................................................54 
2.2.3. 
Exploratory Endpoints ................................................................................................55 
3. 
STUDY DESIGN .......................................................................................................56 
3.1. 
Summary of Study Design ..........................................................................................56 
3.2. 
Screening Period .........................................................................................................57 
3.3. 
Treatment Period ........................................................................................................57 
3.4. 
End-of-Treatment/Safety Follow-up ..........................................................................60 
3.4.1. 
Safety Follow-up for Tislelizumab and/or Ociperlimab .............................................60 
3.5. 
Survival Follow-up .....................................................................................................61 
3.6. 
Discontinuation From Study Drug(s) or From the Study ...........................................61 


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3.6.1. 
Patient Discontinuation From Study Drug(s) .............................................................61 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........62 
3.7. 
End of Study ...............................................................................................................62 
4. 
STUDY POPULATION .............................................................................................63 
4.1. 
Inclusion Criteria ........................................................................................................63 
4.2. 
Exclusion Criteria .......................................................................................................64 
5. 
STUDY DRUGS ........................................................................................................68 
5.1. 
Formulation, Packaging, and Handling ......................................................................68 
5.1.1. 
Tislelizumab ...............................................................................................................68 
5.1.2. 
Ociperlimab ................................................................................................................68 
5.1.3. 
BAT1706 ....................................................................................................................68 
5.2. 
Dosage, Administration, and Compliance ..................................................................69 
5.3. 
Incorrect Administration or Overdose ........................................................................71 
5.4. 
Study Drug Accountability .........................................................................................71 
5.5. 
Dose Delay or Modification .......................................................................................71 
5.5.1. 
Dose Modifications for Ociperlimab and Tislelizumab .............................................72 
5.5.2. 
Dose Modifications for BAT1706 ..............................................................................72 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................73 
6.1. 
Prior Therapy ..............................................................................................................73 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................73 
6.2.1. 
Systemic Corticosteroids ............................................................................................73 
6.2.2. 
Hepatitis B Treatment .................................................................................................73 
6.2.3. 
Hepatitis C Treatment .................................................................................................73 
6.2.4. 
Radiation Therapy ......................................................................................................74 
6.3. 
Prohibited Concomitant Medications/Procedures ......................................................74 
6.4. 
Restricted Concomitant Medications/Procedures .......................................................75 
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................75 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................76 
7.1. 
Screening Period .........................................................................................................76 
7.1.1. 
Informed Consent and Screening Log ........................................................................76 
7.1.2. 
Patient Numbering ......................................................................................................76 
7.1.3. 
Demographic Data and Medical History ....................................................................76 


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7.1.4. 
Women of Childbearing Potential and Contraception ................................................77 
7.1.5. 
Pulmonary Function Tests ..........................................................................................77 
7.1.6. 
Esophagogastroduodenoscopy ....................................................................................77 
7.2. 
Enrollment ..................................................................................................................77 
7.2.1. 
Confirmation of Eligibility .........................................................................................77 
7.2.2. 
Randomization ............................................................................................................78 
7.3. 
Study Drug Dispensation ............................................................................................78 
7.4. 
Safety Assessment ......................................................................................................78 
7.4.1. 
Vital Signs ..................................................................................................................78 
7.4.2. 
Physical Examinations ................................................................................................78 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................78 
7.4.4. 
Laboratory Safety Tests ..............................................................................................79 
7.4.4.1. 
Cardiac Enzyme Monitoring .......................................................................................79 
7.4.5. 
Electrocardiograms .....................................................................................................79 
7.4.6. 
Adverse Events ...........................................................................................................79 
7.4.7. 
Hepatitis B and C Testing ...........................................................................................80 
7.4.8. 
Ophthalmologic Examination .....................................................................................80 
7.5. 
Tumor and Response Evaluations ..............................................................................80 
7.6. 
Pharmacokinetic and Antidrug Antibody Assessments ..............................................82 
7.7. 
Tumor Tissue and Biomarker Assessment Procedures ..............................................82 
7.8. 
Visit Windows ............................................................................................................83 
7.9. 
Unscheduled Visits .....................................................................................................83 
8. 
SAFETY MONITORING AND REPORTING .........................................................84 
8.1. 
Risks Associated With Study Drugs ...........................................................................84 
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab ..............................................84 
8.1.2. 
Risks Associated With BAT1706 ...............................................................................84 
8.2. 
General Plan to Manage Safety Concerns ..................................................................85 
8.2.1. 
Eligibility Criteria .......................................................................................................85 
8.2.2. 
Safety Monitoring Plan ...............................................................................................85 
8.3. 
Adverse Events ...........................................................................................................85 
8.3.1. 
Definitions and Reporting ...........................................................................................85 
8.3.2. 
Assessment of Severity ...............................................................................................86 


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8.3.3. 
Assessment of Causality .............................................................................................86 
8.3.4. 
Follow-up of Adverse Events .....................................................................................87 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................88 
8.4. 
Definition of a Serious Adverse Event .......................................................................89 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................89 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................90 
8.6.1. 
Adverse Event Reporting Period ................................................................................90 
8.6.2. 
Reporting Serious Adverse Events .............................................................................90 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................90 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................91 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................91 
8.6.3. 
Eliciting Adverse Events ............................................................................................92 
8.6.4. 
Disease Progression ....................................................................................................92 
8.6.5. 
Deaths .........................................................................................................................92 
8.6.6. 
Pregnancies .................................................................................................................92 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................92 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................93 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................93 
8.7. 
Management of Adverse Events of Special Interest ...................................................93 
8.7.1. 
Infusion-Related Reactions .........................................................................................93 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms .......................................95 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................95 
8.7.4. 
Adverse Events of Special Interest Related to BAT1706 ...........................................96 
8.7.5. 
Hepatic Function Abnormalities .................................................................................97 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................99 
9.1. 
Statistical Analysis ......................................................................................................99 
9.1.1. 
Analysis Sets ...............................................................................................................99 
9.1.2. 
Patient Disposition ....................................................................................................100 
9.1.3. 
Demographic and Other Baseline Characteristics ....................................................100 
9.1.4. 
Prior and Concomitant Medications .........................................................................100 
9.2. 
Efficacy Analyses .....................................................................................................100 


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9.2.1. 
Primary Efficacy Analysis ........................................................................................100 
9.2.2. 
Secondary Efficacy Analysis ....................................................................................101 
9.2.3. 
Subgroup Analysis ....................................................................................................102 
9.3. 
Safety Analyses ........................................................................................................102 
9.3.1. 
Extent of Exposure ...................................................................................................102 
9.3.2. 
Adverse Events .........................................................................................................102 
9.3.3. 
Laboratory Analyses .................................................................................................103 
9.3.4. 
Vital Signs ................................................................................................................103 
9.3.5. 
Physical examination ................................................................................................103 
9.3.6. 
Electrocardiograms ...................................................................................................104 
9.3.7. 
Eastern Cooperative Oncology Group Performance Status ......................................104 
9.3.8. 
Ophthalmologic examination....................................................................................104 
9.4. 
Pharmacokinetic Analyses ........................................................................................104 
9.5. 
Immunogenicity Analyses ........................................................................................104 
9.6. 
Other Exploratory Analyses .....................................................................................104 
9.7. 
Sample Size Consideration .......................................................................................105 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................106 
10.1. 
Safety Monitoring Committee ..................................................................................106 
10.2. 
Communication .........................................................................................................106 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................107 
11.1. 
Access to Information for Monitoring ......................................................................107 
11.2. 
Access to Information for Auditing or Inspections ..................................................107 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................108 
12.1. 
Regulatory Authority Approval ................................................................................108 
12.2. 
Quality Assurance .....................................................................................................108 
12.3. 
Study Site Inspections...............................................................................................108 
12.4. 
Drug Accountability .................................................................................................108 
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................110 
13.1. 
Ethical Standard ........................................................................................................110 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................110 
13.2.1. 
Protocol Amendments ..............................................................................................110 
13.3. 
Informed Consent .....................................................................................................110 


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13.4. 
Patient and Data Confidentiality ...............................................................................111 
13.5. 
Financial Disclosure .................................................................................................112 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................113 
14.1. 
Data Collection and Management Responsibilities ..................................................113 
14.1.1. 
Data Entry in the Electronic Case Report Form .......................................................113 
14.1.2. 
Data Collection .........................................................................................................113 
14.1.3. 
Data Management/Coding ........................................................................................113 
14.2. 
Data Integrity and In-house Blinding .......................................................................114 
14.3. 
Study Records Retention ..........................................................................................114 
14.4. 
Protocol Deviations ..................................................................................................115 
14.5. 
Study Report and Publications..................................................................................115 
14.6. 
Study and Study Center Closure ...............................................................................116 
14.7. 
Information Disclosure and Inventions ....................................................................116 
15. 
REFERENCES .........................................................................................................118 
16. 
APPENDICES ..........................................................................................................126 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................127 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................133 
APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...................................................................................................................134 
APPENDIX 4. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................135 
APPENDIX 5. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................137 
APPENDIX 6. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................138 
APPENDIX 7. MANAGEMENT GUIDELINES FOR ADVERSE EVENTS 
RELATED TO BAT1706 .........................................................................................148 
APPENDIX 8. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................153 
APPENDIX 9. CHILD-PUGH CLASSIFICATION SCORING SYSTEM .............................162 
APPENDIX 10. BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION ..................................................................................................163 
APPENDIX 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................164 


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LIST OF TABLES 
Table 1: 
Overview of Treatment-Emergent Adverse Events (Safety Analysis Set) .................34 
Table 2: 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Analysis Set) .........................................................................................35 
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs ...........................................................................................................69 
Table 4: 
Administration of Study Drugs and Monitoring Time ...............................................69 
Table 5:  
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Arms ...................................................................................................................90 
Table 6: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................91 
Table 7: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs ................................................................................................................94 
Table 8: 
Immune-Mediated Adverse Events ............................................................................96 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................14 
Figure 2: 
Study Schema .............................................................................................................57 
 


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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Product(s): Ociperlimab, tislelizumab and BAT1706 
Title of Study: A Phase 2, Randomized, Open-labeled Clinical Study Investigating the Efficacy and 
Safety of Ociperlimab in Combination With Tislelizumab Plus BAT1706 and of Tislelizumab Plus 
BAT1706 as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma  
Protocol Identifier: AdvanTIG-206 
Phase of Development: 2 
Number of Patients: Approximately 90 
Study Centers: 
Approximately 30 centers in Mainland China/Taiwan 
Study Objectives: 
Primary: 
• 
To evaluate the efficacy of ociperlimab in combination with tislelizumab plus BAT1706, 
and tislelizumab plus BAT1706 through the objective response rate (ORR), as assessed by 
the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1) as first-line treatment in patients with advanced hepatocellular carcinoma 
(HCC)   
Secondary: 
• 
To assess the efficacy of ociperlimab in combination with tislelizumab plus BAT1706, and 
tislelizumab plus BAT1706, through duration of response (DOR), time to response (TTR), 
disease control rate (DCR), clinical benefit rate (CBR) and progression-free survival (PFS) 
as assessed by the investigators; and overall survival (OS) 
• 
To assess the safety and tolerability of ociperlimab in combination with tislelizumab plus 
BAT1706, and tislelizumab plus BAT1706  
• 
To characterize the pharmacokinetics (PK) of ociperlimab in combination with 
tislelizumab plus BAT1706, and tislelizumab plus BAT1706 
• 
To determine host immunogenicity to ociperlimab, tislelizumab, and BAT1706 
Exploratory: 
• 
To explore potential biomarkers that may correlate with clinical responses/resistance to 
ociperlimab in combination with tislelizumab plus BAT1706, and to tislelizumab plus 
BAT1706 


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Study Endpoints: 
Primary: 
• 
ORR, as assessed by the investigator, defined as the proportion of patients with a 
confirmed complete response (CR) or partial response (PR) per RECIST v1.1 
Secondary: 
• 
DOR, TTR, DCR, CBR, and PFS as assessed by the investigator  
− 
DOR, defined as the time from the first confirmed objective response until the first 
documentation of disease progression or death, whichever comes first 
− 
TTR, defined as the time from the date of first dose of study drug to the first 
documentation of response 
− 
DCR, defined as the proportion of patients who achieve CR, PR, or stable disease 
− 
CBR, defined as the proportion of patients who achieve CR, PR, or durable stable 
disease (stable disease ≥ 24 weeks) 
− 
PFS, defined as the time from the date of the first dose of study drug to the date of first 
documentation of disease progression or death, whichever occurs first 
• 
OS, defined as the time from the date of the first dose of study drug until the date of death 
from any cause 
• 
Incidence and severity of adverse events (AEs), with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE] Version [v] 5.0, vital signs and clinical laboratory test results 
• 
Serum concentrations of ociperlimab, tislelizumab, and BAT1706 at specified timepoints 
• 
Immunogenic responses to ociperlimab, tislelizumab, and BAT1706 evaluated through 
detection of antidrug antibodies (ADAs) 
Exploratory: 
• 
Potential biomarkers including programmed cell death protein ligand-1 (PD‑L1) 
expression, T cell immunoreceptor with Ig and ITIM domains (TIGIT) pathway related 
protein expression (TIGIT, poliovirus receptor/PVR and nectin cell adhesion molecule 
2/nectin-2), tumor mutational burden (TMB)/DNA mutation, blood tumor mutational 
burden (bTMB)/circulating tumor DNA (ctDNA) monitoring/DNA mutation, alpha-
fetoprotein (AFP), gene expression profile (GEP), and the association of biomarkers with 
disease status, and response/resistance to ociperlimab in combination with tislelizumab 
plus BAT1706, and to tislelizumab plus BAT1706 
Study Design 
This is a Phase 2, randomized, multicenter, open-label, 2-arm study to investigate the efficacy and 
safety of ociperlimab in combination with tislelizumab plus BAT1706, and tislelizumab plus 
BAT1706, as first-line treatment in patients with advanced HCC. 
The study will enroll approximately 90 patients randomized in a 2:1 ratio to one of 2 treatment arms: 


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• 
Arm A (n = 60): tislelizumab 200 mg intravenously once every 3 weeks (dosed in 21-day 
cycles) + BAT1706 15 mg/kg intravenously once every 3 weeks (dosed in 21-day cycles) 
+ ociperlimab 900 mg intravenously once every 3 weeks (dosed in 21-day cycles)  
• 
Arm B (n = 30): tislelizumab 200 mg intravenously once every 3 weeks (dosed in 21-day 
cycles) + BAT1706 15 mg/kg intravenously once every 3 weeks (dosed in 21-day cycles) 
Randomization will be stratified according to the following factors: 
• 
PD-L1 expression (visually estimated combined positive score [vCPS] <1% versus ≥1%)  
• 
Macrovascular invasion (MVI)/Extrahepatic spread (EHS) (present versus absent) 
The study schema is shown in Figure 1. 
Figure 1: 
Study Schema 
Abbreviations: HCC, hepatocellular carcinoma; MVI: macrovascular invasion; PD-L1, programmed cell death protein-ligand 
1; Q3W, every 3 weeks, vCPS, visually estimated combined positive score. 
At the beginning of this Phase 2 study, a safety run-in period is planned to investigate the safety, 
tolerability, and PK before expanding the enrollment to additional patients.   
Every effort should be made to ensure that each drug is administrated as originally scheduled.  Patients 
who temporarily withhold or permanently discontinue a study drug due to related AEs may continue on 
the other study drug(s) as long as the patients are experiencing clinical benefit in the opinion of the 
investigator and after discussion with the medical monitor.  However, for patients in Arm A, both 
ociperlimab and tislelizumab should be withheld or permanently discontinued simultaneously, if 
necessary. 
Study Assessments: 
• 
The baseline tumor imaging will be performed ≤ 28 days before randomization.  During the study 
treatment period, tumor response will be evaluated by the investigator every 6 weeks for the first 
48 weeks, and every 12 weeks thereafter, in accordance with RECIST v1.1. 
• 
If, at the investigator’s discretion, a patient could continue to benefit from the assigned study 
drug(s) after progressive disease (PD) per RECIST v1.1 criteria is met, the patient may continue 
their assigned treatment.  


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• 
The following criteria must be met in order to treat patients who may continue to benefit from 
study drug(s) after PD:  
− 
Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
− 
Stable Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1  
− 
Absence of rapid disease progression or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention  
− 
Investigators must obtain written informed consent for treatment beyond radiologic PD 
and inform patients that this practice is not considered standard in the treatment of 
cancer 
− 
The decision to continue study drug(s) beyond initial investigator-assessed progression 
must be agreed with the sponsor medical monitor and documented in the study records. 
Patients who receive study drug(s) beyond disease progression will have tumor assessments 
performed according to the original schedule until all study drug(s) are discontinued.  
• 
If a patient discontinues study drug(s) due to any reason other than PD (eg. toxicity), tumor 
assessments will be performed according to the original schedule until disease progression, death, 
loss to follow-up, withdrawal of consent, or study termination, whichever occurs first. 
• 
Patients will report any AEs and serious adverse events (SAEs), regardless of causality to study 
drugs, occurring within either 30 days after the last dose of study drug (all severity grades, per 
NCI-CTCAE v5.0) or initiation of new anticancer therapy, whichever occurs first.  Patients must 
also report all immune-mediated adverse events (imAEs) occurring up to 90 days after the last 
dose of ociperlimab or tislelizumab, whichever occurs later, regardless of whether or not the 
patient starts a new anticancer therapy.  All 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 study drug. 
• 
The occurrence of any of the following toxicities during the first 21 days of study will be 
considered a dose-limiting toxicity (DLT), if assessed by the investigator as related to the study 
drug administration: 
Hematologic DLTs: 
1. Grade 4 neutropenia lasting > 7 days 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1 x 109/L with a single 
temperature of 38.3°C or a sustained temperature of 38°C for > 1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding indicated for clinical intervention 
5. Grade 4 thrombocytopenia 
6. Grade 4 anemia (life-threatening) 
Non-hematologic DLTs: 
1. Grade 4 or higher toxicity 
2. Grade 3 toxicity lasting for > 7 days despite optimal supportive care 


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Note: The following AEs will not be considered as DLTs: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• Grade 3 rash 
• Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
• Grade 3 to Grade 4 laboratory abnormalities that are not associated with clinical 
sequelae (eg, lactate dehydrogenase increased) 
• ALT/AST from 5x to 10x upper limit of normal (ULN)  the return to baseline in 
≤ 14 days with optimal management  
Clinically important or persistent AEs that are not part of the DLT criteria may also be 
considered a DLT, after review by the sponsor and in consultation with the investigator. 
The Safety Monitoring Committee (SMC) will evaluate the safety data of the study treatments when 
the first 6 DLT-evaluable patients in Arm A and 3 DLT-evaluable patients in Arm B have completed 
the first 21 days of treatment.  Based on these data, the SMC will recommend whether a dose 
modification is needed, or whether the current dosing regimen is tolerable.  The final decision will be 
made by the sponsor.  
• 
For the first 6 patients enrolled in Arm A, if ≤ 1 in 6 patients experience a DLT, the dosing 
regimen is tolerable and will be used in subsequent cycles.  If ≥ 2 in 6 patients experience a 
DLT, the starting dose will be considered as exceeding the maximum tolerated dose 
(MTD), and the sponsor will pause enrollment to allow for further evaluation of the safety 
data. 
• 
For the first 3 patients enrolled in Arm B, if no patient experiences a DLT, the dosing 
regimen is tolerable and will be used in subsequent cycles.  If 1 out of 3 patients 
experience a DLT, an additional 3 patients will be enrolled.  Otherwise, the starting dose 
will be considered as exceeding the MTD, and the sponsor will pause enrollment to allow 
for further evaluation of the safety data. 
• 
If a patient discontinues the study within the first 21 days of study due to reasons other than 
safety, or the clinical examination and/or assessment is incomplete, or the dose intensity of any 
drug is less than 80%, which leads to nonevaluable safety assessments within the first 21 days, 
additional patients may be required to be randomized to replace patients whose safety assessment 
cannot be performed.  
• 
An established SMC will monitor and review the safety results to evaluate the safety and 
tolerability of selected study drug dose, and recommend whether a dose adjustment is needed to 
manage adverse events.  The SMC may recommend modifications to the study, including 
termination due to safety concerns. 
Duration of Patient Participation:  
• 
Screening Period will be ≤ 28 days before randomization. 
• 
Treatment Period will start with the first day of study drug administration and end when the 
patient is discontinued from the study drug(s), for any reason. 
• 
End-of-Treatment/Safety Follow-up Period: The EOT Visit is conducted when the investigator 
determines that one or more study drugs, ie, ociperlimab and tislelizumab in Arm A, tislelizumab 


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in Arm B, and BAT1706 in both arms, will no longer be used.  If routine laboratory tests (eg, 
hematology, serum chemistry) were completed within 7 days of the EOT Visit, these tests do not 
need to be repeated.   
Tumor assessment is required at the EOT Visit if the investigator determines that the study 
drug(s) must be discontinued.  However, the tumor assessment may be omitted at the EOT visit 
provided that ≤ 6 weeks have passed since the last assessment.  Patients who discontinue all 
study drugs prior to disease progression will need to undergo tumor assessment. 
Patients who permanently discontinue ociperlimab and tislelizumab in Arm A, or tislelizumab in 
Arm B, will be asked to return to the clinic for the Safety Follow-up Visit, which is required to be 
conducted 30 (± 7) days after the last dose of the specific study drug(s), unless otherwise 
specified, or before the initiation of subsequent anticancer therapy, whichever occurs first.  
If the decision to end treatment is taken ≥ 23 days after the last dose of ociperlimab and 
tislelizumab in Arm A, or tislelizumab in Arm B, the EOT and the Safety follow-up visits should 
be conducted concurrently within 7 days of the decision to end treatment. 
In addition, patients who discontinue ociperlimab or tislelizumab in Arm A, or tislelizumab in 
Arm B, will be asked to return to the clinic or will be contacted via telephone to assess imAEs 
and concomitant medications (if appropriate, ie, associated with an imAE) at 60 and 90 (± 14) 
days after the last dose of ociperlimab or tislelizumab, whichever is later, regardless of whether 
they started a subsequent anticancer therapy. If patients report a suspected imAE at a follow-up 
visit or a telephone contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
• 
Survival Follow-up: Patients will be followed up for survival and to obtain information on 
subsequent anticancer therapy after discontinuation of all study drugs via telephone calls, patient 
medical records, and/or clinic visits approximately every 3 months (± 14 days) after the Safety 
Follow-up Visit, or as directed by the sponsor until death, withdrawal of consent, loss to follow-
up, or end of study. 
Study Population: Patients with histologically confirmed advanced HCC who have not received 
systemic therapy for the advanced disease, and who have not received treatment targeting PD-1/PD-L1, 
or targeting TIGIT or who have not received bevacizumab (originator or biosimilar) in any prior 
therapy setting. 
Key Eligibility Criteria: Adult patients with histologically confirmed advanced HCC, defined as 
either BCLC Stage C disease, or BCLC Stage B disease that is not amenable to or has progressed after 
loco-regional therapy, and is not amenable to a curative treatment approach, and those who have not 
been previously treated with systemic therapy are eligible.  All patients are required to provide 
archived or fresh tumor samples and have an evaluable PD-L1 expression result (presented as vCPS) 
assessed by the central laboratory.  All patients are required to have a Child-Pugh A classification, 
assessed within 7 days of randomization, and ≥ 1 measurable lesion per RECIST v1.1.  
Patients with active autoimmune disease or an history of autoimmune disease that may relapse, with 
untreated or incompletely treated esophageal or gastric varices with bleeding or high risk of bleeding 
are excluded. 
Investigational Product, Dose, and Mode of Administration: 


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Arm A: 
Ociperlimab will be administered at a dose of 900 mg intravenously once every 3 weeks. 
Tislelizumab will be administered at a dose of 200 mg intravenously once every 3 weeks. 
BAT1706 will be administered at a dose of 15 mg/kg intravenously once every 3 weeks. 
Arm B: 
Tislelizumab will be administered at a dose of 200 mg intravenously once every 3 weeks. 
BAT1706 will be administered at a dose of 15 mg/kg intravenously once every 3 weeks. 
Reference Therapy, Dose, and Mode of Administration: 
Not applicable 
Statistical Methods: 
Analysis Sets: 
• 
The Safety Analysis Set (SAS) includes all patients of each arm who received ≥ 1 dose of 
study drugs.  This will be the primary analysis set for the safety analysis. 
• 
The Intent-to-Treat (ITT) Analysis Set includes all randomized patients.  Patients will be 
analyzed according to their randomized treatment arm (ie, Arm A or Arm B).  This will be 
the primary analysis set for all efficacy analyses.  
• 
The Efficacy Evaluable Analysis Set (EAS) includes all patients in the ITT Analysis Set 
without critical protocol deviation who had measurable disease at baseline per RECIST 
v1.1 by investigator and who had ≥ 1 evaluable post-baseline tumor assessment unless 
discontinued due to clinical PD or death within 7 weeks after the first dose.  This analysis 
set will be used for the sensitivity analysis of the primary efficacy endpoint ORR.  
• 
The DLT Evaluable Analysis Set includes patients enrolled during the safety run-in period 
who  
− 
received ≥ 80% of the scheduled ociperlimab (if applicable), ≥ 80% of the scheduled 
tislelizumab, and ≥ 80% of the scheduled BAT1706 administration during the DLT 
assessment window (ie, within 21 days of the first dose of study drugs), remained on 
study during the DLT observation period, and had sufficient safety evaluation 
performed  
OR 
− 
experienced a DLT within the DLT observation period.  
• 
The PK Analysis Set includes all patients who received ≥ 1 dose of any component of 
study drug per the protocol, and for whom any postdose PK data are available.  
• 
The Immunogenicity Analysis Set includes all patients who received ≥ 1 dose of any 
component of study drugs for whom both baseline ADA results and ≥ 1 postbaseline ADA 
result are available. 
 
Efficacy Analysis: 
Primary Efficacy Analysis 


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The primary efficacy endpoint is ORR as determined by the investigator based on RECIST v 1.1, in 
Arm A and Arm B. ORR is defined as the proportion of patients achieving confirmed best overall 
responses of CR or PR. ORR will be summarized in the ITT Analysis Set with a Clopper-Pearson 95% 
CI constructed to assess the precision of the point estimate.  
The primary efficacy analysis will be conducted when ORR data are mature, which is estimated as 7.5 
months (approximately 5 tumor assessments) after the last patient receives the first dose of the study 
drug, and will be based on the ITT Analysis Set.  
The sensitivity analysis of ORR will be carried out in the Efficacy Evaluable Analysis Set. 
Secondary Efficacy Analysis 
Other efficacy endpoints based on investigator assessed tumor assessments (ie, DOR, PFS, TTR, DCR 
and CBR), as well as OS, will be summarized in the ITT Analysis Set for the secondary efficacy 
analysis.    
The DOR will be analyzed among the responders in the ITT Analysis Set.  The median and other 
quartiles of DOR will be estimated using the Kaplan-Meier method.  The 2-sided 95% CIs will be 
constructed with the generalized Brookmeyer and Crowley method.  Event-free rates at selected 
timepoints for DOR will be estimated using the Kaplan-Meier method with the corresponding 95% CI 
constructed using Greenwood’s formula.  The DOR censoring rule will follow US Food and Drug 
Administration (FDA) Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (2018).   
The PFS and OS will be analyzed in the ITT Analysis Set using methods similar to those described for 
the DOR, except for censoring rules.  The PFS censoring rule will follow the same as the DOR 
censoring rule.  For OS, patients will be censored either at the date that the patient was last known to be 
alive or the data cutoff date, whichever comes first, in the absence of death. 
The TTR will be analyzed in the ITT Analysis Set using sample statistics such as mean, median, and 
standard deviation for patients who have achieved an objective response.  
The DCR and CBR will be summarized similarly as the ORR in the ITT Analysis Set, and also in the 
Efficacy Evaluable Analysis Set for the sensitivity analysis. 
Safety Analyses: 
Safety will be assessed by monitoring and recording of AEs and laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis).  Vital signs, physical examinations, and 
electrocardiogram (ECG) findings will also be used in determining the safety profile.  The severity of 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 5.0 (NCI-CTCAE v5.0).  The incidence of DLT events and treatment-
emergent adverse events (TEAEs) will be reported as the number (percentage) of patients with TEAEs 
by 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. 


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Extent of exposure to a study drug will be summarized descriptively as the number of cycles received 
(number and percentage of patients), duration of exposure, cumulative total dose received per patient, 
dose intensity (mg/day), and relative dose intensity (%). 
The number (and percentage) of patients with a dose reduction, treatment interruption, or study drug 
discontinuation will be summarized with the respective reasons. 
The AE verbatim descriptions (as recorded by the investigator on the electronic case report form 
[eCRF]) will be classified into standardized medical terminology using the MedDRA®. 
The DLTs will be summarized for the safety run-in period. 
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.  The TEAE classification also 
applies to imAEs that are recorded up to 90 days after the last dose of ociperlimab and tislelizumab , 
regardless of whether or not the patient starts a new anticancer therapy.  All SAEs considered related to 
the study drug(s) that are brought to the attention of the investigator should be reported regardless of  
the time since the last dose of study drug.  Only those AEs that were treatment-emergent will be 
included in the summary tables.  All AEs, treatment-emergent or otherwise, will be presented in the 
patient data listings. 
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 ≥ 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 
the study drug or with missing assessment of the causal relationship.  
All TEAE, SAEs, deaths, ≥ Grade 3 TEAEs, imAEs, AEs of special interest related to BAT1706, 
treatment-related TEAEs, and TEAEs that led to treatment discontinuation and dose modification 
(interruption/delay/reduction, as appropriate) will be summarized. 
Safety data will be summarized using the Safety Analysis Set and by arm. 
Clinical laboratory data with values outside of the normal ranges will be identified.  Selected laboratory 
data will be summarized by grade and by worst postbaseline change.  Changes in vital signs will also 
be summarized by visit. 
 
Pharmacokinetic Analyses: 
The ociperlimab, tislelizumab,  and BAT1706 serum concentration data will be tabulated and 
summarized by visit/cycle at which these samples are collected.  Descriptive statistics will include 
means, medians, ranges, and standard deviations, as appropriate.  
Additional PK analyses may be conducted, as appropriate. 
Immunogenicity Analyses: 
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 


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neutralizing ADAs will be reported for evaluable patients.  The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allows. 
Sample Size Consideration: 
This study plans to enroll approximately 90 patients, with a 2:1 randomization to 
• Arm A (60 patients): ociperlimab + tislelizumab + BAT1706 
• Arm B (30 patients): tislelizumab + BAT1706  
These patients will be enrolled to evaluate the preliminary efficacy of ociperlimab in combination with 
tislelizumab plus BAT1706, and tislelizumab plus BAT1706.  
No formal hypothesis testing is planned in the efficacy evaluation. 
 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADAs 
antidrug antibodies 
AE 
adverse event 
AFP 
alpha-fetoprotein  
ALT 
alanine aminotransferase 
 
AST 
aspartate aminotransferase 
AUC 
area under the concentration 
BCLC 
Barcelona Clinic Liver Cancer 
BGB-A1217 
ociperlimab 
BGB-A317 
tislelizumab  
BOR 
best overall response 
bTMB 
blood tumor mutational burden 
CBR 
clinical benefit rate 
CD 
cluster of differentiation 
CNS 
central nervous system 
Cmax 
maximum concentration 
CR 
complete response 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EAS 
Efficacy Evaluable Analysis Set 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EMA 
European Medicines Agency 
EOT 
End-of-Treatment (Visit) 
FDG 
fluorine-18 [F-18] fluorodeoxyglucose 
GCP 
Good Clinical Practice 
GEP 
gene expression profiling 
HBV 
hepatitis B virus 
HbsAg 
hepatitis B surface antigen 
HbsAb 
hepatitis B surface antibody 
HCC 
hepatocellular carcinoma 


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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
INF 
interferon 
IgG 
immunoglobulin G 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
ITIM 
immunoreceptor tyrosine-based inhibitory motif 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NK 
natural killer (cells) 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein-ligand 1 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
Preferred Term 
PVR 
poliovirus receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TACE 
transarterial chemoembolization 
Tbil 
total bilirubin 
TEAE 
treatment-emergent adverse event 


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Abbreviation 
Definition 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
TMB 
tumor mutational burden 
Tregs 
regulatory T (cells)  
TIL 
tumor-infiltrating lymphocyte 
TTR 
time to response 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
vCPS 
visually estimated combined positive score 
VEGF 
vascular endothelial growth factor 
 


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1. 
INTRODUCTION AND RATIONALES 
1.1. 
Background Information on Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is a major global health problem, accounting for 85-90% of all 
reported cases of liver cancer (a term with which HCC is often used interchangeably) (El-Serag 
and Rudolph 2007).  According to the World Health Organization’s GLOBOCAN 2012 
database, liver cancer was the sixth most common type of cancer that year, with 782,000 new 
cases worldwide; it was also the second most common cause of cancer-related mortality, 
responsible for an estimated 746,000 deaths (Torre et al 2015). 
Most HCC cases (> 80%) occur in Eastern Asia and in sub-Saharan Africa, with typical 
incidence rates of > 20 per 100,000 individuals.  China alone accounts for approximately 50% of 
both new HCC cases and HCC-related deaths worldwide (Torre et al 2015).  Southern European 
countries, such as Spain, Italy, and Greece, tend to have more moderate incidence rates 
(approximately10 to 20 per 100,000 individuals), whereas North America, South America, 
Northern Europe, and Oceania have a relatively low incidence of HCC (< 5 per 100,000 
individuals) (El-Serag 2012). 
A variety of risk factors are known to be causative for HCC.  These include infection with 
hepatitis viruses, aflatoxin B, tobacco, vinyl chloride, heavy alcohol intake, non-alcoholic fatty 
liver disease, hemochromatosis, and diabetes.  Together, hepatitis B virus (HBV) and hepatitis C 
virus (HCV) account for 80-90% of all HCC cases worldwide (Bosch 2005).  Chronic HBV 
infection is the dominant risk factor for the disease in most areas of Asia, with the exception of 
Japan (El-Serag 2012), while chronic infection with HCV is the leading cause of HCC in 
Western countries and in Japan (Choo 2016). 
1.2. 
Current Treatment of Hepatocellular Carcinoma  
Treatment options for HCC are based on the disease stage at diagnosis per the Barcelona Clinic 
Liver Cancer (BCLC) classification system, which draws from a combination of Eastern 
Cooperative Oncology Group  Performance Status (ECOG PS) (Appendix 3), Child-Pugh 
classification criteria for liver function (Appendix 9), and extent of disease (Llovet et al 2004) to 
define disease staging for HCC. Approximately 30% of HCC cases are diagnosed at the early 
stages (ie, BCLC stages 0 or A) and are amenable to potentially curative treatments, including 
liver transplantation, resection, or locoregional procedures such as radiofrequency ablation and 
percutaneous ethanol injection.  However, there is a high rate (70%) of HCC recurrence within 5 
years (Oikonomopoulos et al 2016). 
In intermediate-stage HCC (ie, BCLC Stage B), transarterial chemoembolization (TACE) is the 
recommended treatment modality (Han and Kim 2015), but the data are difficult to interpret in 
the context of BCLC staging; the data supporting the recommendation were not categorized 
according to BCLC classification (Han and Kim 2015). Nonetheless, patients experience disease 
progression after TACE treatment and become ineligible for further TACE therapy. 
The majority (approximately 70%) of patients diagnosed with HCC present with unresectable 
disease (ie, BCLC Stage C) (Mazzaferro et al 1996).  In 2008, sorafenib (NEXAVAR 
Prescribing Information [PI]), a multi-kinase inhibitor, was approved by the United States (US) 
Food and Drug Administration (FDA) for use in this patient population.  It inhibits multiple 


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intracellular (CRAF, BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR1/2/3, and 
PDGFRβ), thus impeding tumor growth and angiogenesis. 
Clinical data have illustrated a robust sorafenib-derived treatment benefit for HCC patients, 
irrespective of the underlying cause of their disease (Lee and Han 2010).  Currently, sorafenib is 
recommended in all published guidelines (Keating 2017; Heimbach et al 2017; National 
Comprehensive Cancer Network [NCCN] 2020) for patients with advanced HCC and relatively 
preserved liver function who are not candidates for either resection or liver transplantation, and 
who have disease progression after locoregional therapies (Bruix et al 2012). 
However, sorafenib is difficult for patients to tolerate.  The most common side effects include 
hypertension, hemorrhage, hand-foot skin reaction, diarrhea, sensory neuropathy, weight loss, 
rash, alopecia, anorexia, and pain in the abdomen (NEXAVAR PI).  As reported in an 
observational field study, 54% and 40% of patients treated with sorafenib have required dose 
reduction and treatment interruption, respectively (Iavarone et al 2011).  Given that the median 
overall survival (OS) in advanced-stage HCC patients treated with sorafenib is < 12 months, and 
in light of the relatively poor tolerability of the drug, novel therapies are needed for this patient 
population. 
Another multiple tyrosine kinase inhibitor, lenvatinib (LENVIMA Prescribing Information for 
the Unites States, Europe, and China) was approved for the first-line treatment of patients with 
unresectable HCC by the US FDA and the European Medicines Agency (EMA) in 2015; and by 
the National Medical Products Administration (NMPA) in 2018. Lenvatinib was compared to 
sorafenib in terms of its efficacy in treating advanced-stage HCC in a Phase 3 study, Study 
REFLECT, conducted in patients with unresectable HCC, and it has established the 
noninferiority of lenvatinib to sorafenib in a comparison of OS (Eisai 2017).  The tolerability and 
safety profile of oral lenvatinib in the REFLECT trial in patients with unresectable HCC was 
also generally similar to that of sorafenib (Al-Salama 2019). 
Approved first-line treatment options for patients presenting with unresectable HCC had been 
limited to systemic therapies with multikinase inhibitors, such as sorafenib and lenvatinib and 
oxaliplatin-based chemotherapy, such as FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin) 
which was approved for advanced HCC in China (Zhou 2017) until atezolizumab plus 
bevacizumab was approved by the FDA (atezolizumab prescribing information), the EMA 
(atezolizumab summary of product characteristics) ,and the NMPA in 2020, based on the interim 
analysis results of Study IMbrave150 (Finn et al 2020a). 
IMbrave150, a Phase 3 study of atezolizumab, an anti-programmed cell death ligand 1 (PD-L1) 
antibody, plus bevacizumab, an anti-vascular endothelial growth factor (VEGF) inhibitor, 
showed that treatment with atezolizumab plus bevacizumab was associated with significantly 
improved OS (hazard ratio [HR] = 0.58, p < 0.001) and progression-free survival (PFS) (HR = 
0.59, p < 0.001) than sorafenib in patients with advanced unresectable HCC not previously 
treated with systemic therapy (Finn et al 2020a). Serious toxic effects were noted in 38% of the 
patients who received the combination therapy; however, no new or unexpected toxic effects 
were observed.  
Orient-32, an investigational Phase 3 study of sintilimab, an anti-PD-1 inhibitor, plus IBI305, a 
bevacizumab biosimilar, versus sorafenib in unresectable or metastatic, systemic treatment-naive 
HCC, demonstrated similar improvement in OS (HR = 0.57, p < 0.0001) and PFS (HR = 0.57, p 


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< 0.0001) with the combination therapy versus sorafenib (Ren et al 2020). This further supports 
the potential use of an anti-PD-1 antibody with an anti-VEGF inhibitor in the first-line HCC 
setting. 
Treatments after disease progression on sorafenib or chemotherapy include regorafenib 
(STIVARGA Prescribing Information) and carbozantinib (CABOMETYXUS Prescribing 
Information), and ramucirumab in patients with alfa-fetoprotein (AFP) ≥ 400 ng/mL 
(CYRAMZA Prescribing Information).  
Despite these treatments, a high unmet medical need remains for patients with advanced HCC. 
1.2.1. 
Anti-PD-1/Anti-PD L1 or Anti-PD-1/Anti-PD L1-Combination Therapy for 
Advanced Hepatocellular Carcinoma 
The immune checkpoint-inhibitory receptor known as programmed cell death protein-1 (PD-1) is 
mainly expressed in activated T-cells (Topalian et al 2012, Bersanelli et al 2017). The PD-1 
signaling cascade negatively regulates T-cell receptor activities while attenuating T-cell 
proliferation and function, with the ultimate consequence of T-cell exhaustion. 
The expression of PD-1 is markedly upregulated in tumor-infiltrating lymphocytes (TILs), and 
the expression of PD-L1 is significantly increased in tumor cells and tumor-associated immune 
cells in the presence of stimulating cytokines (eg, interferon-alpha [IFN-α] and interferon gamma 
[IFN-γ]) in the tumor microenvironment.  Furthermore, increased PD-1 expression in TILs 
and/or PD-L1 expression in tumor cells and tumor-associated stromal cells has been observed in 
many types of solid tumors (Jin and Yoon 2016, Patel and Kurzrock2015, Van Der Kraak et al 
2016, McDaniel et al 2016, Gong et al 2011). 
Based on the data from Phase 2 studies, several anti-PD-1 therapies have been approved in the 
US and China, eg, nivolumab with or without ipilimumab, pembrolizumab monotherapy 
(received FDA accelerated approval), and camrelizumab (received NMPA conditional approval) 
(OPDIVO prescribing information, KEYTRUDA prescribing information, Wang 2020). 
Nivolumab monotherapy did not show statistically significant OS improvement compared with 
sorafenib (HR = 0.84, p = 0.0419) in first-line HCC patients.  However, clinical benefit was 
observed with a median OS (mOS) of 16.4 months for nivolumab and 14.7 months for sorafenib 
(HR = 0.85 [95% CI: 0.7, 1.02]; p = 0.0752) (Yau et al 2019).  
In addition to these observed clinical activities of anti-PD-1 monotherapy, novel combination of 
anti-PD-1/PD-L1 with anti-VEGF agents have demonstrated improved survival benefit 
compared with sorafenib in first-line HCC (Finn et al 2020a, Ren et al 2020). In a Phase 1b study 
of lenvatinib plus pembrolizumab in patients with unresectable HCC with no prior systemic 
therapy, the confirmed objective response rate (ORR) of 100 patients was 36.0% per RECIST 
v1.1.by independent imaging review; and the median DOR was 12.6 months (Finn 2020b).  
These data support combining treatment targeting PD-1/PD-L1 pathway with anti-angiogenic 
agents as first-line therapy in patients with HCC. 
1.3. 
Background Information on Ociperlimab 
Ociperlimab (also known as BGB-A1217) is a humanized immunoglobulin G (IgG) 1 
monoclonal antibody binding to T-cell immunoglobulin and immunoreceptor tyrosine-based 


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inhibitory motif (ITIM) domain (TIGIT) under clinical development for the treatment of human 
malignancies.  
TIGIT (also known as VSIG9, VSTM3, or WUCAM) is a 26-kDa type I transmembrane 
glycoprotein and an immune checkpoint receptor, and member of the poliovirus receptor 
(PVR)/nectin family that plays an important role in promoting T-cell exhaustion in both chronic 
viral infections and tumor escape from immune surveillance (Yu et al 2009; Boles et al 2009; 
Stanietsky et al 2009; Levin et al 2011; Johnston et al 2014). TIGIT was initially discovered in a 
genomic search for genes specifically expressed in T cells that had a protein domain that 
consisted of inhibitory signaling motifs.  The genes and circulating DNAs (cDNAs) coding for 
TIGIT were cloned and characterized in mouse and human cells (Yu et al 2009).  Mature human 
TIGIT contains 223 amino acid residues (National Center for Biotechnology Information 2018).  
Its extracellular domain consists of amino acid residues 1 to 120, and the transmembrane domain 
and cytoplasmic C-terminal tail comprises residues 121 to 223. 
TIGIT-deficient mice (TIGIT-/-) showed increased susceptibility to an experimental autoimmune 
model (Joller et al 2014).  Natural killer (NK) cells that overexpressed TIGIT produced less 
IFN-γ upon TIGIT/PVR ligation.  In contrast, NK cells form TIGIT-deficient mice produced 
more IFN-γ in the presence of PVR-expressing target cells (Li et al 2014).  Agonistic anti-TIGIT 
antibody could reduce the production of proinflammatory cytokines including IFN-γ and 
interleukin (IL)-17 by antigen-restimulated splenocytes and decrease antigen-specific 
proliferation.  Consistent with these observations, the blockade of the TIGIT pathway in vivo by 
TIGIT-blocking antibody alone or in combination with an anti-PD-1 antibody reduced tumor 
growth in syngeneic mouse models (College of American Pathologist [CAP] guidelines 2018; 
Argast et al 2018; Dixon et al 2018). These findings strongly suggest that TIGIT is a critical 
immune checkpoint receptor in the maintenance of immune tolerance. 
TIGIT is primarily expressed on immune cells, such as T cells, and NK cells (Manieri et al 
2017).   When expressed on effector T cells (cluster of differentiation [CD] 4+ [CD4+] and 
CD8+), activation of TIGIT has been shown to reduce cytokine production and T-cell 
proliferation, both of which could be rescued by TIGIT-blocking antibodies or TIGIT expression 
knockdown (Lozano et al 2012; Joller et al 2014; Chauvin et al 2015). A similar phenomenon 
was also observed for NK cells (Stanietsky et al 2009; Zheng et al 2017). 
TIGIT is also expressed on FoxP3+ regulatory T (Treg) cells, especially in tumor tissues 
(Joller et al 2014; Kurtulus et al 2015). TIGIT-positive Treg cells demonstrated greater 
suppressive functions when compared to TIGIT-negative Treg cells, with higher expression of 
effector molecules, such as IL-10, granzymes, and Fgl2 (Joller et al 2014). A high TIGIT/CD226 
ratio in Treg cells is associated with increased Treg frequencies in tumors and poor clinical 
outcome upon immune checkpoint blockade (Fourcade et al 2018).  Some studies have also 
shown that TIGIT suppresses immune responses mediated by dendritic cells by binding with 
PVR, especially in enhancement of IL-10 production and the inhibition of IL-12 production (Yu 
et al 2009). 
As an immune “checkpoint” molecule, TIGIT initiates inhibitory signaling in immune cells when 
engaged by its ligands, PVR (CD155) and PVR–related 2 (PVR-L2) (CD112, or nectin-2).  
These ligands are primarily expressed on antigen-presenting cells  and tumor cells (Casado et al 
2009; Stanietsky et al 2009; Yu et al 2009; Levin et al 2011). The binding affinity of TIGIT to 


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PVR (equilibrium dissociation constant [KD]: approximately 1 nM) is much higher than to 
PVR-L2 and whether the TIGIT: PVR-L2 interaction is functionally relevant in mediating 
inhibitory signals remains to be determined.  The co-stimulatory receptor, CD226, binds to the 
same ligands with lower affinity (KD: approximately 100 nM) but delivers a positive signal and 
enhances cytotoxicity of T cells and NK cells (Bottino et al 2003; Stanietsky et al 2009). 
High-affinity binding of TIGIT to PVR could compete off CD226-PVR interaction, therefore 
reducing T cells or NK cells activation (Stanietsky et al 2009). 
The cytoplasmic tail of TIGIT has an inhibitory ITIM and an immunoreceptor tail tyrosine-like 
motif.  In NK cells, TIGIT engagement induces the phosphorylation of tyrosine residues in its 
ITIM and immunoreceptor tail tyrosine-like motifs through the Src kinases Fyn and Lck.  The 
phosphorylation of TIGIT then leads to binding of Grb2 and β-arrestin 2 and the subsequent 
recruitment of SHIP-1 and SHP-2 to terminate PI3K and NK-κB signaling in the NK cells 
(Stanietsky et al 2009; Liu et al 2013). Engagement of agonistic TIGIT antibody induced T-cell 
receptor complex disruption (Stanietsky et al 2009). In addition, interaction between TIGIT and 
PVR on dendritic cells could lead to phosphorylation of PVR and modulation of ERK activation 
in dendritic cells (Yu et al 2009).  
Up-regulation of TIGIT expression in TILs has been reported in many types of cancers, such as 
lung (Tassi et al 2017), stomach (He et al 2017), breast (Gil Del Alcazar et al 2017), esophageal 
(Xie et al 2016), HCC (Chiu et al 2020), brain (Hung et al 2018), acute myeloid leukemia (Kong 
et al 2016), and melanoma (Mahnke and Enk 2016). Interestingly, TIGIT expression appears to 
be minimally expressed by peripheral effector cells while being significantly up-regulated by 
tumor localized effector cells, which strongly suggests that the tumor microenvironment utilizes 
TIGIT signaling to further suppress/evade immune-mediated tumor cytotoxicity (Johnston et al 
2014). Further, up-regulation of TIGIT signaling plays an important role in immune tolerance to 
cancer, similar to its function in the presence of chronic viral infections (Chauvin et al 2015; Yin 
et al 2018). The blockade of the TIGIT receptor alone or in combination with PD-1/PD-L1 
blockade has been shown both in vitro and in vivo to rescue functionally “exhausted” T cells 
(Johnston et al 2014; Chauvin et al 2015). In mouse models, TIGIT blockade in combination 
with anti–PD-1/PD-L1 antibodies demonstrated significantly better antitumor efficacy than 
either monotherapy (Johnston et al 2014; Dixon et al 2018).  
In mouse models, Fc with effector functions is critical for TIGIT antibody-mediated antitumor 
activity (College of American Pathologist [CAP] guidelines 2018; Argast et al 2018; Leroy et al 
2018). In the CT26.WT mouse colon cancer model, anti-mouse TIGIT antibody of mIgG2a 
isotype (antibody-dependent cellular cytotoxicity [ADCC] enabling) demonstrated potent 
antitumor activity as monotherapy and in combination with anti-PD-1 antibody.  In contrast, 
anti-TIGIT antibody with Fc devoid of effector functions did not show any of the antitumor 
efficacies in the same model, indicating that Fc-mediated effector functions are required for 
TIGIT antibody-mediated antitumor effects.  In addition, the observed efficacy was associated 
with an increased activity of effector T cells (CD8+ and CD4+) and also with Treg depletion 
within the tumor microenvironment.  Argast and colleagues’ (College of American Pathologist 
[CAP] guidelines 2018; Argast et al 2018) also observed that effector functions were critical for 
TIGIT antibody-induced in vivo efficacy. Waight and colleagues (Waight et al 2018) reported 
that the interaction of anti-TIGIT with gamma fragment crystallizable region (Fc) receptor 


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(FcγR) on antigen-presenting cells enhanced antigen-specific T cell responses and antitumor 
activity. 
Moreover, exhausted T cells demonstrate that upregulation of the inhibitory immune receptor 
TIGIT represents a hallmark in the process of T cell exhaustion in liver cancer.  In combination 
with PD-1 inhibition, targeting TIGIT with antagonistic antibodies resulted in synergistic 
inhibition of liver cancer growth in immunocompetent mice (Ostroumov et al 2020) .  
Taken as a whole, targeting TIGIT provides a potential mechanism to rescue immune cells 
(eg, T cells, NK cells, and dendritic cells) from the immunosuppressive tumor 
microenvironment, thereby inducing an efficient antitumor immune response.  The strategy of 
blocking antibodies that target the PD-1/PD-L1 pathway has achieved remarkable results in the 
treatment of many different tumor types.  However, based upon the rate of primary and 
secondary resistance to PD-1 blockade, it is apparent that additional immuno-regulatory 
mechanism(s) underlie tumor immune escape.  Indeed, research shows that the TIGIT pathway 
cooperates with PD-1 to maximize the suppression of effector TILs and promote resistance to 
anti-PD-1 therapy.  Therefore, TIGIT represents an ideal target with the potential to significantly 
improve and/or extend the therapeutic benefit of anti-PD-1 therapy, which could offer a 
synergistic inhibition of cancer growth in patients with HCC. 
1.3.1. 
Nonclinical Experience 
1.3.1.1. 
Pharmacology 
Ociperlimab binds to the extracellular domain of human TIGIT with high specificity and affinity 
(KD = 0.135 nM), as demonstrated by target-binding assays and surface plasmon resonance 
characterization.  It competitively blocks the binding of TIGIT to PVR.  Ociperlimab has shown 
antitumor activity in both the GL261 mouse glioma tumor model and the CT26.WT mouse colon 
cancer model in humanized TIGIT knock-in mice.  Additionally, in the MC-38 mouse colon 
cancer model in humanized TIGIT knock-in mice, ociperlimab in combination with anti–mouse 
PD-1 significantly inhibited tumor growth compared with either therapy alone. 
Ociperlimab has the constant region of a wild-type human IgG1 to enable the Fc-mediated 
effector functions.  Ociperlimab has demonstrated competent binding to complement 1q (C1q) 
and all FcγRs, including FcγRI, FcγRIIA, FcγRIIB, and FcγRIIIA, in in vitro binding assays, and 
induces ADCC against TIGIT-overexpressing cell line, but no ADCC or complement-dependent 
cytotoxicity against primary T cells in the cell-based assays. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding 
pharmacology studies. 
1.3.1.2. 
Toxicology 
Humanized TIGIT knock-in mice containing human TIGIT gene and cynomolgus monkeys were 
selected for nonclinical safety evaluation of ociperlimab based on the homology of TIGIT amino 
acid sequence, binding affinity, and efficacy studies.  
Cynomolgus monkeys was the most relevant species based on the homology sequence of TIGIT, 
although it demonstrates a relatively lower ociperlimab-binding affinity compared with human 
TIGIT (with the concentration for 50% of maximal effect [EC50] 756-fold weaker).  


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Ociperlimab does not bind to mouse TIGIT due to the significant sequence divergence between 
human and mouse TIGIT; however, ociperlimab demonstrates a comparable binding affinity in 
TIGIT receptor occupancy assays with CD3+ splenocytes from humanized TIGIT knock-in mice 
compared to CD3+ human peripheral blood mononuclear cells (PBMCs) (with EC50 of 48.8 
ng/mL versus 63.2 ng/mL, respectively).  In addition, ociperlimab shows significant inhibition of 
GL261 tumor growth in humanized TIGIT knock-in mice at a dose of 0.4 mg/kg and above via 
weekly intraperitoneal dosing.  
The toxicity and safety profile of ociperlimab was characterized in a 4-week repeated-dose 
toxicity study in humanized TIGIT knock-in mice and a 13-week repeat dose toxicology study in 
cynomolgus monkeys.  These toxicity studies were conducted in accordance with Good 
Laboratory Practice (GLP) regulations.  Furthermore, ociperlimab was evaluated in a 4-week 
repeated-dose study in humanized TIGIT knock-in mice with subcutaneous MC-38 tumors.  The 
dose levels spanned from the intended human therapeutic doses to 10-fold higher in the 4-week 
mouse studies and 20-fold higher in the 13-week monkey study.  The cynomolgus monkey was 
considered the relevant species for toxicity studies based on the target sequence homology and 
cross-species TIGIT-binding activities of ociperlimab.  Tissue cross-reactivity was evaluated in 
normal frozen tissues from humans.  Cytokine release response was also evaluated using fresh 
human PBMCs. 
No apparent toxicity was noted in humanized mice after repeated dosing of ociperlimab at either 
5 or 50 mg/kg weekly for 4 weeks, nor in monkeys after repeated dosing at 10, 30, or 100 mg/kg 
once every 2 weeks for 13 weeks.  The toxicokinetic profile was characterized in both the mouse 
and monkey studies and the systemic exposure appeared to be dose proportional with no sex 
difference in either study.  A trend of accumulation was noted after repeated doses in mice; 
however, no accumulation was observed over the 13-week dosing period in monkeys.  No 
immunotoxicity was apparent, as no changes in clinical pathology or histopathology were 
observed in these studies.  Immunogenicity with positive antidrug antibodies (ADAs) against 
ociperlimab was noted in several mice dosed at 5 and 50 mg/kg over the 4 weeks; however, with 
the exception of 1 animal that had a strong ADA response at 5 mg/kg dose, most of these 
animals showed weak ADA signals or the signals were proved to be false positives.  In monkeys, 
positive ADAs against ociperlimab were observed in 6 of 10, 3 of 10, and 4 of 10 animals during 
the dosing period and 3 of 4, 2 of 4, and 2 of 4 during the recovery period, at dose levels of 10, 
30, and 100 mg/kg, respectively.  The anti-ociperlimab antibodies showed a rapid clearance of 
ociperlimab in serum in a few individual animals but did not appear to have an effect on the 
overall systemic exposure (area under the concentration-time curve[AUC]) or toxicity 
assessment. 
Tissue cross-reactivity of ociperlimab was evaluated in normal human frozen tissues using an 
immunohistochemistry method and appropriate positive and negative controls.  No specific 
binding of ociperlimab was noted with normal human tissues.  A variety of factors might 
contribute to the negative results, including negligible target expression in normal tissues 
(Yang 2016; Human Protein Atlas 2019) and sensitivity of the immunohistochemistry method. 
No significant increase in cytokine release was observed from an in vitro cytokine release assay 
after treatment of non-activated PBMCs with ociperlimab when compared to human IgG.  The 
results suggested that ociperlimab has potentially low risks of causing acute cytokine release 
syndrome. 


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Overall, no apparent toxicity was noted in the monkey or transgenic mouse toxicity studies.  No 
unexpected tissue cross-reactivity was found in human or monkey tissues.  The toxicokinetic 
profile was well characterized with dose-proportional increases in systemic exposure without 
apparent accumulation or sex difference.  Immunogenicity was observed without apparent 
immunotoxicity or effect on the systemic exposure.  The no-observed-adverse-effect level 
(NOAEL) of ociperlimab was 50 mg/kg in the 4-week mouse study and 100 mg/kg in the 
13-week monkey toxicity study.  The safety profile of ociperlimab is considered adequate to 
support first-in-human dosing. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.3.2. 
Clinical Experience  
1.3.2.1. 
Clinical Pharmacology 
As of the data cutoff date of 16 June 2020, preliminary pharmacokinetic (PK) data of 
ociperlimab are available from a total of 11 patients treated with ociperlimab at 50 mg (n = 1), 
150 mg (n = 3), 450 mg (n = 4), and 900 mg (n = 3) dose levels in combination with tislelizumab 
200 mg in the dose-escalation portion of Study BGB-900-105.  Ociperlimab serum 
concentrations declined in a biexponential manner after intravenous infusion and the ociperlimab 
exposures (Cmax and AUC) increased approximately dose-proportionally from 50 mg to 900 mg.  
Peripheral TIGIT receptor occupancy data were available for 11 enrolled patients treated with 
ociperlimab at 50 mg (n = 1), 150 mg (n = 3), 450 mg (n = 4), and 900 mg (n = 3) dose levels in 
Study BGB-900-105.  Complete TIGIT receptor occupancy (100%) was observed on CD8, CD4, 
NK and Treg cells in peripheral blood at all the tested dose levels.  
1.3.2.2. 
Preliminary Safety Profile  
The first-in-human BGB-900-105 study evaluating the safety and tolerability of ociperlimab in 
combination with tislelizumab in advanced solid tumors is still ongoing. 
As of 16 June 2020, 11 dose-limiting toxicity (DLT)-evaluable patients received ≥ 1 dose of 
ociperlimab combined with tislelizumab 200 mg once every 3 weeks in the dose escalation stage.  
The dosage of ociperlimab ranged from 50 mg to 900 mg once every 3 weeks: 1 patient at 
50 mg once every 3 weeks, 3 patients at 150 mg once every 3 weeks, 4 patients at 450 mg once 
every 3 weeks, and 3 patients at 900 mg once every 3 weeks.  The maximum administered dose 
was ociperlimab 900 mg combined with tislelizumab 200 mg once every 3 weeks as of the data 
cutoff date.  The maximum tolerated dose (MTD) was not reached.  Ociperlimab was safe and 
well-tolerated up to the dose level of 900 mg once every 3 weeks.  No DLTs, treatment-related 
serious adverse events (SAEs), or Grade 4 or Grade 5 treatment-emergent adverse events 
(TEAEs) occurred during the treatment period at any dose level.  The clinical activity 
documented as stable disease can be observed in 1 patient at each of the following ociperlimab 
doses of 150 mg, 450 mg, and 900 mg.  
After the data cutoff date of 16 June 2020, 6 additional patients have been enrolled and dosed at 
the maximum administered dose of ociperlimab 900 mg combined with tislelizumab 200 mg 
once every 3 weeks.  Exploration of more dose levels is ongoing. 


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As of the data cutoff date of 16 June 2020, 8 (72.7%) of the 11 patients had ≥ 1 TEAE.  Most 
TEAEs were Grade 1 or Grade 2.  Three TEAEs (atrial flutter, pericardial effusion malignant, 
and dyspnea), which occurred in 1 patient each, were Grade 3.  Treatment-related TEAEs, and 
serious TEAEs occurred in 3 (27.3%) patients each.  Treatment-related TEAEs included 
influenza, aspartate aminotransferase increased, and dry skin in 1 patient; abdominal pain, dry 
eye, and diarrhea in 1 patient; and fatigue in 1 patient.  All treatment-related TEAEs were 
Grade 1. 
Serious TEAEs included atrial flutter in 1 patient, dyspnea in 1 patient, and pericardial effusion 
malignant in 1 patient.  All serious TEAEs were Grade 3.  These 3 serious TEAEs were 
considered not related to study drug treatment by the investigator 
No patients had Grade 4 or Grade 5 TEAEs, serious treatment-related TEAEs, TEAEs leading to 
treatment discontinuation, or TEAEs leading to death (Table 1).  No TEAE met the criteria of 
DLT. 
The most commonly reported TEAEs were fatigue (3 [27.3%]) and diarrhea and aspartate 
aminotransferase (AST) increased (2 [18.2%] each).  All other TEAEs occurred in 
1 (9.1%) patient each (Table 2). 
Refer to the Ociperlimab Investigator’s Brochure for detailed safety information. 
 


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Table 1: 
Overview of Treatment-Emergent Adverse Events (Safety Analysis Set) 
 
Ociperlimab 
50 mg + 
tislelizumab 
200 mg  
(N = 1) 
n (%) 
Ociperlimab 
150 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg + 
tislelizumab 
200 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg + 
tislelizumab 
200 mg 
(N = 5) 
n (%) 
Total 
(N = 11) 
n (%) 
Any TEAE 
1 (100.0) 
3 (100.0) 
3 (75.0) 
1 (33.3) 
8 (72.7) 
Any treatment-related TEAE 
1 (100.0) 
0 (0.0) 
2 (50.0) 
0 (0.0) 
3 (27.3) 
≥ Grade 3 TEAE 
1 (100.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
3 (27.3) 
≥ Grade 3 treatment-related TEAE 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Serious TEAE 
1 (100.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
3 (27.3) 
Serious treatment-related TEAE 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
TEAE leading to treatment 
discontinuation 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Treatment-related TEAE leading 
to treatment discontinuation 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
TEAE leading to death 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Abbreviations: N, total number of patients treated; TEAE, treatment-emergent adverse event. 
Notes: A patient with multiple occurrences of an AE is counted only once in the AE category.  Treatment-related TEAE includes patients who had a 
tislelizumab- or ociperlimab-related TEAE. 
Data cutoff date: 16 June 2020 
 


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Table 2: 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set) 
System Organ Class 
Preferred Term 
Ociperlimab 
50 mg + 
tislelizumab 
200 mg  
(N = 1) 
n (%) 
Ociperlimab 
150 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg + 
tislelizumab 
200 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Total 
(N = 11) 
n (%) 
Patients with ≥ 1 TEAE 
1 (100.0) 
3 (100.0) 
3 (75.0) 
1 (33.3) 
8 (72.7) 
Gastrointestinal disorders 
1 (100.0) 
1 (33.3) 
2 (50.0) 
0 (0.0) 
4 (36.4) 
Diarrhoea 
0 (0.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Abdominal pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Constipation 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Dry mouth 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
General disorders and 
administration site conditions 
1 (100.0) 
0 (0.0) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Fatigue 
1 (100.0) 
0 (0.0) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Musculoskeletal and connective 
tissue disorders 
0 (0.0) 
1 (33.3) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Back pain 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Flank pain 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
1 (9.1) 
Groin pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Infections and infestations 
1 (100.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Influenza 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Otitis externa 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Investigations 
1 (100.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
2 (18.2) 


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System Organ Class 
Preferred Term 
Ociperlimab 
50 mg + 
tislelizumab 
200 mg  
(N = 1) 
n (%) 
Ociperlimab 
150 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg + 
tislelizumab 
200 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Total 
(N = 11) 
n (%) 
Aspartate aminotransferase 
increased 
1 (100.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
2 (18.2) 
Nervous system disorders 
1 (100.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Neuralgia 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Somnolence 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Respiratory, thoracic, and 
mediastinal disorders 
0 (0.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Cough 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Dyspnoea 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Skin and subcutaneous tissue 
disorders 
1 (100.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
2 (18.2) 
Drug eruption 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
1 (9.1) 
Dry skin 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Blood and lymphatic system 
disorders 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Anaemia 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Cardiac disorders 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Atrial flutter 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Ear and labyrinth disorders 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Ear discomfort 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Eye disorders 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 


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System Organ Class 
Preferred Term 
Ociperlimab 
50 mg + 
tislelizumab 
200 mg  
(N = 1) 
n (%) 
Ociperlimab 
150 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg + 
tislelizumab 
200 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg + 
tislelizumab 
200 mg 
(N = 3) 
n (%) 
Total 
(N = 11) 
n (%) 
Dry eye 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Neoplasms benign, malignant, 
and unspecified (incl cysts and 
polyps) 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Cancer pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Pericardial effusion malignant 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Psychiatric disorders 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Confusional state 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; N, total number of patients treated; NCI-CTCAE, National Cancer Institute Common 
Terminology Criteria for Adverse Events; PT, Preferred Term; SOC, System Organ Class; TEAE, treatment-emergent adverse event. 
Notes: A patient with multiple occurrences of an AE is counted only once in the AE category.  MedDRA version 22.0 was used to code adverse events.  
Adverse events were graded using NCI-CTCAE version 5.0 per protocol.  Events are sorted in descending order of the number of patients for SOC and PT in 
the Total column.   
Data cutoff date: 16 June 2020 
 


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1.3.2.3. 
Preliminary Efficacy Profile 
The first-in-human study BGB-900-105 evaluating the efficacy of ociperlimab in combination 
with tislelizumab in advanced solid tumors is still ongoing.  As of 16 June 2020, the clinical 
activity documented as stable disease can be observed in 1 patient each at ociperlimab doses of 
150 mg, 450 mg, and 900 mg. 
1.3.2.4. 
Clinical Experience With Other TIGIT Inhibitors 
To date, first-in-human Phase 1 and Phase 2 clinical studies have been initiated for 6 anti-TIGIT 
antibodies: MTIG7192A from Genentech/Roche (NCT02794571 and NCT03563716), 
BMS-986207 from Bristol-Myers Squibb (NCT02913313), MK-7684 from Merck Sharp & 
Dohme (NCT02964013), OMP-313M32 from OncoMed (NCT03119428), ASP8374 from 
Astellas/Potenza (NCT03260322), and AB-154 from Arcus (NCT03628677).  The goals for 
these clinical studies are to evaluate the safety and efficacy of anti-TIGIT antibodies alone and/or 
in combination with anti-PD-1 or anti-PD-L1 antibodies. 
To date, clinical data have been released for OncoMed’s OMP-313M32 (Sharma et al 2018), 
Merck’s MK-7684 (Golan et al 2018), and Genentech/Roche’s tiragolumab (Bendell et al 2020; 
Rodriguez-Abreu et al 2020). A total of 68 patients have been treated with MK-7684 alone or 
MK-7684 in combination with pembrolizumab (an anti–PD-1 antibody) in a Phase 1 study 
sponsored by Merck Sharp & Dohme, with doses of MK-7684 ranging from 2.1 mg to 700 mg.  
The preliminary results showed that MK-7684 was well tolerated in the dose escalation phase of 
the study, with no DLT.  Adverse events (AEs) that occurred in > 15% of patients were fatigue 
(n = 5, 15%) for MK-7684 monotherapy and pruritus (n = 10, 21%) for MK-7684 and 
pembrolizumab combination therapy.  Furthermore, only 2 treatment-related AEs ≥ Grade 3 
were reported (Grade 3 anemia and Grade 3 diarrhea) for monotherapy and 5 treatment-related 
AEs ≥ Grade 3 were reported for combination with pembrolizumab (5 Grade 3: alanine 
aminotransferase [ALT] increased, colitis, Gamma-glutamyl transferase [γGT] increased, 
hypersensitivity, and rash maculopapular).  Of the 34 evaluable patients treated with MK-7684 
alone, one partial response (PR) (1/34 [3.0%]) and a 35% disease control rate (DCR) were 
observed.  For combination of MK-7684 and pembrolizumab, 6 PRs (6/34 [18%]) and a 
48% DCR were observed.  In addition, PK findings were linear above 200 mg. 
Eighteen patients have been treated with OMP-313M32 alone in a Phase 1 study sponsored by 
OncoMed, with doses ranging from 0.3 mg/kg to 20 mg/kg.  The preliminary results showed that 
OMP-313M32 was well tolerated in the dose escalation phase of the study, with no DLT.  
Treatment-related AEs that occurred in > 15% of patients were rash (n = 5; 27.8%), fatigue 
(n = 3, 16.7%), nausea (n = 3, 16.7%), and pruritus (n = 3, 16.7%) for OMP-313M32 
monotherapy.  Grade 3 or higher treatment-related AEs included rash (n = 3, 16.7%), fatigue 
(n = 1, 5.6%), hypophosphatemia (n = 1, 5.6%), and autoimmune hepatitis (n = 1, 5.6%).  Based 
upon the safety profile of OMP-313M32 monotherapy, OncoMed has initiated the dose 
expansion with the combination of OMP-313M32 and nivolumab (an anti–PD-1 antibody) in 
patients with non-small cell lung, head and neck, esophageal, gastric, cervical, triple negative 
breast, anal, and hepatocellular cancers or with microsatellite instability-high tumors 
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The Phase 1 data for tiragolumab was released at the 2020 American Association of Cancer 
Research meeting (Bendell et al 2020).  No objective responses occurred in 24 patients treated 
with tiragolumab monotherapy in Phase 1a.  However, in Phase 1b, 5 of 44 patients (11.4%) 
treated with tiragolumab combined with atezolizumab had achieved PR (Bendell et al 2020).  In 
the Phase 1a (tiragolumab monotherapy) cohort, there were no Grade 3-5 immune-mediated AEs 
(imAEs).  Grade 1-2 imAEs included infusion-related reaction (n = 2, 8%), rash (n = 2, 8%), 
hepatitis (n = 1, 4%), and pancreatitis (n = 1, 4%).  In the Phase 1b (tiragolumab combined with 
atezolizumab) cohort, 4% of patients experienced Grade 3-5 imAEs; no Grade 5 imAEs were 
associated with tiragolumab and/or atezolizumab.  These imAEs included infusion-related 
reaction (n = 4, 8%), rash (n = 14, 29%), hepatitis (n = 10, 20%), pancreatitis (n = 1, 2%), 
hyperthyroidism (n = 4, 8%), hypothyroidism (n = 3, 6%), and anemia (n = 1, 2%). 
A total of 135 patients with previously untreated PD-L1-selected non-small cell lung cancer 
(NSCLC) were treated with tiragolumab 600 mg by intravenous infusion once every 3 weeks 
plus atezolizumab 1200 mg by intravenous infusion once every 3 weeks (n = 67) or atezolizumab 
1200 mg by intravenous infusion once every 3 weeks plus placebo by intravenous infusion once 
every 3 weeks (n = 68) in a Phase 2 study (CITYSCAPE) sponsored by Genentech/Roche.  
Patients were randomly assigned to 1 of these treatment groups and were stratified by tumor 
proportion score (TPS) (1% to 49% or ≥ 50%), histology (squamous versus nonsquamous), and 
tobacco use (yes or no).  Preliminary efficacy results showed a clinically meaningful 
improvement in ORR and PFS in patients treated with tiragolumab plus atezolizumab 
(ORR, 31%; PFS, 5.42 months) compared with those treated with atezolizumab plus placebo 
(ORR, 16%; PFS, 3.58 months).  This improvement was still observed 6 months later: 
tiragolumab plus atezolizumab (ORR, 37%; PFS, 5.55 months) compared with atezolizumab plus 
placebo (ORR, 21%; PFS, 3.88 months).  In addition, analysis at this 6-month follow-up 
timepoint showed a greater improvement in ORR in patients in the PD-L1 TPS ≥ 50% subgroup 
who received tiragolumab plus atezolizumab (ORR, 66%) compared with atezolizumab plus 
placebo (ORR, 24%).  Preliminary safety results showed that treatment with tiragolumab plus 
atezolizumab was well tolerated; results were generally similar between the 2 treatment groups.  
More patients in the tiragolumab plus atezolizumab group experienced imAEs compared with 
those in the atezolizumab plus placebo group (46 [69%] versus 32 [47%]); most imAEs were 
Grade 1 or Grade 2 events of infusion-related reaction and rash and were manageable.  Based on 
these observed efficacy and safety results, Genentech/Roche is conducting an ongoing Phase 3 
study (SKYSCRAPER-01) in first-line PD-L1 TPS ≥ 50% NSCLC (NCT04294810).  
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse events 
were manageable, and the safety profile seems to be consistent as reported across different solid 
tumor indications.  
All of these findings support further development of anti-TIGIT antibody in combination with 
existing therapeutic modalities. 


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1.4. 
Background Information on Tislelizumab as a PD-1 Inhibitor 
1.4.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity 
and affinity (dissociation constant [KD] = 0.15 nM).  It competitively blocks binding efforts by 
both PD-L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated 
negative signaling in T cells.  In in vitro cell-based assays, tislelizumab was observed to 
consistently, and in a dose-dependent manner, enhance the functional activity of human T cells 
and pre-activated, primary PBMC.  Tislelizumab has demonstrated in-vivo antitumor activity in 
several allogeneic xenograft models, in which PBMC were co-injected with human cancer cells 
(A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
Tislelizumab is an IgG4-variant antibody to FcγR such as FcγRI and FcγRIIIA, and it has very 
low binding affinity to C1q, a subunit of complement 1.  In vitro assays with tislelizumab 
suggest either low or no ADCC, antibody-dependent cellular phagocytosis, or 
complement-dependent cytotoxicity effects in humans (Labrijn et al 2009).  Tislelizumab was 
specifically engineered to abrogate these potential mechanisms of T-cell clearance and potential 
resistance to anti-PD-1 therapy. 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.4.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys and in a 13-week, repeat-dose toxicology study in 
cynomolgus monkeys.   
Overall, no apparent toxicity was noted in mouse or monkey toxicity studies.  No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in the human whole-blood assay.  The toxicokinetic profile was well 
characterized, with dose-proportional increases in systemic exposure without apparent 
accumulation or sex difference.  Immunogenicity was observed without apparent 
immunotoxicity or effect on the systemic exposure.  The NOAEL of tislelizumab in the 13-week 
monkey toxicity study was considered to be 30 mg/kg.  
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.4.3. 
Clinical Pharmacology 
Population PK analysis was conducted using data from 798 patients with solid tumors or 
classical Hodgkin lymphoma who received doses of 0.5, 2.0, 5.0, and 10 mg/kg once every 
2 weeks, 2.0 and 5.0 mg/kg once every 3 weeks, and 200 mg once every 3 weeks.   


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Population PK analysis demonstrated that baseline age, race, alanine aminotransferase, AST, 
bilirubin, lactate dehydrogenase, estimated glomerular filtration rate, ECOG PS, 
immunogenicity, and sum of products of perpendicular diameters in classical Hodgkin 
lymphoma patients did not show statistically significant impact on the PK of tislelizumab.  
Although tumor size, albumin, and tumor type were significant covariates on CL, while body 
weight, sex, and tumor type were significant covariates on Vc, these covariates are not expected 
to have a clinically relevant impact on tislelizumab exposure.  Exposure-response analysis 
indicated that there was a lack of clinically significant exposure-response relationships for ORR 
and safety endpoints across a variety of advanced solid tumors and classical Hodgkin lymphoma  
for tislelizumab.  Population PK analysis supports fixed-dosing across different ethnic groups. 
1.4.4. 
Prior Clinical Experience of Tislelizumab 
As of 20 May 2020, 1181 patients with solid tumors had been treated with tislelizumab 
monotherapy in 5 clinical studies.   
A pooled monotherapy analysis was conducted to provide a comprehensive review of the 
tislelizumab safety profile.  Patients included in this analysis (N=1181) had a median age of 60.0 
years with 67.1% of them being male.  Median treatment exposure duration was 3.7 months 
(range: 0.1 to 55.3) and median study follow-up duration was 9.9 months (range: 0.1 to 58.9). 
Refer to the Tislelizumab Investigator’s Brochure for more detailed information on tislelizumab 
safety and efficacy data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1. 
Treatment-Emergent Adverse Events Assessed as Related to Tislelizumab 
Of the 1181 patients with solid tumors treated with tislelizumab monotherapy, 788 (66.7%) 
experienced ≥ 1 treatment-related TEAE.  The most commonly occurring TEAEs (≥ 5% of 
patients) assessed as related to tislelizumab irrespective of grade were AST increased 
(136 patients, 11.5%), alanine aminotransferase (ALT) increased (125  patients, 10.6%), 
hypothyroidism (106 patients, 9.0%), rash (97 patients, 8.2%), and pruritus and fatigue 
(95 patients each, 8.0%), anaemia (89 patients, 7.5%), blood bilirubin increased (77 patients, 
6.5%), diarrhoea (71 patients, 6.0%), decreased appetite (65 patients, 5.5%), proteinuria (60 
patients, 5.1%), nausea (59 patients, 5.0%). 
One hundred sixty-seven patients (14.1%) experienced at least 1 ≥ Grade 3 TEAE assessed as 
related to tislelizumab.  The most frequent ≥ Grade 3 TEAEs that occurred in ≥ 1% of the 
patients were AST increased (21 patients, 1.8%), ALT increased (17 patients, 1.4%), and 
anaemia (13 patients, 1.1%).  
1.4.4.1.1. Treatment-Emergent Serious Adverse Events 
Of the 1181 patients with solid tumors treated with tislelizumab monotherapy, 415 (35.1%) 
experienced ≥ 1 treatment-emergent SAE.  The most commonly occurring treatment-emergent 
SAEs (≥ 1% of patients) (irrespective of relationship to study drug) were pneumonia (41 
patients, 3.5%), and pyrexia and ascites (15 patients each, 1.3%), upper gastrointestinal 
haemorrhage (13 patients, 1.1%), abdominal pain and pneumonitis (12 patients each, 1.0%). 
One hundred seven patients (9.1%) experienced ≥ 1 tislelizumab-related treatment-emergent 
SAE.  The most common treatment-emergent SAEs (≥ 5 patients) deemed related to tislelizumab 


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were pneumonitis (11 patients, 0.9%), AST increased (6 patients, 0.5%), and colitis, ALT 
increased, and pyrexia (5 patients each, 0.4%).  All other tislelizumab-related treatment emergent 
SAEs occurred in < 5 patients. 
1.4.4.1.2. Immune-Mediated Adverse Events  
Anti-PD-1 therapies are known to cause imAEs in some patients and therefore have been defined 
as adverse events (AEs) of special interest (AESI) in tislelizumab clinical studies and as such are 
being monitored closely. 
Of the 1113 patients with solid tumors included in the pooled analysis of imAEs, 233 (20.9%) 
experienced ≥ 1 imAE of any grade.  The most commonly occurring imAEs of any grade  (≥ 3% 
of patients) were hypothyroidism (69 patients, 6.2%), hyperthyroidism (37 patients, 3.3%), and 
rash (34 patients, 3.1%).  Analysis of the patients with ≥ 1 imAE that was also ≥ Grade 3 in 
severity showed that 52 patients (4.7%) experienced such events.  The most commonly occurring 
imAEs (≥ 0.5% of patients) that were ≥ Grade 3 in severity were ALT increased (9 patients, 
0.8%), and AST increased and pneumonitis (7 patients each, 0.6%). 
1.4.4.1.3. Infusion-Related Reactions 
Infusion-related reactions, including high-grade hypersensitivity reactions, after administration 
of tislelizumab are uncommon.   
Of the 1181 patients treated with tislelizumab monotherapy , 45 (3.8%) experienced ≥ 1 
infusion-related reaction of any grade.  The most commonly occurring infusion-related reactions 
of any grade were infusion-related reactions (28 patients, 2.4%), pyrexia (10 patients, 0.8%), and 
nausea (4 patients, 0.3%).  There were 2 patients (0.2%) with ≥ Grade 3 infusion-related 
reactions and all other events occurred in single instances; these included rash, flushing, 
hypotension, and spinal pain. 
1.4.4.1.4. Liver Laboratory Abnormalities 
Of the 932 patients with solid tumors included in the analysis of drug-induced liver injury, 
33.0% of patients experienced ALT or AST > 1x upper limit of normal (ULN) but ≤ 3x ULN and 
3.6% of patients had ALT or AST > 5x the ULN but ≤ to 10x the ULN.  ALT or AST were > 3x 
the ULN with total bilirubin> 2x the ULN in 25 patients (2.7%). 
Of the 249 patients with HCC in the adjudicated analysis of drug-induced liver injury in BGB-
A317-208, an open-label, single-arm, multicenter Phase 2 study of tislelizumab monotherapy in 
patients with previously treated unresectable HCC, 56.2% of patients experienced ALT or AST > 
1x ULN but ≤ to 3x ULN and 9.6% of patients had ALT or AST > 5x ULN but ≤ to 10x ULN.  
ALT or AST were > 3x ULN with total bilirubin > 2x ULN in 18 patients (7.2%). 
1.4.4.1.5. Fatal Adverse Events 
Out of 1181 patients treated with tislelizumab monotherapy who were included in the analysis, 
18 patients (1.5%) experienced a fatal AE ≤ 30 days after the last study drug dose.  A total of 
9 patients (0.8%) experienced fatal AEs that were deemed related to tislelizumab, including 
hepatic failure (2 patients, 0.2%); and large intestinal obstruction, pneumonitis, respiratory arrest, 
respiratory failure, hepatitis acute, brain oedema, and death (1 patient each, 0.1%). 


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1.4.4.2. 
Efficacy Assessment of Tislelizumab 
Efficacy data of tislelizumab monotherapy in HCC are available from 2 ongoing monotherapy 
studies, BGB-A317_Study_001 (data cutoff: 26 August 2020) and BGB-A317-102 (data cutoff: 
31 May 2020), which are summarized below. 
1.4.4.2.1. Study BGB-A317_Study_001 
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation (0.5 to 
10 mg/kg) and dose-finding component with 3 parts (2 and 5 mg/kg given either once every 2 or 
3 weeks, and a fixed dose of 200 mg given once every 3 weeks) to establish MTD, if any, and a 
recommended Phase 2 dose (RP2D).  Phase 1a was followed by a Phase 1b component to 
investigate efficacy in select tumor types at the RP2D to further evaluate safety and tolerability 
of tislelizumab.  Indication-specific cohorts included esophageal cancer (EC), gastric cancer, 
HCC, and NSCLC cohorts. 
Responses were assessed by the investigator per the Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1) criteria. 
There were 451 patients treated in the study and 441 patients were included in the Efficacy 
Evaluable Analysis Set (EAS).  The EAS includes all treated patients who had at least 
1 measurable baseline target lesion and had at least 1 evaluable postbaseline tumor assessment.  
This set included 49 patients in the HCC cohort. 
The RP2D and schedule for tislelizumab was determined to be 200 mg administered once every 
3 weeks.  At the data cutoff date of 26 August 2020, of the 49 patients in the HCC cohort, no 
patients (0%) had a CR and 6 patients (12.2%) had a confirmed PR. Additionally, 17 patients 
(34.7%) had a best overall response (BOR) of stable disease.  A total of 24 patients (48.9%) had 
a best response of progressive disease (PD) in this cohort. 
1.4.4.2.2. Study BGB-A317-102 
Study BGB-A317-102 is a non-randomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors.  Phase 1 includes a dose verification substudy and 
a substudy of PK evaluation of the products derived from 2 manufacturing processes and scales.  
Phase 2 evaluates the activity and safety of tislelizumab at its RP2D of 200 mg given once every 
3 weeks in indication-specific expansion cohorts. 
Responses were assessed by the investigator per the RECIST v1.1 criteria. 
Of the 300 patients treated in Study BGB-A317-102, a total of 249 patients were included in the 
EAS.  The EAS includes all treated patients who had at least 1 measurable baseline target lesion 
and had at least 1 evaluable postbaseline tumor assessment.  The EAS included 18 patients in the 
HCC cohort. 
At the data cutoff date of 31 May 2020, of the 18 patients in the HCC cohort, no patients (0%) 
had a CR and 3 patients (16.7%) had a confirmed PR. Additionally, there were 7 patients 
(38.9%) with a BOR of stable disease.  A total of 8 patients (44.4%) had a best response of PD in 
this cohort. 


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1.5. 
Background Information on BAT1706, a Bevacizumab Biosimilar 
BAT1706 is a similar biological product to the bevacizumab injection (Bevacizumab Injection, 
brand name Avastin® [hereafter referred to as “Avastin”]).  Bevacizumab contains a type of 
recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody as the active 
ingredient and binds with high affinity to human VEGF. 
The expression of VEGF receptors (VEGFRs) is markedly elevated in the blood vessels of many 
tumors.  Through its mechanism of action of neutralizing, bevacizumab VEGF is able to 
specifically inhibit tumor angiogenesis and block the growth and metastasis of tumors. 
Bevacizumab can selectively bind with high affinity to all human VEGF A isoforms and blocks 
the binding of VEGF to VEGFR-1 and VEGFR- 2, thereby neutralizing the bioactivity of VEGF.  
To date, more than a million patients globally have undergone treatment with bevacizumab, the 
world’s first anti-VEGF antibody that has been proven to significantly extend the OS and PFS in 
multiple cancers.  BAT1706 is a recombinant humanized anti-VEGF monoclonal antibody 
injection, which is a proposed biosimilar of Avastin.  BAT1706 has been compared against US- 
and European Union (EU)-sourced Avastin in a comprehensive comparative analytical and 
nonclinical study program, which is summarized in the BAT1706 Investigator’s Brochure.  The 
results from these investigations provide evidence of the structural and functional similarity of 
BAT1706 to Avastin. 
1.5.1. 
Nonclinical Experience 
1.5.1.1. 
Pharmacology 
The results of comparative in vitro pharmacodynamic research showed that BAT1706 and 
Avastin both exhibited specific binding with VEGF- A121 and VEGF- A165, which was 
consistent with literature reports.  The biological activity of BAT1706 was also found to be 
comparable to that of Avastin within the predetermined range of (1.0 ± 0.2) x 104 U/mg. 
The anti-tumorigenic effect of BAT1706 and Avastin in several models of human cancer 
(NSCLC, ovarian cancer, and rhabdomyosarcoma) was also investigated.  These results showed 
that treatment with BAT1706 and Avastin at higher doses (5 mg/kg in NSCLC and 
rhabdomyosarcoma and 10 mg/kg in ovarian cancer) was effective in all 3 tumor models, and 
none was effective at lower doses (0.5 mg/kg in NSCLC and rhabdomyosarcoma and 1 mg/kg in 
ovarian cancer).  Except for the 0.5 mg/kg dose in the rhabdomyosarcoma model, all other doses 
showed similar pharmacodynamic effects for BAT1706 and Avastin, and the tumor growth 
curves showed a high degree of coincidence.  
The results of a PK study conducted suggested equivalency in in vivo metabolic processes of 
BAT1706 and Avastin.  The concentration of the drug in blood plasma revealed extremely slow 
elimination, consistent with literature reports.  
Please refer to the BAT1706 Investigator Brochure for more detailed information on the 
pharmacology of BAT1706. 


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1.5.1.2. 
Toxicology 
Toxicokinetic parameters assessed showed no significant gender-based difference in the drug 
exposure and that the plasma drug concentration, mean area under the plasma concentration-time 
curve from 0 hours to time t (AUC0-t), and maximum concentration (Cmax) were dose-related.  
The values of AUC0-t, elimination half-life (t1/2), clearance (CLz), and Cmax for the same dose (4 
mg/kg) of BAT1706 and Avastin were not notably different. 
Results of the nonclinical toxicology studies demonstrated that BAT1706 has good local 
tolerance for intravenous administration, with no impact on the central nervous system (CNS),  
or cardiovascular or respiratory systems, no immunogenicity or severe immunotoxicity, and no 
specific binding to non-target tissues in the body when compared with Avastin. 
A study conducted to observe the irritant effects on the administration sites as well as the 
surrounding tissues for BAT1706 did not reveal any irritation reactions at the vascular injection 
sites during or after drug administration. 
An evaluation of the effects of BAT1706 injection on in vitro hemolysis and red blood cell 
(RBC) agglutination in rabbits showed that BAT1706 had no in vitro hemolytic or RBC 
agglutination-causing effects in rabbits. 
Please refer to the BAT1706 Investigator Brochure for more detailed information on the 
toxicology of BAT1706. 
1.5.2. 
Clinical Experience 
The pharmacokinetics of BAT1706 has been studied in 2 Phase 1 studies: 
• BAT1706-001-CR, a randomized, double-blind, single-dose, 3-arm parallel design 
comparative pharmacokinetic and safety Phase 1 study of BAT1706 versus EU-
sourced Avastin and US-sourced Avastin administered in healthy subjects 
• BAT1706-002-CR, a Randomized, double-blind, single-dose, 2 parallel groups study 
to compare the pharmacokinetics and safety of BAT1706 injection with bevacizumab 
(European Product) in healthy subjects 
The 2 Phase 1 studies BAT1706-001-CR and BAT1706-002-CR revealed that a single 
intravenous infusion of BAT1706 (1 mg/kg) is safe and well tolerated in healthy subjects.  There 
were no deaths reported during either study, and only 1 serious TEAE which was unrelated to 
BAT1706 as determined by the investigator.  The key PK parameters of both Phase 1 studies 
also revealed that BAT1706 is a bioequivalent of Avastin (bevacizumab).  No ADA positive 
result was reported for any subject included in either study. 
A Phase 3 study of BAT1706, BAT1706-003-CR, a multicenter, randomized, double-blind, 
study of BAT1706 versus EU- sourced Avastin plus chemotherapy in patients with advanced 
non-squamous NSCLC is ongoing.  
1.5.2.1. 
Clinical Pharmacology 
The Phase 1 study BAT1706-001-CR compared the PK of BAT1706 with that of EU-sourced 
Avastin and US-sourced Avastin in healthy subjects after a single intravenous infusion (1 
mg/kg).  The results showed that PK parameters were similar between the 3 drug products.  The 


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mean concentration profiles for BAT1706, EU- and US- sourced Avastin were similar over the 
entire sampling time interval. 
The PK results of another Phase 1 study BAT1706-002-CR are consistent with results observed 
in the Phase 1 study BAT1706-001-CR.  The BAT1706-002-CR study compared the PK of 
BAT1706 with bevacizumab (Avastin) and showed that the change of concentration-time curve 
over time was similar between the BAT1706 injection group and the bevacizumab group.  The 
geometric mean ratio and 90% CI of the major PK parameters (AUC0-inf, AUC0-t, and Cmax) were 
in the acceptable equivalent range (0.8 to 1.25), indicating that PK of BAT1706 injection is 
equivalent to bevacizumab. 
Please refer to the BAT1706 Investigator Brochure for more detailed information on the clinical 
pharmacology of BAT1706. 
1.5.2.2. 
 Clinical Safety 
Study BAT1706-001-CR 
The Phase 1 study BAT1706-001-CR assessed the safety of BAT1706 and compared that to the 
safety of EU-sourced Avastin and US-sourced Avastin in healthy subjects.  A total of 125 
healthy subjects received a single, 1 mg/kg administration of 1 of 3 study drugs: BAT1706, 
EU-sourced Avastin, or US-sourced Avastin, as a 90-minute intravenous infusion.  The results 
revealed that a single intravenous infusion of BAT1706 is safe and well tolerated, associated 
with mild injection site reactions. 
There were no deaths or TEAEs leading to premature withdrawal reported during the study.  One 
subject in the BAT1706 group reported a serious TEAE of fibula fracture, which was unrelated 
to study drug (as assessed by the investigator) and resolved during the study.  
Overall, 107 subjects (85.6%) experienced ≥ 1 TEAE during the study.  The incidence of 
subjects experiencing ≥ 1 TEAE was slightly higher in the BAT1706 group (37 subjects, 92.5%) 
than in the EU-sourced Avastin group (34 subjects, 79.1%), and the US-sourced Avastin group 
(36 subjects, 85.7%).  
The majority of TEAEs reported (≥ 7.5%) in the BAT1706 group were: upper respiratory tract 
infection (13 subjects, 32.5%), headache (10 subjects, 25.0%), contusion (6 subjects, 15.0%), 
nasopharyngitis (5 subjects, 12.5%), skin abrasion (4 subjects, 10.0%), and ligament sprain (3 
subjects, 7.5%).  Upper respiratory tract infection and headache were the most common TEAEs 
reported in all the 3 treatment groups.  
A majority of the TEAEs reported during the study were mild in intensity.  Only 2 subjects (1  
subject [2.5%] in the BAT1706 group and 1 subject [2.4%] in the US-sourced Avastin group) 
experienced a TEAE of severe intensity (fibula fracture and muscle enzyme increased, 
respectively), both of which were unrelated to the study drug as assessed by the investigator.  
A total of 62 subjects (49.6%) reported at least 1 TEAE considered to be related to the study 
drug: 22 (55.0%) subjects in the BAT1706 group, 21 subjects (48.8%) in the EU-sourced 
Avastin group, and 19 subjects (45.2%) in the US-sourced Avastin group.  The majority of 
reported TEAEs assessed as related to BAT1706 (≥5%) were headache (7 subjects, 17.5%), 
upper respiratory tract infection (5 subjects, 12.5%), and nausea (2 subjects, 5%).  In the 
EU-sourced Avastin group, the incidence of reported TEAEs was also similar: headache (7 


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subjects, 16.3%) and upper respiratory tract infection (5 subjects, 11.6%).  In the US-sourced 
Avastin group the reported TEAEs were similar: headache (4 subjects, 9.5%) and upper 
respiratory tract infection (3 subjects, 7.1%). 
Study BAT1706-002-CR 
The Phase 1 study BAT1706-002-CR assessed the safety of BAT1706 and compared it with that 
of bevacizumab (European product) in healthy subjects.  A total of 80 healthy subjects received a 
single, 1 mg/kg administration of study drug (39 subjects in the BAT1706 injection group and 41 
subjects in the bevacizumab group [European product]).  The study results showed that both 
drugs were safe and well tolerated.  No death or SAE was reported throughout the study.  
The overall incidences of AEs and AEs in each category were comparable between the 2 groups.  
The overall incidence of TEAEs in the BAT1706 injection group was 59.0%.  The most common 
TEAEs reported in ≥ 10.0% of subjects by Preferred Term (PT) included ALT increase (9 
subjects, 23.1%), AST increase (6 subjects, 15.4%), and white blood cell count decrease (4 
subjects, 10.3%).  The overall incidence of TEAE in the bevacizumab group was 46.3%.  The 
most common TEAE reported in ≥ 10.0% by PT included hypertriglyceridemia (6 subjects, 
14.6%) and ALT increase (5 subjects, 12.2%). 
None of the subjects reported injection site reactions during the study. 
The incidence and severity of TEAEs were similar between the BAT1706 injection group and 
the bevacizumab (European product) group.  Most of the TEAEs that occurred in the BAT1706 
and the bevacizumab group were of Grade 1 or 2 (CTCAE, version 4.03).  In the BAT1706 and 
bevacizumab group, 1 subject (2.6%) and 7 subjects (17.1%) respectively, had ≥ Grade 3 
TEAEs.  In the BAT1706 group, 1 subject (2.6%) developed Grade 3 hypertriglyceridemia.  No 
subject developed a Grade 4 or 5 TEAE.  In the bevacizumab group, 1subject (2.4%) had Grade 
3 and Grade 4 hypokalemia, 5 subjects (12.2%) had Grade 3 hypertriglyceridemia, and 1  subject 
(2.4%) had Grade 4 hypertriglyceridemia.  In the bevacizumab group no subject developed 
Grade 5 TEAE. 
The incidence of study drug-related TEAEs in the BAT1706 group was 38.5%.  The study drug-
related TEAEs reported in ≥ 5.0% of patients by PT included ALT increase (15.4%), AST 
increase (7.7%), white blood cell count decrease (5.1%), blood albumin decrease (5.1%), 
hyperglycemia (5.1%) and hematuria (5.1%).  The incidence of study drug-related TEAEs in the 
bevacizumab group was 24.4%.  The study drug-related TEAEs reported in ≥ 5.0% of patients by 
PT included ALT increase (7.3%). 
Please refer to the BAT1706 Investigator Brochure for more detailed information on the safety of 
BAT1706. 
1.6. 
Study Rationale 
As described in previous sections, anti-PD-1/PD-L1 treatment in combination with anti-
angiogenic agents has demonstrated significant improvement in patient survival compared with 
sorafenib.  This combination is becoming the new worldwide standard-of-care in the first-line 
HCC setting, with the approval of atezolizumab plus bevacizumab.  Tislelizumab monotherapy 
has shown clinical activity in previously treated HCC, comparable with that of other agents of 
the same molecule class, with a tolerable and manageable safety profile.  Therefore, tislelizumab 


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in combination with BAT1706 is expected to provide clinical benefit comparable to that of other 
combination of anti-PD-1/PD-L1 plus anti-angiogenesis treatments.  
Despite the wealth of evidence supporting the role of TIGIT in promoting tumor immune 
tolerance, TIGIT blockade alone (ie, ociperlimab monotherapy) is unlikely to result in an 
effective antitumor response according to existing anti-TIGIT clinical data (see Section 1.3).  
However, TIGIT represents a hallmark in the process of T-cell exhaustion in liver cancer.  
Compared to PD-1, TIGIT expression more reliably identified exhausted CD8 T cells at different 
stages of their differentiation.  In combination with PD-1 inhibition, targeting of TIGIT with 
antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in 
immunocompetent mice (Ostroumov et al 2020). 
Taking these data into account, the combinations of tislelizumab plus BAT1706, with or without 
ociperlimab, are designed to prove the concept of synergistic benefit of adding TIGIT blockade 
to an anti-PD-1-based regimen by evaluating the effect of adding ociperlimab to the tislelizumab 
plus BAT1706 regimen.  This approach is intended to maximize the patient’s potential 
therapeutic benefit while simultaneously achieving the clinical objective of characterizing the 
safety and efficacy of the combination of ociperlimab with tislelizumab and BAT1706. 
1.6.1. 
Rationale for Dose Selection 
1.6.1.1. 
Rationale for the Selection of Ociperlimab Dose in Combination with 
Tislelizumab and BAT1706 
Ociperlimab doses ranging from 50 mg to 900 mg once every 3 weeks, in combination with 
200 mg of tislelizumab once every 3 weeks were explored in the ongoing Ph1/1b Study 
BGB-900-105.  All the tested ociperlimab dose levels cleared the DLT window without any 
significant safety or tolerability events.  The ociperlimab exposures increased in an 
approximately dose-proportional manner (Ociperlimab Investigator’s Brochure).  As of 07 
August 2020, the maximum administered ociperlimab dose of 900 mg, was selected as RP2D. 
Complete TIGIT receptor occupancy was observed on circulating T cells and NK cells in 
peripheral blood at all the tested doses in the Phase 1 study.  However, since the correlation 
between TIGIT receptor occupancy in periphery and receptor occupancy in tumor tissues is 
unknown, quantitative systems pharmacology (QSP) modeling was performed and preliminary 
results predict near complete TIGIT receptor occupancy in tumor tissues at doses of 450 mg and 
above.  Due to the lack of information on the impact of immunogenicity on ociperlimab PK, a 
conservative estimate of 900 mg dose, which was deemed to be safe and tolerable in patients, 
was selected.  This dose level increases the likelihood of efficacious concentrations and 
saturation of TIGIT receptors in tumor tissues completely over the entire dosing interval.  
Absence of any dose-dependent safety events in the ongoing Phase 1 study additionally supports 
selecting this dose for further evaluation.  The preliminary ociperlimab PK data from the 
ongoing BGB-900-105 study indicates lack of significant relationship between the ociperlimab 
exposures and patients’ body weight, thus supporting the selection of a fixed dose for 
ociperlimab. 
As discussed in Section 1.6.1.3, the potential for drug-drug interaction with therapeutic 
antibodies is low, and these monoclonal antibodies are unlikely to influence drug-metabolizing 
enzymes or transporters.  Considering the different therapeutic targets of immune-checkpoint 


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inhibitors and VEGF, the RP2D of ociperlimab 900 mg administered intravenously once every 3 
weeks with tislelizumab 200 mg will also be applicable to the combination of ociperlimab plus 
tislelizumab and BAT1706 regimen. 
1.6.1.2. 
Rationale for the Selection of Tislelizumab Dose 
The PK, safety, and efficacy data obtained from the first-in-human study 
BGB-A317_Study_001, as well as other clinical study data, were analyzed in aggregate to 
determine the recommended dose for studies of tislelizumab.  The dose of 200 mg intravenously 
once every 3 weeks was selected for further evaluation. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear 
dose-dependence across these regimens.  Similarly, confirmed ORRs in patients treated with 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared 
to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once every 3 weeks. 
According to PK data from BGB A317_Study_001, Phase 1a, the clearance of tislelizumab was 
found to be independent of body weight, ethnicity, and sex, and the observed serum exposure of 
a 200-mg dose fell between the serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose 
range with comparable safety and efficacy rates). 
Additionally, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared with body-weight-based cohorts.  Of 
the evaluable patients treated (n = 13), 3 patients (23%) had a BOR of PR, 4 patients (31%) had a 
BOR of stable disease, and 6 patients (46%) had a BOR of PR.  Therefore, clinical activity with 
a manageable and tolerable safety profile is expected to be maintained in patients receiving 
tislelizumab 200 mg every 3 weeks. 
Tislelizumab 200 mg administered intravenously every 3 weeks is the approved dosage for 
tislelizumab (BaiZeAn® Product information) in China.  This dosage has been demonstrated to 
be tolerable with clinical manageable safety profile in previously treated HCC patients. 
Therefore, the recommended dosage of 200 mg once every 3 weeks will be utilized for the 
tislelizumab combination studies with BAT1706 and ociperlimab; however, alternate doses or 
dose schedules may be evaluated based on emerging clinical data.  
1.6.1.3. 
Rationale for the Selection of BAT1706 Dose in Combination with Tislelizumab  
The Phase 1b study GO30140 showed durable antitumor responses and significantly improved 
PFS outcomes with atezolizumab plus bevacizumab than with atezolizumab monotherapy, which 
suggests that both atezolizumab and bevacizumab contribute to the overall treatment benefit of 
the combination in patients with HCC (Lee et al 2020). 
Atezolizumab selectively targets PD-L1 to prevent interaction with receptors PD-1 and B7-1, 
thus reversing T-cell suppression (Herbst et al 2014).  Modest single-agent activity in HCC has 
been observed with bevacizumab (Boige et al 2012, Siegal et al 2008).  Bevacizumab is a 
monoclonal antibody that targets VEGF, inhibits angiogenesis and tumor growth, and showed 
response rates of 13% to 14% in single-agent Phase 2 studies in patients with advanced liver 
cancer (Siegel et al 2008, Finn et al 2009). As a monotherapy and in combination with PD-L1 


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inhibitors, bevacizumab has shown immunomodulatory effects in other tumor types, with 
promising clinical benefit and a good safety profile (Wallin et al 2016, McDermott et al 2018). 
BAT1706 is a proposed biosimilar to Avastin (bevacizumab).  Several analytical assays and 
stress degradation studies have been conducted to compare multiple lots of BAT1706 and 
Avastin.  Specifically, the data indicate that BAT1706 is at least as pure as Avastin and relevant 
biological functional assays also showed similar results.  BAT1706 showed similar reactions 
during the incubating conditions and similar degradation rates as Avastin.  Therefore, the data 
have demonstrated that BAT1706 is similar to the reference product US-Avastin, and the 
comparator EU-Avastin (BAT1706 Investigator’s Brochure). 
BAT1706 will be administered intravenously at a dosage of 15 mg/kg once every 3 weeks which 
is the approved dosage for bevacizumab (Avastin local labels).  The potential for drug-drug 
interaction between tislelizumab and BAT1706 is very low because BAT1706 and tislelizumab 
are therapeutic monoclonal antibodies.  Both are expected to be degraded into amino acids and 
recycled into other proteins and are unlikely to influence drug-metabolizing enzymes or 
transporters.  The different therapeutic targets of immune checkpoint and VEGF may suggest 
different safety profiles and different spectrums of related AEs.  The combination isn’t expected 
to exacerbate the known safety risk of either study drug. 
Moreover, the same dosage of Avastin and its biosimilar was administered in combination with 
other anti-PD-1/PD-L1 inhibitors (Finn et al 2020a; Ren et al 2020), and was tolerable and 
clinical manageable. Therefore, BAT1706 at a dosage of 15 mg/kg once every 3 weeks will be 
used for the combination with tislelizumab.  
1.6.2. 
Rationale for Combination of Ociperlimab With Tislelizumab and BAT1706 in 
the First-Line Treatment of Advanced Hepatocellular Carcinoma 
As described earlier, anti-PD-1/PD-L1 inhibitor monotherapy has shown clinical benefit in 
previously treated HCC (OPDIVO prescribing information, KEYTRUDA prescribing 
information, Qin et al 2020). However, it does not show significant improvement compared with 
sorafenib in first-line HCC patients (Yau et al 2019).  Given the promising anti-tumor activity of 
anti-PD-1 antibodies reported in HCC and given that TIGIT may improve the therapeutic benefit 
of anti-PD-1 therapy, the combination of ociperlimab and tislelizumab may bring significant 
clinical benefit in this indication and support further clinical development. 
Modest single-agent activity has been observed with bevacizumab in HCC patients (Boige et al 
2012, Siegal et al 2008).  In combination with PD-L1 inhibitors, bevacizumab has shown 
immunomodulatory effects in other tumor types, with promising clinical benefits and a good 
safety profile (Wallin et al 2016).  The positive results of the IMbrave150 study and Orient32 
study demonstrate the synergistic benefit of combining anti-PD-1/PD-L1 inhibitors with anti-
angiogenic agents. 
Targeting TIGIT provides a potential mechanism to rescue immune cells from the 
immunosuppressive tumor microenvironment, thereby inducing an efficient antitumor immune 
response.  Research shows that the TIGIT pathway cooperates with PD-1 to maximize the 
suppression of effector TILs as well as promote resistance to anti-PD-1 therapy.  Antibodies 
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Therefore, TIGIT represents an ideal target with the potential to significantly improve and/or 
extend the therapeutic benefit of anti-PD-1 therapy in HCC. 
Given the promising antitumor activity of anti-PD-1 antibodies in combination with anti-
angiogenic agents reported in patients with HCC and given the scientific rationale that TIGIT 
may improve the therapeutic benefit of anti-PD-1 therapy, the combination of ociperlimab,  
tislelizumab and BAT1706 may bring significant clinical benefit in this indication and support 
further clinical development. 
1.6.3. 
Biomarker Strategy Rationale 
A number of biomarkers have been identified that correspond with  response to immunotherapy 
for patients with HCC. 
PD-L1 expression has been demonstrated to be positively correlated with response to anti-PD-1 
therapy across tumor types (Cristescu et al 2018).  Although PD-L1 expression has not been 
widely approved to be a predictive factor for anti-PD(L)-1 treatment in patients with HCC, 
higher PD-L1 expression was shown to be associated with better response and survival benefit 
(Studies A317-001, CHECKMATE-040, CHECKMATE-459, Keynote-224, NCT02989922), 
indicating the potential role of PD-L1 in predicting response to anti-PD(L)-1 therapies.  Internal 
HCC data (A317-001/102) and TCGA database analysis demonstrated that PD-L1 expression 
positively correlates with TIGIT expression, implying that PD-L1 expression may work as the 
surrogate marker for TIGIT expression.  High expression of PD-L1 (TPS ≥ 50%) is also 
correlated with a better response in patients with NCSLC treated with atezolizumab plus 
tiragolumab (CITYSCAPE study), but its role in predicting the efficacy of the anti-
TIGIT therapy in patients with HCC has not been reported so far.  In summary, these data 
support further exploration of the correlation of PD-L1 expression with response to tislelizumab 
plus BAT1706 and ociperlimab.  
Tumor mutational burden (TMB) works as the surrogate marker for neo-antigen prediction and 
has been reported to positively correlate with the response to anti-PD(L)-1, and serves as an 
independent biomarker from PD-L1, indicating that its combination with PD-L1 may lead to 
predictive synergy (Fumet et al 2020; Cristescu et al 2018). In patients with HCC, the correlation 
between TMB and anti-PD(L)-1 therapy has not been extensively reported, and needs further 
exploration in future studies.  Blood TMB (bTMB) demonstrated good correlation with TMB 
when assessed with large panels, which has been explored due to its non-invasiveness, and has 
been reported to predict clinical benefit with anti-PD(L)-1 therapy in several clinical studies 
(Studies POPLAR, OAK, MYSTIC) (Gandara et al 2018). Circulating tumor DNA (ctDNA) 
monitoring can be derived from a bTMB panel.  The GO30140 study in patients with HCC has 
reported the role of baseline ctDNA in predicting response to atezolizumab plus bevacizumab.  
These data indicate the potential role of bTMB/ctDNA monitoring in predicting response to anti-
PD(L)-1 therapies in HCC.  Apart from TMB, DNA mutation can also be explored from the 
(b)TMB detection panel to identify genes/pathways associated with response/resistance to 
immunotherapies.  In summary, the role of (b)TMB in predicting response/resistance to 
tislelizumab plus BAT1706 and ociperlimab can be explored.  
Gene expression profile (GEP) panels have been designed to investigate immune features (tumor 
immunogenicity, interferon gamma signature, immune cell population abundance, etc) and tumor 
features (epithelial-mesenchymal transition, angiogenesis, hypoxia, cell adhesion, etc).  IFNγ 


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signature has been shown to be positively correlated with response to anti- PD(L)-1 monotherapy 
across tumor types (Cristescu et al 2018).  Publications or presentations for HCC (Lee et al 2020, 
Sangro et al 2020), have reported the association of GEP panels (selected genes) with response to 
anti-PD(L)-1 immunotherapies. Apart from their potential predictive value, GEP panels can be 
designed to explore underlying resistance mechanisms such as immunosuppressive cytokines and 
cells to guide potential therapeutic strategies (Fumet et al 2020; Cristescu et al 2018). In 
summary, the role of GEP in predicting response/resistance to tislelizumab plus BAT1706 and 
ociperlimab can be further explored. 
The correlation between the expression of the TIGIT pathway molecules (TIGIT, PVR and 
nectin-2) and the response to anti-TIGIT related therapies is unclear.  TIGIThigh immune cells are 
mainly composed of exhausted T and Treg cells (Zheng et al 2017), although TIGIThigh immune 
cells may not optimally represent more responsive immune cells in the tumor microenvironment.  
As one of the molecules mediating the antitumor role of ociperlimab, TIGIT may play a critical 
role in the Fcγ receptor mediated activation of myeloid and NK cells through crosslinking, which 
depends on TIGIT expression.  Consequently, the correlation of TIGIT expression with response 
to tislelizumab plus BAT1706 and ociperlimab can be further explored.  As the ligands for 
TIGIT, PVR and nectin-2 are differently expressed across tumor types and even within a single 
tumor type (SITC-2019-COM902), whether their expression correlates with response to 
ociperlimab and tislelizumab plus BAT1706 as well as the regulation of their expression await 
further exploration. 
Alpha-fetoprotein (AFP) has been reported to be a prognostic/diagnostic biomarker for HCC 
(Wang 2018).  Whether AFP plays a potential role in predicting the response to ociperlimab in 
combination with tislelizumab plus BAT1706 will be further explored in this study. 
Consequently, PD-L1, TMB/DNA mutation, bTMB/ctDNA monitoring/DNA mutation, AFP, 
GEP and TIGIT/PVR/nectin-2 can be explored in tumor or blood samples to identify their 
potential predictive value, as well as resistance mechanisms in patients who receive ociperlimab 
in combination with tislelizumab plus BAT1706, and tislelizumab plus BAT1706. 
1.7. 
Benefit-Risk Assessment 
Patients with advanced HCC represent a population with an unmet medical need, although 
significant improvements in survival have been reported with anti-PD-1/PD-L1 inhibitor 
combined with anti-angiogenic agents when compared with sorafenib as first-line therapy.  
The safety profile of tislelizumab monotherapy is considered as acceptable based on previous 
nonclinical and clinical data.  Ociperlimab combined with tislelizumab 200 mg once every 
3 weeks is safe and well-tolerated, with no DLTs, no treatment-related SAEs, or treatment-
related high-grade AEs occurring during the treatment period for each dose level in the ongoing 
BGB-900-105 Phase 1/1b study as of 16 June 2020. 
Bevacizumab has been used in clinical practice for more than 15 years.  Its well-established 
clinical efficacy and safety profiles support further development for combination therapy 
approaches.  (Garcia 2020).  Combining BAT1706, a biosimilar of bevacizumab, with 
checkpoint inhibitors isn’t expected to exacerbate the known AEs related to immune checkpoint 
inhibitors, considering the different therapeutic targets. 


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Given the unmet medical need and limited treatment options for this indication, the benefit/risk 
assessment, based on the available safety and efficacy data of anti-TIGIT monoclonal antibodies 
with or without anti-PD-1/PD-L1 antibodies and the available efficacy data from the PD-1 
antibodies and their combination with bevacizumab in this indication, the benefit/risk of the 
combination of tislelizumab and BAT1706 with or without ociperlimab is considered favorable.  
This Phase 2 study will be conducted in order to evaluate the potential benefit and safety of 
ociperlimab with tislelizumab plus BAT1706 and tislelizumab plus BAT1706.  
A Safety Monitoring Committee (SMC) will be established to regularly monitor the safety of 
ociperlimab, tislelizumab, and BAT1706. 
1.8. 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To evaluate the efficacy of ociperlimab in combination with tislelizumab plus 
BAT1706, and tislelizumab plus BAT1706 through the objective response rate 
(ORR), as assessed by the investigator according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST v1.1) as first-line treatment in patients with 
advanced hepatocellular carcinoma 
2.1.2. 
Secondary Objectives 
• To assess the efficacy of ociperlimab in combination with tislelizumab plus 
BAT1706, and tislelizumab plus BAT1706, through duration of response (DOR), 
time to response (TTR), disease control rate (DCR), clinical benefit rate (CBR) and 
progression-free survival (PFS) as assessed by the investigators; and overall survival 
(OS) 
• To assess the safety and tolerability of ociperlimab in combination with tislelizumab 
plus BAT1706, and tislelizumab plus BAT1706  
• To characterize the pharmacokinetics (PK) of ociperlimab in combination with 
tislelizumab plus BAT1706, and tislelizumab plus BAT1706 
• To determine host immunogenicity to ociperlimab, tislelizumab, and BAT1706 
2.1.3. 
Exploratory Objectives 
• To explore potential biomarkers that may correlate with clinical responses/resistance 
to ociperlimab in combination with tislelizumab plus BAT1706, and to tislelizumab 
plus BAT1706 
2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoints 
• ORR, as assessed by the investigator, defined as the proportion of patients with a 
confirmed complete response (CR) or partial response (PR) per RECIST v1.1 
2.2.2. 
Secondary Endpoints 
• DOR, TTR, DCR, CBR, and PFS as assessed by the investigator 
− DOR, defined as the time from the first confirmed objective response until the 
first documentation of disease progression or death, whichever comes first 
− TTR, defined as the time from the date of first dose of study drug to the first 
documentation of response 
− DCR, defined as the proportion of patients who achieve CR, PR, or stable disease 


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− CBR, defined as the proportion of patients who achieve CR, PR, or durable stable 
disease (stable disease ≥ 24 weeks) 
− PFS, defined as the time from the date of the first dose of study drug to the date of 
first documentation of disease progression or death, whichever occurs first 
• OS, defined as the time from the date of the first dose of study drug until the date of 
death from any cause 
• Incidence and severity of adverse events (AEs), with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE] v5.0, vital signs, and clinical laboratory test results 
• Serum concentrations of ociperlimab, tislelizumab, and BAT1706 at specified 
timepoints 
• Immunogenic responses to ociperlimab, tislelizumab, and BAT1706 evaluated 
through detection of ADAs 
2.2.3. 
Exploratory Endpoints 
• Potential biomarkers including programmed cell death protein ligand-1 (PD‑L1) 
expression, T cell immunoreceptor with Ig and ITIM domains (TIGIT) 
pathway-related protein expression (TIGIT, poliovirus receptor/PVR and nectin cell 
adhesion molecule 2/nectin-2), tumor mutational burden (TMB)/DNA mutation, 
blood tumor mutational burden (bTMB)/ctDNA monitoring/DNA mutation, alpha-
fetoprotein (AFP), gene expression profile (GEP), and the association of biomarkers 
with disease status, and response/resistance to ociperlimab in combination with 
tislelizumab plus BAT1706, and to tislelizumab plus BAT1706 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a Phase 2, randomized, multicenter, open-label, 2-arm study to investigate the efficacy 
and safety of ociperlimab in combination with tislelizumab plus BAT1706, and  tislelizumab 
plus BAT1706, as first-line treatment in patients with advanced HCC. 
The study will enroll approximately 90 patients randomized in a 2:1 ratio to one of 2 treatment 
arms: 
• Arm A (n = 60): ociperlimab 900 mg intravenously once every 3 weeks (dosed in 
21-day cycles) + tislelizumab 200 mg intravenously once every 3 weeks (dosed in 
21-day cycles) + BAT1706 15 mg/kg intravenously once every 3 weeks (dosed in 21-
day cycles)  
• Arm B (n = 30): tislelizumab 200 mg intravenously once every 3 weeks (dosed in 
21-day cycles) + BAT1706 15 mg/kg intravenously once every 3 weeks (dosed in 21-
day cycles) 
Randomization will be stratified according to the following factors: 
• PD-L1 expression (visually estimated combined positive score [vCPS] <1% versus 
≥1%) by SP263.  The vCPS score is the total percentage of the tumor area covered by 
tumor cells with PD-L1 membrane staining at any intensity and tumor-associated 
immune cells with PD-L1 staining at any intensity. 
• Macrovascular invasion (MVI)/Extrahepatic spread (EHS) (present versus absent) 
The study schema is shown in Figure 2. 
At the beginning of this Phase 2 study, a safety run-in period is planned to investigate the safety, 
tolerability, and PK before expanding the enrollment to additional patients.  
Every effort should be made to ensure that each drug is administrated as originally scheduled.  
Patients who temporarily withhold or permanently discontinue a study drug due to related AEs 
may continue on the other study drug(s) as long as the patients are experiencing clinical benefit 
in the opinion of the investigator and after discussion with the medical monitor.  However, for 
patients in Arm A, both ociperlimab and tislelizumab should be withheld or permanently 
discontinued simultaneously, if necessary. 


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Figure 2: 
Study Schema 
 
Abbreviations: HCC, hepatocellular carcinoma; MVI: macrovascular invasion; PD-L1, programmed cell death 
protein-ligand 1; Q3W, every 3 weeks, vCPS, visually estimated combined positive score. 
3.2. 
Screening Period 
Screening evaluations will be performed ≤ 28 days before randomization.  
Patients who agree to participate in this study will sign the informed consent form (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.  
Tumor imaging (computed tomography [CT] with or without contrast, or magnetic resonance 
imaging [MRI]) must be performed ≤ 28 days before randomization. 
3.3. 
Treatment Period 
The treatment period will start on the first day of study drug administration and end when the 
patient is discontinued from the study drug(s) for any reason. 
After completing all screening activities, eligible patients will be randomized in a 2:1 
(Arm A: Arm B) ratio to receive ociperlimab + tislelizumab + BAT1706 (Arm A), or 
tislelizumab + BAT1706 (Arm B). 
Study drug(s) will be administered as follows: 
• Arm A: tislelizumab 200 mg intravenously once every 3 weeks followed by  
BAT1706 15 mg/kg intravenously once every 3 weeks followed by ociperlimab 900 
mg intravenously once every 3 weeks  
• Arm B: tislelizumab 200 mg intravenously once every 3 weeks followed by 
BAT1706 15 mg/kg intravenously once every 3 weeks 
No crossover between Arm A and Arm B will be allowed. 


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Eligible patients will be stratified by the following factors: 
• PD-L1 expression (vCPS < 1% versus ≥ 1%) by SP263 
• MVI/EHS (present versus absent) 
During the study treatment period, tumor response will be evaluated by the investigator every 6 
weeks in the first 48 weeks, and every 12 weeks thereafter, in accordance with RECIST v1.1. 
If, at the investigator’s discretion, a patient could continue to benefit from the assigned study 
drug(s) after PD per RECIST v1.1 criteria is met, the patient may continue their assigned 
treatment.  
The following criteria must be met in order to treat patients who may continue to benefit from 
study drug(s) after PD:  
• Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
• Stable ECOG PS ≤ 1  
• Absence of rapid disease progression or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention  
• Investigators must obtain written informed consent for treatment beyond radiologic 
PD and inform patients that this practice is not considered standard in the treatment of 
cancer 
• The decision to continue study drug(s) beyond initial investigator-assessed disease 
progression must be agreed by the sponsor medical monitor and documented in the 
study records. 
Patients who receive study drug(s) beyond disease progression will have tumor assessments 
performed according to the original schedule until all study drug(s) are discontinued. 
If a patient discontinues study drug(s) due to any reason other than PD (eg. toxicity), tumor 
assessments will be performed according to the original schedule until disease progression, 
death, loss to follow-up, withdrawal of consent, or until the study terminates, whichever occurs 
first. 
Patients will report any AEs and SAEs, regardless of causality to study drugs, occurring within 
either 30 days after the last dose of study drug (all severity grades, per NCI CTCAE v5.0) or 
initiation of new anticancer therapy, whichever occurs first.  Patients must also report all imAEs 
occurring up to 90 days after the last dose of ociperlimab or tislelizumab, whichever occurs later, 
regardless of whether or not the patient starts a new anticancer therapy.  All 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 study drug. 
To determine the PK properties of ociperlimab, tislelizumab, and BAT1706 and host 
immunogenic response to ociperlimab, tislelizumab, and BAT1706, blood samples will be 
collected at various timepoints as outlined in Appendix 1. 
Vital signs, physical examinations, ECOG PS change, electrocardiogram (ECG) results, and 
other examinations will also be used for safety assessment. 


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Dose-limiting toxicities: The occurrence of any of the following toxicities during the first 21 
days of study will be considered a DLT, if assessed by the investigator as related to the study 
drug administration: 
Hematologic DLTs: 
1. Grade 4 neutropenia lasting > 7 days 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1 x 109/L with a 
single temperature of 38.3°C or a sustained temperature of 38°C for > 1 hour) 
3. Grade 3 neutropenia with infection 
4. Grade 3 thrombocytopenia with bleeding indicated for clinical interventions 
5. Grade 4 thrombocytopenia 
6. Grade 4 anemia (life-threatening) 
Non-hematologic DLTs: 
1. Grade 4 or higher toxicity 
2. Grade 3 toxicity lasting for > 7 days despite optimal supportive care 
Note: The following AEs will not be considered DLTs: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• Grade 3 rash 
• Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
• Grade 3 or Grade 4 laboratory abnormalities that are not associated with clinical 
sequelae (eg, lactate dehydrogenase increased) 
• ALT/AST from 5x to 10x ULN that return to baseline in ≤ 14 days with optimal 
management  
Clinically important or persistent AEs that are not part of the DLT criteria may also be 
considered a DLT, after review by the sponsor and in consultation with the investigator. 
The SMC will evaluate the safety data of the study treatments when the first 6 DLT-evaluable 
patients in Arm A and 3 DLT-evaluable patients in Arm B have completed the first 21 days of 
treatment.  Based on these data, the SMC will recommend whether a dose modification is needed 
or whether the current dosing regimen is tolerable.  The final decision will be made by the 
sponsor.  
Arm A: For the first 6 patients enrolled in Arm A, if ≤ 1 in 6 patients experience a DLT, the 
dosing regimen is tolerable and will be used in subsequent cycles.  If ≥ 2 in 6 patients experience 
a DLT, the starting dose will be considered as exceeding the MTD, and the sponsor will pause 
enrollment to allow for further evaluation of the safety data. 
Arm B: For the first 3 patients enrolled in Arm B, if no patient experiences a DLT, the dosing 
regimen is tolerable and will be used in subsequent cycles.  If 1 out of 3 patients experiences a 
DLT, an additional 3 patients will be enrolled.  Otherwise, the starting dose will be considered as 


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exceeding MTD, and the sponsor will pause enrollment to allow for further evaluation of the 
safety data. 
If a patient discontinues the study within the first 21 days of study due to reasons other than 
safety, or the clinical examination and/or assessment is incomplete, or the dose intensity of any 
drug is less than 80%, which leads to non-evaluable safety assessments within the first 21 days, 
additional patients may be required to be randomized to replace patients whose safety assessment 
cannot be performed. 
Safety assessments are further detailed in Section 7.4 and the Schedule of Assessments 
(Appendix 1).  
3.4. 
End-of-Treatment/Safety Follow-up  
The End-of -Treatment (EOT) Visit is conducted when the investigator determines that one or 
more study drugs, ie, tislelizumab and ociperlimab in Arm A, tislelizumab in Arm B, or 
BAT1706 in both arms, will no longer be used.  If routine laboratory tests (eg, hematology, 
serum chemistry) were completed within 7 days of the EOT Visit, these tests do not need to be 
repeated.  
Tumor assessment is required at the EOT Visit if the investigator determines that the study 
drug(s) must be discontinued.  However, the tumor assessment may be omitted at the EOT visit 
provided that < 6 weeks have passed since the last assessment.  Patients who discontinue all 
study drugs prior to disease progression will need to undergo tumor assessment. 
3.4.1. 
Safety Follow-up for Tislelizumab and/or Ociperlimab 
Patients who permanently discontinue ociperlimab and tislelizumab in Arm A, or tislelizumab in 
Arm B, will be asked to return to the clinic for the Safety Follow-up Visit, which is required to 
be conducted 30 (± 7) days after the last dose of the specific study drug(s), unless otherwise 
specified, or before the initiation of subsequent anticancer therapy, whichever occurs first.  
If the decision to end treatment is taken ≥ 23 days after the last dose of ociperlimab and 
tislelizumab in Arm A or tislelizumab in Arm B, the EOT and Safety follow-up visits should be 
conducted concurrently within 7 days of the decision to end treatment. 
In addition, patients who discontinue ociperlimab or tislelizumab in Arm A, or tislelizumab in 
Arm B, will be asked to return to the clinic or will be contacted via telephone to assess imAEs 
and concomitant medications (if appropriate, ie, associated with an imAE) at 60 and 90 (± 14) 
days after the last dose of ociperlimab or tislelizumab, whichever is later, regardless of whether 
they started a subsequent anticancer therapy. If patients report a suspected imAE at a follow-up 
visit or a telephone contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6.  Patients will be asked for 
any subsequent anticancer therapy information at the EOT/Safety Follow-up visits or telephone 
contacts. 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up visits. 


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3.5. 
Survival Follow-up 
Patients will be followed-up for survival and to obtain information on subsequent anticancer 
therapy after discontinuation of all study drugs via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months (± 14 days) after the Safety Follow-up Visit or 
as directed by the sponsor until death, loss to follow-up, withdrawal of consent, or study 
completion by the sponsor.  
3.6. 
Discontinuation From Study Drug(s) or From the Study  
3.6.1. 
Patient Discontinuation From Study Drug(s) 
Patients have the right to discontinue study drug(s) at any time for any reason.  In addition, the 
investigator has the right to discontinue a patient from study drug(s) at any time.  Patients who 
discontinue the study drug(s) for reasons other than PD should be followed for an assessment of 
antitumor activity (Section 7.5), safety (Section 7.4) and survival (Section 3.5), if possible. 
If the decision to discontinue the study drug(s) is made, all study drugs should be discontinued.  
The primary reason for study drug discontinuation should be documented on the appropriate 
electronic case report form (eCRF).  Patients may discontinue study drug(s) for reasons that 
include, but are not limited to, the following: 
• Radiographic PD per RECIST v1.1 
• AE 
• 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 drug(s) 
• Use of any concurrent 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) (Section 6.3) 
• 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 if they are consistently 
noncompliant. 


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3.6.2. 
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 
• Death 
• Loss to follow-up 
3.7. 
End of Study 
The end of 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, whichever occurs first.  Alternatively, the end of 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: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study.  Should 
this be necessary, prematurely discontinued patients should be seen as soon as possible for an 
EOT Visit.  
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 IRBs/ IECs of the early termination of the study. 
At the end of study, any patients who, in the opinion of the investigator, continue to benefit from 
study drugs at study termination, may be offered the option to continue the study drug(s) in a 
company-sponsored clinical trial until it is commercially available in the country of the patient’s 
residence. 
The sponsor has the right to close a site at any time.  The decision will be communicated to the 
site in advance.  Reasons for closing a site may include, but are not limited to, the following:  
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• GCP noncompliance 
• Completion of study activity (ie, all patients have completed the study, and all 
obligations have been fulfilled) 


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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all 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. Aged ≥ 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. Has a histologically confirmed HCC, which is either BCLC Stage C disease, or BCLC 
Stage B disease that is not amenable to or has progressed after loco-regional therapy, and 
is not amenable to a curative treatment approach 
4.  Tumor tissue (archival tumor tissues as formalin-fixed paraffin-embedded blocks or 
approximately 15 [≥ 6] freshly cut unstained slides) is required for an evaluable PD-L1 
expression result presented as vCPS by SP263 and for retrospective analysis of other 
exploratory biomarkers. 
A fresh biopsy is mandatory in the absence of archival tumor tissues. 
5. Has received no prior systemic therapy for HCC  
Note: Patients who have received prior liver loco-regional therapy (eg, transarterial 
chemoembolization [TACE]) are not excluded.  Neoadjuvant/adjuvant use of small 
molecule tyrosine kinase inhibitors before/after liver locoregional therapy, eg, liver 
surgery or TACE, is permitted if progression is documented on or after the locoregional 
therapy. 
6. At least 1 measurable lesion as defined per RECIST v1.1 
Note: A lesion in an area subjected to prior loco-regional therapy, including previous 
TACE and radiofrequency ablation (RFA), is not considered measurable unless, since the 
therapy, there has been evidence of lesion progression as defined by RECIST v1.1. 
7. ECOG PS ≤ 1 
8. Patients with a history of treated and, at the time of screening, stable central nervous 
system (CNS) metastases are eligible, provided they meet all the following: 
a. Brain imaging at Screening shows no evidence of interim progression, clinically 
stable for ≥ 2 weeks and no evidence of new brain metastases 
b. Have measurable and/or evaluable disease outside the CNS 
c. No ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 3 
days prior to randomization; anticonvulsants at a stable dose are allowed  
d. No stereotactic radiation or whole-brain radiation within 14 days of randomization 
9. Adequate organ function, as indicated by the following laboratory values, during 
screening and before randomization: 


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a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
− ANC ≥ 1.5 x 109/L 
− Platelets ≥ 75 x 109/L 
− Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration equation 
c. Child-Pugh A classification for liver function assessed within 7 days of 
randomization. 
− Serum albumin ≥ 29 g/L 
− Serum total bilirubin ≤ 3 mg/dl 
d. AST and ALT ≤ 5 x ULN 
e. For patients not receiving therapeutic anticoagulation: International normalized ratio 
(INR) or activated partial thromboplastin time (aPTT) ≤ 2 x ULN 
f. Proteinuria < 2+ (within 7 days of randomization).  Patients discovered to have  ≥ 2+ 
proteinuria at baseline should undergo a 24-hour urine collection and must 
demonstrate < 1 g of protein in 24 hours. 
10. Women of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and for ≥ 120 days after the last dose of 
tislelizumab, and have a negative urine or serum pregnancy test ≤ 7 days before 
randomization. 
11. Nonsterile men must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of tislelizumab 
− A sterile man is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
− Males with known “low sperm counts” (consistent with “sub-fertility”) 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. known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC 
histology 
2. Tumor thrombus involving main trunk of portal vein (ie, VP4) or inferior vena cava 
3. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug 
specifically targeting T-cell costimulation or checkpoint pathway; prior treatment with 
bevacizumab or its biosimilars 
4. Any major surgical procedure or any liver loco-regional therapy (ie, TACE, transcatheter 
embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) ≤ 28 


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days before randomization.  Patients must have recovered adequately from the toxicity 
and/or complications from the intervention prior to randomization. 
5. Any prior history of ≥ Grade 2 hepatic encephalopathy 
6. Active leptomeningeal disease or uncontrolled, untreated brain metastasis. 
7. Active autoimmune diseases or history of autoimmune diseases that may relapse. 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
8. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast) 
9. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization  
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) 
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 randomization 
11. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 2 weeks of intervention) 
12. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc.  Patients with 
significantly impaired pulmonary function or who require supplemental oxygen at 
baseline must undergo an assessment of pulmonary function at screening 
13. Infection (including tuberculosis) requiring systemic antibacterial, antifungal, or antiviral 
therapy within 14 days of randomization 


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Note: Antiviral therapy is permitted for chronic hepatitis B virus (HBV) or hepatitis C 
virus (HCV) infection. 
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 and treated and stable 
hepatitis B patients (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. 
15. Known history of HIV infection 
16. Prior allogeneic stem cell transplantation or organ transplantation 
17. 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. 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) 
(Appendix 5) Classification ≥ II within 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. Inadequately controlled hypertension (defined as systolic blood pressure [BP] ≥ 150 
mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of ≥ 3 BP 
readings on ≥ 2 sessions) that cannot be managed by standard anti-hypertension 
medications ≤ 28 days before randomization 
h. Any episode of syncope or seizure ≤ 28 days before randomization  
18. Untreated or incompletely treated esophageal or gastric varices with bleeding or high risk 
of bleeding. 
Note: Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of 
varices (small to large) must be assessed and treated per local standard of care prior to 
enrollment.  Patients who have undergone an EGD within 6 months before randomization 
do not need to repeat the procedure. 
19. A history of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 28 days of 
randomization 
20. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation) 
21. Current or recent (within 10 days of randomization) use of aspirin (≥ 325 mg/day) or 
treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol 
22. Current or recent (within 10 days of randomization) use of full-dose oral or parenteral 
anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) 
purpose 


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Note: Prophylactic anticoagulation for the patency of venous access devices is allowed 
provided the activity of the agent results in an INR < 1.5 x ULN and aPTT is within 
normal limits within 14 days of randomization.  For prophylactic use of anticoagulants or 
thrombolytic therapies, local label-approved dose levels may be used. 
23. A history of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or 
intra-abdominal abscess within 6 months of randomization 
24. History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction 
including sub-occlusive disease related to the underlying disease or requirement for 
routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months of 
randomization 
Note: Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at 
the time of initial diagnosis may be enrolled if they had received definitive (surgical) 
treatment for symptom resolution. 
25. Evidence of abdominal free air that is not explained by paracentesis or recent surgical 
procedure 
26. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
27. History of severe hypersensitivity reactions to other monoclonal antibodies 
28. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin) 
or any investigational therapies within 14 days or 5 half-lives (whichever is longer) 
before randomization, or has received palliative radiation treatment or other local 
regional therapies within 14 days of randomization.  
29. 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) 
30. Was administered a live vaccine ≤ 28 days before randomization, through 60 days after 
the last dose of tislelizumab or ociperlimab, whichever is later 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines that are live vaccines are not allowed. 
31. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, or 
affect the explanation of drug toxicity or AEs, or result in insufficient or impaired 
compliance with study conduct 
32. Women who are pregnant or are breastfeeding 
33. Concurrent participation in another therapeutic clinical study 
Note: Concurrent participation in observational or non-interventional 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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5. 
STUDY DRUGS 
5.1. 
Formulation, Packaging, and Handling 
5.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, USP type I), containing a total of 100 mg of antibody in 10 mL of isotonic solution.  
Tislelizumab has been aseptically filled in single-use vials with a Flurotec-coated butyl rubber 
stopper and an aluminum cap.  Each vial is packaged into a single-carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions specified on the label.  Shaking 
should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal.  Refer to the Tislelizumab Investigator’s Brochure for other details regarding 
tislelizumab. 
5.1.2. 
Ociperlimab 
Ociperlimab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20 mL glass vial, USP type I) containing a total of 300 mg antibody in 15 mL of buffered 
isotonic solution.  ociperlimab has been aseptically filled in single-use vials with a Flurotec-
coated butyl rubber stopper and an aluminum cap.  Each vial is packaged into a single-carton 
box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions specified on the label.  Shaking 
should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal.  Refer to the Ociperlimab Investigator’s Brochure for other details regarding 
ociperlimab. 
5.1.3. 
BAT1706 
BAT1706 is a similar biological product of the bevacizumab injection (Bevacizumab Injection, 
brand name Avastin®).  BAT1706 contains a recombinant humanized immunoglobulin G1 
(IgG1) monoclonal antibody as the active ingredient and binds with high affinity to human 
VEGF. 
BAT1706 is formulated for intravenous injection in a single-use vial containing a total of 25 
mg/mL of antibody (100 mg diluted in a 4 mL volume or 400 mg diluted in 16 mL).  BAT1706 
vials should be protected from light, and never frozen or shaken. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions specified on the label.  


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Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal.  Refer to the BAT1706 Investigator’s Brochure for other details regarding 
BAT1706.  
5.2. 
Dosage, Administration, and Compliance 
The first dose of study drugs is to be administered within 2 business days of randomization.  
Dosing schedules for all arms, broken out by individual treatment arm, are provided in Table 3.  
Dosing administration and monitoring times, broken out by individual treatment arm, are 
provided in Table 4.  
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs 
Study drugs 
Dose 
Timing of Administration 
Route of 
Administration 
Duration of 
Treatment 
Tislelizumab 200 mg  
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.3 
BAT1706 
15 mg/kg 
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.3  
Ociperlimab 
900 mg  
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.3 
Table 4: 
Administration of Study Drugs and Monitoring Time 
Cycle 
Tislelizumab Plus BAT1706 With Ociperlimab/Tislelizumab Plus BAT1706  
Day 1, Cycle 1 
Tislelizumab infusion over 60 (± 5) minutes, followed by BAT1706 infusion 
over 90 (± 15 ) minutes, followed by ociperlimab infusion over 60 (± 5) minutes 
(Arm A)  
or  
Tislelizumab infusion over 60 (± 5) minutes followed by BAT1706 infusion over 
90 (± 15) minutes (Arm B)  
Patient monitoring for ≥ 120 minutes 
Day 1, Cycle 2, if 
tolerated 
Tislelizumab infusion over 30 (± 5) minutes, followed by BAT1706 infusion 
over 60 (± 10) minutes, followed by ociperlimab infusion over 30 (± 5) minutes 
(Arm A)  
or  
Tislelizumab infusion over 30 (± 5) minutes followed by BAT1706 infusion over 
60 (± 10) minutes (Arm B)  
Patient monitoring for ≥ 60 minutes 
Day 1, Cycle 3 
onwards, if 
tolerated 
Tislelizumab infusion over 30 (± 5) minutes, followed by BAT1706 infusion 
over 30 (± 10) minutes, followed by ociperlimab infusion over 30 (± 5) minutes 
(Arm A) 
or  
Tislelizumab infusion over 30 (± 5) minutes followed by BAT1706 infusion 30 
(± 10) minutes (Arm B)  
Patient monitoring for ≥ 60 minutes 


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Treatment Administration 
In Arm A, tislelizumab 200 mg will be administered followed by BAT1706 15 mg/kg, followed 
by ociperlimab 900 mg on Day 1 of each 21-day cycle (once every 3 weeks). 
In Arm B, tislelizumab 200 mg will be administered followed by BAT1706 15 mg/kg on Day 1 
of each 21-day cycle (once every 3 weeks). 
The dose of BAT1706 will be based on the baseline weight, defined as the weight of the patient 
(in kilograms) measured ≤ 14 days before the initiation of study drug, and will remain the same 
throughout the study unless there is a weight change of > 10%.  If re-assessment of baseline 
weight is needed, the latest baseline weight should always be used to calculate percent change in 
weight for all subsequent doses. 
The initial infusion (Day 1, Cycle 1) will be delivered over 60 minutes for tislelizumab, over 90 
minutes for BAT1706, and over 60 minutes for ociperlimab.  If this infusion regimen is well 
tolerated, then the subsequent infusion (Day 1 Cycle 2) may be administered over 30 minutes for 
tislelizumab and ociperlimab, and over 60 minutes for BAT1706.  
If well tolerated, the subsequent infusions (Day 1 Cycle 3 onwards) of each study drug may be 
administered over 30 minutes, which is the shortest period permissible for infusion (see Table 4).  
The study drugs must be administered by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter.  Specific instructions for product preparation and administration are provided in the 
Pharmacy Manual. 
Use of a volumetric pump is recommended to control the infusion speed and to avoid potential 
infusion reactions associated with too rapid administration.  The pump may not be needed if the 
infusion speed is controlled through alternative means and is consistent with approved 
institutional procedures.  
At the end of the infusion period, the line should be flushed with enough normal saline to make 
sure that all of the study drugs are administered to the patient. 
As a routine precaution, after infusion of the study drugs on Day 1 of Cycle 1, patients must be 
monitored for ≥ 120 minutes.  If the infusion completion time was shortened, on Day 1 Cycle 2 
patients must be monitored for ≥ 60 minutes, and from Cycle 3 onward, a ≥ 60‑minute 
monitoring period is required.  Regardless of the infusion completion time, patients must be 
monitored in an area with resuscitation equipment and emergency agents.   
The study drugs must not be concurrently administered with any other drug (Section 6).  
All patients will be monitored continuously for AEs.  Treatment modifications (eg, dose delay, 
interruption, or discontinuation) will be based on specific laboratory and AE criteria, as 
described in Section 5.5.  Guidelines for dose modification, treatment interruption, or 
discontinuation and for managing imAEs and infusion-related reactions are provided in 
Section 8.7 and Appendix 6.  


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5.3. 
Incorrect Administration or Overdose 
Any incorrect administration of ociperlimab or BAT1706, or overdose of tislelizumab (defined 
as ≥ 600 mg in a 24-hour period) should be noted in the patient’s chart and on the appropriate 
eCRF. 
An incorrect administration or overdose of study drug(s) is not itself an AE, but it may result in 
an AE.  AEs associated with an incorrect administration or overdose of study drugs will be 
recorded on the AE eCRF.  Any SAEs associated with an incorrect administration or overdose 
must be reported within 24 hours of awareness via the SAE reporting process as described in 
Section 8.6.2.  Supportive-care measures should be administered as appropriate. 
5.4. 
Study Drug Accountability 
The study drugs required for completion of this study (ociperlimab, tislelizumab, and BAT1706) 
will be provided by the sponsor.  The investigational site will acknowledge receipt of the study 
drugs.  Any damaged shipments will be replaced.  
Accurate records of all study drug received, dispensed, returned, and disposed of should be 
recorded on the site’s Drug Inventory Log.  Refer to the Pharmacy Manual for details on 
managing study drugs.  
5.5. 
Dose Delay or Modification 
Every effort should be made to administer the study drugs in a synchronized manner according 
to the planned dose and schedule as described in Section 5.2.  In the event of significant 
toxicities, dosing of one or more study drugs may be delayed and/or interrupted based on the 
guidelines provided below.  Reasons for dose interruptions or delays, the supportive measures 
taken, and the outcome will be documented in the patient's chart and recorded in the eCRF.  
If the administration of ociperlimab plus tislelizumab (in Arm A) or tislelizumab (in Arm B) is 
delayed for ≤ 10 days, or BAT1706 (in both arms) is delayed ≤ 3 days during a planned dosing 
cycle (eg, Cycle 3 Day 1), the drug(s) should be administered in the current cycle, at the end of 
the delay.  If the study drugs need to be withheld for > 10 days, they should be omitted from the 
current cycle and administration should restart on Day 1 of the next planned cycle (eg, Cycle 4 
Day 1) to remain synchronized with the administration of other study drug(s). 
Patients who temporarily withhold or permanently discontinue a study drug due to related AEs 
may continue on the other study drug(s) as long as the patients are experiencing clinical benefit 
in the opinion of the investigator and after discussion with the medical monitor.  However, for 
patients in Arm A, both ociperlimab and tislelizumab should be withheld or permanently 
discontinued simultaneously, if necessary. 
If treatment is delayed due to TEAEs, treatment may resume only after the AEs have returned to 
baseline or ≤ Grade 1 severity, excluding alopecia or any AE that, in the opinion of the 
investigator, is not considered a safety risk to the patient.  If a treatment delay is due to 
worsening of hematologic or biochemical parameters, the frequency of relevant blood tests 
should be increased as clinically indicated.  In general, dose delays for reasons other than 
management of AEs are prohibited. 


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The tumor assessment schedule will not be altered even if the administration of study drugs is 
delayed.  
Management guidelines for infusion-related reactions and imAEs and AEs related to BAT1706 
in patients are presented in Section 8.7 and Appendix 6 and Appendix 7 respectively. 
5.5.1. 
Dose Modifications for Ociperlimab and Tislelizumab  
No dose reduction or increase is allowed for ociperlimab and tislelizumab.  However, dose 
interruption or dose delay is allowed.  A dose interruption is an interruption of an infusion that 
has begun.  A dose delay is a deviation from prescribed dosing schedule (ie, the drug is withheld 
after the visit window).  For patients in Arm A, both ociperlimab and tislelizumab should be 
withheld or permanently discontinued simultaneously, if necessary. 
If a dose delay is required due to AEs related to ociperlimab and/or tislelizumab in Arm A, both 
ociperlimab and tislelizumab should be held and restarted at the same time, if applicable.  
If an AE leading to discontinuation is considered related to ociperlimab and/or tislelizumab, both 
ociperlimab and tislelizumab should be discontinued.  Exceptions may be considered after 
consultation between the investigator and the medical monitor.  
A dose delay of ≤ 12 weeks for ociperlimab and tislelizumab in Arm A and tislelizumab in Arm 
B is allowed under the above guidance and at the discretion of the investigator after consultation 
with the medical monitor or designee.  If the delay is > 12 weeks, the patient should be 
permanently discontinued from ociperlimab and tislelizumab in Arm A and tislelizumab in Arm 
B, unless the patient is likely to derive clinical benefit at the discretion of the investigator after 
consultation with the medical monitor or designee.  
5.5.2. 
Dose Modifications for BAT1706 
No dose reduction is allowed for BAT1706 after the safety run-in period.  Dose interruption and 
dose delay is allowed for BAT1706. 
A dose delay of ≤ 42 days for BAT1706 in Arm A and Arm B due to AEs related to BAT1706 is 
allowed.  If BAT1706 is delayed for > 42 days, the patient should be permanently discontinued 
from BAT1706, unless the patient is likely to derive clinical benefit at the discretion of the 
investigator after consultation with the medical monitor or designee. 


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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
The exclusion criteria (Section 4.2) specify that patients should not have received prior therapies 
targeting PD-1, PD-L1, PD-L2, TIGIT, or any other antibody or drug specifically targeting T-
cell costimulation or checkpoint pathways or any prior treatment with bevacizumab or its 
biosimilar before randomization. 
6.2. 
Permitted Concomitant Medications/Procedures 
Unless noted otherwise, most concomitant medications and therapies are allowed at the 
discretion of the investigator if they are deemed necessary and are in keeping with local 
standards of medical care for supportive care (eg, antiemetics, antidiarrheals, hematopoietic 
growth factors, red blood cell/platelet transfusions) and in a patient’s interest.  Opiates and other 
medication required for palliative management of patients are allowed.  Patients must notify the 
investigator of all concurrent medications used during the study.  
All concomitant medications will be recorded on the eCRF, including all prescription and 
over-the-counter medicines, herbal supplements, and intravenous medications and fluids.  
6.2.1. 
Systemic Corticosteroids 
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 6) and must be administered at nonimmunosuppressive doses (≤ 10 mg/day of 
prednisone or equivalent) before the next administration of tislelizumab with or without 
ociperlimab.  The short-term use of steroids as prophylactic treatments (eg, patients with contrast 
allergies to diagnostic imaging contrast dyes) is permitted.  
6.2.2. 
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 
randomization and continue treatment during the study and for 6 months after study drug 
discontinuation. 
6.2.3. 
Hepatitis C Treatment 
The sponsor does not require patients with active hepatitis C to receive treatment with antiviral 
therapy.  Patients with detectable HCV RNA who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study.  Investigators can consider 
treatment with antiviral agents, in accordance with international or local guidelines.  However, 
interferon-based therapy for HCV is not permitted during the study.  Patients who are given 
antiviral therapy must initiate treatment > 2 weeks before randomization and continue treatment 
during the study and for 6 months after study drug treatment discontinuation.  


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6.2.4. 
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 if the following criteria are met: 
• Repeat imaging shows no new sites of bone metastases; 
• The lesion being considered for palliative radiation is not a target lesion per 
RECIST v1.1; 
• The case is discussed with the medical monitor and he/she 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 the investigator’s discretion and after consultation 
with the medical monitor.  Whenever possible, these patients should have a tumor assessment of 
the lesion(s) before receiving the radiation therapy to rule out PD.  It is not required to withhold 
study drugs during palliative radiotherapy. 
6.3. 
Prohibited Concomitant Medications/Procedures 
The following medications/therapies are prohibited: 
• Any concurrent 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 [with anticancer activity included in the label, regardless of 
cancer type ]) for ≤ 14 days (or ≤ 5 half-lives, whichever is longer) before 
randomization and during the study. 
• Any concurrent anticancer surgeries or locoregional therapies (eg, TACE, 
transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, 
ablation) ≤ 28 days of randomization and during the study.  
• Live vaccines administered ≤ 28 days before randomization through the 60 days after 
the last dose of ociperlimab or tislelizumab, whichever is later. 
• Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 28 days or 5 half-lives (whichever is longer) of 
randomization and during the study. 
• Herbal remedies with immunostimulatory properties (eg, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions 
(eg, hypericin) within 14 days (or within 5 half-lives, whichever is longer) before 
randomization and during the study.  Patients must notify the investigator of all herbal 
remedies used during the study.  
• Use of warfarin or Coumadin-like products (including for prophylactic use) is 
prohibited 
− Prophylactic use of low-dose anticoagulants, unfractionated heparin or low-
molecular-weight heparin is permitted. 


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• Current use of full-dose anticoagulants, thrombolytic therapy at therapeutic doses, or 
anti-platelet therapy are prohibited.  However, if a patient experiences a venous 
thromboembolism (VTE) event while still receiving the study drug, it may still be 
possible for the patient to remain on study medication despite anticoagulation 
treatment (See Section 4.2) 
• Concomitant chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) while 
receiving study drugs is prohibited.  However, for the symptomatic relief of medical 
conditions (eg, headache, fever), sporadic or short-term intake of oral NSAIDs is 
allowed, when co-administered with proton-pump inhibitors to reduce potential GI 
damage.  
6.4. 
Restricted Concomitant Medications/Procedures 
The following medications 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 an 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. 
• Radiation therapy is not allowed, except for palliative radiation therapy, as described 
in Section 6.2.4.  
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications 
Information regarding clinical drug interactions with ociperlimab is not available and no 
dedicated drug-drug interaction studies are planned.  However, the potential for drug-drug 
interaction between the study drugs (ociperlimab and tislelizumab) and other drug products is 
very low because ociperlimab and tislelizumab are therapeutic monoclonal antibodies.  Because 
ociperlimab and tislelizumab are expected to be degraded into amino acids and recycled into 
other proteins, they are unlikely to influence drug-metabolizing enzymes or transporters. 


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7. 
STUDY ASSESSMENT AND PROCEDURES  
A table of scheduled study assessments is provided in Appendix 1.  Patients will be closely 
monitored for safety and tolerability throughout the study.  All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.   
7.1. 
Screening Period 
Screening evaluations will be performed ≤ 28 days of randomization.  A patient who agrees to 
participate in this study will sign the ICF before undergoing any screening assessment.  The 
screening period begins on the first day that a screening assessment is conducted.  Screening 
evaluations may be repeated as needed within the screening period.  The investigator is to assess 
patient eligibility according to the latest screening assessment results. 
Results of standard-of-care tests or examinations performed before informed consent has been 
obtained and within 28 days of randomization may be used for the purposes of screening rather 
than repeating the standard-of-care tests, unless otherwise indicated. 
Rescreening under limited conditions may be allowed after consultation with the sponsor 
(eg, when a patient’s laboratory result narrowly misses laboratory criterion and it is correctable 
and not due to rapidly deteriorating condition or progression of disease).  Rescreening is allowed 
only once. 
Procedures conducted only during the Screening Visit are described in this section.  For the 
description of other assessments that are conducted during screening as well as throughout the 
study, refer to the safety assessments (Section 7.4), tumor and response evaluations (Section 7.5), 
PK and ADA assessments (Section 7.6), and tumor tissue and biomarker assessment procedures 
(Section 7.7) sections. 
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.  The 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.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
7.1.2. 
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.  
7.1.3. 
Demographic Data and Medical History 
Demographic data will include age or date of birth, sex, and self-reported race or ethnicity.  


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Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
and tobacco consumption (ie, never, previous, and current); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before randomization.  
Cancer history will include an assessment of prior anticancer surgery, prior locoregional therapy 
to liver, prior radiotherapy, and prior drug therapy including start and stop dates, best response, 
and reason for discontinuation.  Radiographic studies performed before study entry may be 
collected for review by the investigator.  Pre-existing AEs at baseline should be recorded as 
medical history. 
7.1.4. 
Women of Childbearing Potential and Contraception 
Urine or serum pregnancy test (for women of childbearing potential, including women who have 
had a tubal ligation) must be performed and documented with a negative result within 7 days of 
randomization.  Urine pregnancy tests will be performed at each visit prior to dosing, and at the 
EOT/Safety Follow-up Visit.  A serum pregnancy test must be performed if the urine pregnancy 
test is positive or equivocal. 
Childbearing potential is defined as the physiological ability to become pregnant.  Refer to 
Appendix 4 for contraception guidelines and definitions of “women of childbearing potential” 
and “women of no childbearing potential.” 
7.1.5. 
Pulmonary Function Tests 
Patients who are suspected of having or known to have serious and/or severe respiratory 
conditions, or who exhibit significant respiratory symptoms unrelated to the underlying cancer, 
or who have a history of thoracic radiotherapy will undergo pulmonary function testing that may 
include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
screening period to assist the determination of suitability for the study. 
The test may be repeated as clinically indicated while on study (refer to Appendix 1 for details). 
7.1.6. 
Esophagogastroduodenoscopy 
All patients must undergo an EGD and all size of varices (small to large) must be assessed and 
treated per local standard of care prior to enrollment. 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient.  The results of all 
screening procedure and relevant medical history must be available before eligibility can be 
determined.  All inclusion criteria must be met and none of the exclusion criteria may apply.  No 
eligibility waivers will be granted.  
After a patient is screened and the investigator determines that the patient is eligible for 
randomization, study site personnel will complete an Eligibility Confirmation Packet and email it 
to the medical monitor or designee to confirm the enrollment in writing.  Study site personnel 


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should ensure that a medical monitor’s confirmation has been received before proceeding with 
study procedures.  
7.2.2. 
Randomization 
Site personnel will access the IRT system to randomize the patient and assign study drugs by 
permuted block stratified randomization.  
All patients are required to receive the study drug(s) within 2 business days of randomization and 
treatment assignment. 
7.3. 
Study Drug Dispensation 
Ociperlimab, tislelizumab, and BAT1706 will be dispensed and administered as described in 
Section 5.2.  
7.4. 
Safety Assessment 
7.4.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, respiratory rate, and 
blood pressure (systolic and diastolic).  Pulse rate and blood pressure will be measured while the 
patient is in a seated position after resting for 10 minutes.  
If coinciding with administration of study drugs, the patient’s vital signs should be recorded 
within 60 minutes of study drug administration.  For patients treated with BAT1706, vital signs 
will be measured at the end of BAT1706 infusion and 2 (± 1) hours after the end of the infusion, 
and during the study if clinically indicated. 
Height should only be measured and recorded during screening.  Weight will be measured before 
study drug administration in every cycle. 
7.4.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of the head, eyes, ears, nose, and throat and of the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Any abnormality 
identified during screening will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) and recorded on the 
eCRF with appropriate disease/condition terms. 
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.  
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS (Appendix 3) will be assessed during the study.  Each patient’s ECOG PS will be 
assessed at the Screening Visit, pretreatment on Day 1 of each treatment cycle, and at the 
EOT/Safety Follow-up visits. 


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7.4.4. 
Laboratory Safety Tests  
Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Appendix 2. 
If laboratory tests at screening are not performed ≤ 7 days of randomization on Day 1 of Cycle 1, 
these tests should be repeated and reviewed before randomization.  After Cycle 1, laboratory 
tests are to be conducted and results are to be reviewed within 48 hours before study drug 
administration.  
Thyroid assessments will be performed as specified in Appendix 1. 
Details about sample collection and shipment will be provided in a separate instruction manual.  
Investigators should use results from the same local laboratories for assessing eligibility, safety 
monitoring, and dosing decision for each patient.  
7.4.4.1. 
Cardiac Enzyme Monitoring   
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatine kinase (CK) and CK-MB are monitored in all tislelizumab studies to protect study 
patients and to quantify the risk of muscle inflammation (see Appendix 1 for the blood collection 
schedule and Appendix 6 for guidelines for management of suspected immune-mediated 
myocarditis, respectively).  
CK and CK-MB testing will be implemented for all patients at Screening, repeated at all 
scheduled visits during the first 3 treatment cycles, all predose assessments from Cycle 4 
onwards, and the EOT/Safety Follow-up Visit (30 days after the last dose).  If CK-MB 
fractionation is not available, serum troponins (troponin I and/or T) may be tested instead.  
7.4.5. 
Electrocardiograms  
ECG recordings will be obtained during Screening, at the EOT/Safety Follow-up Visit, and as 
clinically indicated.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings.  
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the site. 
All ECGs are to be obtained before other assessments scheduled at that same time (eg, vital sign 
measurements, blood draws).  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) before each ECG collection. 
7.4.6. 
Adverse Events 
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0.  
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6 . 


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7.4.7. 
Hepatitis B and C Testing 
Testing will be performed at Screening (and as clinically indicated) and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], 
and HCV antibody) and viral load assessment (HBV DNA and HCV RNA).  
For patients who have detectable HBV DNA or HCV RNA at Screening, a respective viral load 
test will be performed every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc) starting from Cycle 5. 
Blood samples will be collected on Day 1 of Cycle 1 before dosing of study drug, stored and 
may be analyzed if patients develop hepatic AEs. 
7.4.8. 
Ophthalmologic Examination 
Ophthalmologic examination, as described below, will be performed on all patients during 
Screening, and subsequently throughout the study. 
Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) 
will be assessed by an ophthalmologist at Screening.  Eye exam, visual acuity test, and optical 
coherence tomography (or equivalent diagnostic test for retinal examination) captured as 
standard of care prior to obtaining written informed consent and within 28 days of randomization 
may be used for the Screening evaluation.  Patients will undergo repeat assessments by an 
ophthalmologist approximately every 15 weeks (± 7 days) during study treatment and a final 
assessment during the  EOT Visit for ociperlimab and/or tislelizumab. 
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 ophthalmologist will be made for further management guidance. 
7.5. 
Tumor and Response Evaluations 
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 Day 1 of Cycle 1 for the first 48 weeks, and every 12 weeks (± 7 days) thereafter, based on 
RECIST v1.1. Tumor assessments must be performed on schedule regardless of whether the 
study drug(s) have been administered or withheld, ie, they should not be adjusted for delays in 
cycles.  
Screening assessments and each subsequent assessment must include CT scans (with 
oral/intravenous contrast) of the chest, abdomen, and pelvis.  If a contraindication exists, other 
modalities can be allowed after consultation with the medical monitor (eg, MRI, CT without 
contrast); bone scan or positron-emission tomography (PET) is required if clinically indicated.  
Other known or suspected sites of disease must be included in the imaging assessments (neck, 
brain, etc).  For patients who are suspected to have CNS metastases, CT/MRI of the head is 
required at baseline.  MRI may be used when it is the standard of care at a site, regardless of 
whether or not CT is contraindicated. 


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The liver should be imaged using tri-phasic scans (ie, late arterial phase, portal venous phase, 
and delayed/equilibrium phase are required).  Every effort should be made to keep the 
methodology consistent across visits for a subject (ie, phases acquired, timing for each phase, 
etc). 
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). 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a PET/CT scanner, the CT 
acquisition must be consistent with the standards of a diagnostic CT scan. 
• Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening if 
clinically indicated.  If bone metastases are present at screening and cannot be seen 
on CT or MRI scans, TC-99m or PET bone scans should be repeated when a CR is 
suspected in a target lesion or when progression in bone is suspected. 
• CT scans of the head, 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 assessment of target lesion and 
non-target lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 8).  The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits.  
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later after the first response or at the next scheduled assessment timepoint. 
If, at the investigator’s discretion, a patient could continue to benefit from study drugs after PD 
per RECIST v1.1 criteria, the patient may continue to receive study drug(s).  The following 
criteria must be met in order to treat patients who may continue to benefit from study drug(s) 
after PD:  
• Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
• Stable ECOG PS ≤ 1 
• Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, cord 
compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment beyond radiologic 
PD and inform patients that this practice is not considered standard in the treatment of 
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• The decision to continue study drug(s) beyond initial investigator-assessed 
progression must be agreed with by the sponsor medical monitor and documented in 
the study records. 
Tumor assessment should continue as planned in patients receiving study drug(s) after initial 
investigator-assessed PD. Tumor assessment in such patients should continue until all study 
drugs are discontinued.  
A patient who discontinues study drugs for reasons other than PD (eg, toxicity) will continue to 
undergo tumor assessments in accordance with the original schedule until PD, withdrawal of 
consent, loss to follow-up, death, or until study termination, whichever occurs first. 
7.6. 
Pharmacokinetic and Antidrug Antibody Assessments 
Ociperlimab, tislelizumab, and BAT1706 may elicit an immune response.  Patients with signs of 
any potential immune response will be closely monitored.  Validated screening and confirmatory 
assays will be employed to detect ADAs at multiple timepoints throughout the study.  In 
addition, blood samples will be collected for characterization of ociperlimab, tislelizumab and 
BAT1706  PK at the timepoints specified in the Appendix 1.  
PK and ADA assays of ociperlimab, tislelizumab, and BAT1706 will be managed through a 
central laboratory.  Serum samples will be assayed for ociperlimab, tislelizumab and BAT1706 
concentrations using validated immunoassays.  
• ADA assays: Serum samples will be tested for the presence of ADAs to ociperlimab, 
tislelizumab and BAT1706 using a validated immunoassay. 
• PK assays: Serum samples will be assayed for ociperlimab, tislelizumab and 
BAT1706 concentrations using a validated immunoassay. 
Refer to the laboratory manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples. 
7.7. 
Tumor Tissue and Biomarker Assessment Procedures 
Instructions for the processing, storage, and shipping of samples will be provided in the study 
laboratory manual.  Refer to the Schedule of Assessments (Appendix 1) for sample collection 
timepoints. 
Archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] blocks or approximately 
15 freshly cut unstained FFPE slides [≥ 6]) need to be sent for central laboratory assessment of 
PD-L1 status during the screening period (an evaluable PD-L1 result presented as vCPS by 
SP263 is required, with vCPS score being defined as the total percentage of the tumor area 
covered by tumor cells with PD-L1 membrane staining and tumor-associated immune cells with 
PD-L1 staining at any intensity) and for retrospective analysis of other exploratory biomarkers 
related to response and resistance for all patients in a sponsor-designated central/local laboratory. 
These exploratory biomarkers include TMB/DNA mutation, TIGIT/PVR/nectin-2 and GEP.  
Submission of < 15 unstained slides is not a protocol deviation. 
A fresh tumor biopsy at a tumor lesion is mandatory if there are no available archival tumor 
samples during the screening period.  Optional fresh biopsies in patients who have confirmed PD 


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will also be collected in the two cohorts during the study from accessible tumor sites.  If feasible, 
any follow-up biopsy should ideally be taken from the same tumor lesion as the baseline biopsy.  
Written patient consent is required for fresh tumor biopsies. 
For fresh biopsies, acceptable samples include core needle biopsies for nonsuperficial tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions.  Tumor tissue should be of good quality based on total and viable tumor 
content.  Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable. 
Blood samples will be obtained for the evaluation of exploratory biomarkers including 
bTMB/ctDNA monitoring/DNA mutation, which will be collected at baseline (predose on Cycle 
1 Day 1, required), at the time of first tumor response (predose on Day 1 of the following cycle, 
optional), and at the time of PD (optional) (approximately 10 mL for each timepoint).  In 
addition, local laboratory assessments of AFP are required at baseline (predose on Cycle 1 Day 
1).  Written patient consent is required for blood sample collections. 
7.8. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1).  All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified.  Assessments scheduled on the day of study drug 
administration (Day 1) of each cycle should be performed before any study drug is given unless 
otherwise noted.  Laboratory results must be reviewed before dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled for the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of Cycle 1.  
7.9. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/physical examination, ECOG PS, AE review, concomitant 
medications and procedure reviews, radiographic assessments, physical examination of the liver, 
spleen, and lymph nodes, disease-related constitutional symptoms, and hematology and clinical 
chemistry laboratory assessments.  The date and reason for the unscheduled visit must be 
recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests 
may be performed based on the investigator’s assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 


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8. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drugs 
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab 
Ociperlimab and tislelizumab are investigational agents that are currently in clinical 
development.  Limited safety data are available in patients, and the full safety profile has not 
been characterized.  The following recommendation is based on results from nonclinical and 
clinical studies with tislelizumab and ociperlimab and published data on other molecules within 
the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions.  AEs observed with anti-PD-1 therapy are presented in Section 8.7.3.  
Ociperlimab-mediated TIGIT inhibition may further increase the risk of imAEs.  However, no 
apparent immunotoxicity, or toxicity in general, has been observed in animal models treated with 
ociperlimab.  Furthermore, in the absence of activation, peripheral effector T-cells do not 
typically express TIGIT, thereby minimizing any potential negative additive effect as it relates to 
peripheral immune tolerance. 
Although most imAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Suggested workup procedures for suspected imAEs are provided in 
Appendix 6.  
8.1.2. 
Risks Associated With BAT1706 
In Study BAT1706-001-CR, the most commonly reported TEAEs in heathy subjects 
administered a single dose (1 mg/kg) of BAT1706 were upper respiratory tract infection, 
headache, contusion, nasopharyngitis, skin abrasion, nausea,  and ligament sprain.  
In Study BAT1706-002-CR, the most commonly reported TEAEs in heathy subjects 
administered with a single dose (1 mg/kg) of BAT1706 were ALT increase, AST increase, white 
blood cell count decrease, white blood cell count increase, neutrophil count increase, positive 
urine blood, γ -glutamyl transpeptidase increase, blood albumin decrease, neutrophil count 
decrease, hyperglycemia, and hematuria. 
The most common adverse reactions observed in Avastin patients at a rate > 10% and at least 
twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste 
alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative 
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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 ociperlimab and tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered.  Specifically, 
patients who are at risk for treatment-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 viral vaccine ≤ 28 days 
before randomization are excluded from the study.  
Refer to Section 4.2 for the full list of exclusion criteria.  
8.2.2. 
Safety Monitoring Plan 
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0.  Patients will be assessed for safety (including laboratory 
values) according to the schedule in Appendix 1.  
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, recording of AEs (see Table 5), physical examinations, laboratory measurements 
(hematology, clinical chemistry, etc), 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 autoimmune conditions or infection. 
At the start of each cycle, study drug(s) will be administered only after clinical laboratory results 
have been reviewed.  Administration of study drugs will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (for additional information, see Section 5.2).  
Serum samples will be drawn for determination of ADAs to ociperlimab, tislelizumab, and 
BAT1706 in all randomized patients.  
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 study 
drugs, whether considered related to study drugs or not. 


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Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or an association with a significantly worse 
outcome 
• New conditions detected or diagnosed after study drug administration even though 
the condition might have been present before the start of the study 
• Signs, symptoms, or clinical sequelae of a suspected interaction 
• Signs, symptoms, or clinical sequelae of a suspected overdose of any of the study 
drugs 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) related to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all patient identifiers will be obscured 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 per 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 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care, activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous.  Severity is a measure of intensity 
(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 drugs and the 
occurrence of each AE or SAE using their best clinical judgement.  Alternative causes, such as 


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natural history of the underlying diseases, concomitant therapy, and other risk factors, and the 
temporal relationship of the AE or SAE to the study drugs should be considered and investigated.  
The investigator should consult the, Ociperlimab Investigator’s Brochure, Tislelizumab 
Investigator’s Brochure, and BAT1706 Investigator’s Brochure in the determination of his/her 
assessment. 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor.  However, it is very important that the 
investigator always assesses causality for every SAE before transmission of the SAE report to 
the sponsor because the causality assessment is one of the criteria used when determining 
regulatory reporting requirements.  The investigator may change his/her opinion of causality 
after considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drugs (ie, there are facts, evidence, or arguments to suggest 
possible causation).  A number of factors should be considered in making this assessment 
including: 
• Temporal relationship of the AE to the administration of study drug(s)/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drugs 
• Biological plausibility 
An AE should be considered “related” to study drugs if any of the following are met; otherwise, 
the event should be assessed as “not related” if: 
• 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[s]).  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 up with each 
patient and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed up 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 


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investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs.  This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and that worsen significantly during the study.  The definition of clinically significant 
is based on the judgement of the investigator.  In general, these are the laboratory test 
abnormalities or other abnormal assessments that:  
• 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 5x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF.  
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 changes.  The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 


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8.4. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE.  It does not refer to an AE 
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 ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere 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 based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the study drug’s reference safety information [RSI]) and 
meets the definition of an serious adverse drug reaction (SADR), the specificity or severity of 
which is not consistent with those noted in the Ociperlimab Investigator’s Brochure, 
Tislelizumab Investigator’s Brochure, and BAT1706 Investigator’s Brochure. 


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8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.6.1. 
Adverse Event Reporting Period 
After the ICF has been signed, but before the administration of the study drugs, only SAEs 
should be reported to the sponsor. 
After initiation of study drugs, all AEs and SAEs, regardless of relationship to study drugs, will 
be reported until either 30 days after last dose of study drugs or initiation of subsequent 
anticancer therapy, whichever occurs first.  Serious or nonserious imAEs should be reported until 
90 days after the last dose of study drugs, regardless of whether the patient starts a subsequent 
anticancer therapy.  All 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.  
AEs and SAEs should be recorded as described in Table 5.  For the follow-up period for AEs, 
see Section 8.3.4.  For the definition of TEAEs, see Section 9.3.2. 
Table 5:  
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Arms 
Event type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEsa 
Signing of informed 
consent 
Up to 30 days after last dose, initiation of a 
new anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Nonserious AEs due to PD 
Do not record (see Section 8.6.4) 
All nonserious AEs, 
except those due to PD 
First dose of study drug 
Up to 30 days after last dose, initiation of a 
new anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study drug 
Up to 90 days after last dose (regardless of 
initiation of new anticancer therapy), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
a All 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. 
8.6.2. 
Reporting Serious Adverse Events 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 6. 


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Table 6: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Time frame for 
making initial/follow-
up reporta 
Documentation method 
Reporting method 
All SAEs 
Within 24 hours after 
first knowledge of the 
SAE 
SAE report 
Electronic submission of 
SAE Form to safety 
portalb 
Abbreviations: AE, adverse events; EDC, electronic data capture; SAE, serious adverse event. 
a Report follow-up information that is clinically relevant and pertaining 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, 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 EDC.  If the 
electronic submission is not available for any reason, a paper SAE form should be submitted by email or fax. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours, as outlined above in Section 8.6.2.1.  The SAE report 
should always be completed as thoroughly as possible, including all available details of the 
event, and forwarded to the sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form.  The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1.  The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a drug under 
clinical investigation. 
The investigator, or other responsible person according to local requirements will comply with 
the applicable local regulatory requirements related to the reporting of SAEs to regulatory 
authorities and the IRB/IEC. 
All SUSARs (as defined in Section 8.5) will be submitted to all applicable regulatory authorities 
and investigators for ociperlimab and tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC.  The investigator should place copies 
of safety reports from the sponsor in the investigator site file. 


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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. 
Disease Progression 
PD, which is expected in this study population and measured as an efficacy endpoint, should not 
be recorded as an AE term.  Similarly, nonserious AEs that are clearly consistent with the pattern 
of progression of the underlying disease and are considered unequivocally due to PD should not 
be recorded.  However, if there is any uncertainty as to whether a nonserious AE is due to PD, it 
should be recorded as an AE.  All SAEs and deaths regardless of relatedness to PD should be 
recorded and reported (see Section 8.6.2).  
8.6.5. 
Deaths 
Death is an outcome and not usually considered an AE.  If the only information available is death 
and the cause of death is unknown, then the death is reported as an event (eg, “death,” “death of 
unknown cause,” or “death unexplained”). 
8.6.6. 
Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving study drugs 
or within 120 days after the last dose of study drugs, a pregnancy report form must be completed 
and expeditiously submitted to the sponsor to facilitate outcome follow-up.  Information on the 
status of the mother and child will be forwarded to the sponsor.  Generally, follow-up will be no 
longer than 6 to 8 weeks after the estimated delivery date.  Any premature termination of the 
pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should always be reported as an 
SAE.  Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drugs should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 


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To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information documents:  
• Ociperlimab Investigator’s Brochure 
• Tislelizumab Investigator’s Brochure 
• BAT1706 Investigator’s Brochure 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events 
Because treatment with anti-PD-1 or immune checkpoint inhibitors can cause autoimmune 
disorders, AEs considered by the investigator to be immune-mediated (see Section 8.7.3) should 
be classified as imAEs and identified as such on the eCRF AE page until Day 90 after treatment 
discontinuation.  
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
that are commonly seen with immune checkpoint inhibitors, in Appendix 6. 
An extensive list of potential imAEs appears in Section 8.7.3, Table 8.  All conditions like those 
listed should be evaluated to determine whether they are imAEs based on a similar diagnostic 
process to those reactions that are presented in more detail in Appendix 6. 
8.6.9. 
Recording Infusion-Related Reactions 
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension.  Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.  Each 
individual sign and symptom of an infusion reaction should be recorded each as a separate AE in 
the eCRF and identified as an infusion-related reaction.  
Refer to the eCRF completion guidelines for details. 
8.7. 
Management of Adverse Events of Special Interest 
As a routine precaution, after infusion of the study drugs on Day 1 of Cycle 1, patients must be 
monitored for ≥ 120 minutes.  If the infusion completion time was shortened, patients must be 
monitored for ≥ 60 minutes on Day 1 Cycle 2, and from Cycle 3 onward, a ≥ 30‑minute 
monitoring period is required.  Regardless of the infusion completion time, patients must be 
monitored in an area with resuscitation equipment and emergency agents.  
The management guidelines for infusion-related reactions, severe hypersensitivity reactions, and 
imAEs according to the NCI-CTCAE criteria are outlined in the following subsections. 
8.7.1. 
Infusion-Related Reactions 
Patients should be closely monitored for infusion-related reactions.  Immediate access to an 
Intensive Care Unit or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) must be 
available to treat infusion-related reactions. 


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Treatment modifications for symptoms of infusion-related reactions due to study drugs is 
provided in Table 7. 
Table 7: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs 
NCI-CTCAE grade 
Treatment modification for study drugs  
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Any worsening is 
closely monitored.  Medical management as 
needed.   
Grade 2 - moderate 
Therapy or infusion interruption indicated but the 
patient responds promptly to symptomatic 
treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion.  Infusion may be resumed at 50% 
of previous rate after infusion-related reactions 
have resolved or decreased to Grade 1 in severity.  
Any worsening is closely monitored.  Proper 
medical management should be instituted as 
described in the text that follows this table.   
Grade 3 - severe 
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.  Proper medical 
management should be instituted as described in 
the text that follows this table. 
The patient should be withdrawn from the study 
drug(s) associated with the infusion-related 
reaction. 
Grade 4 - life-threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described in 
the text that follows this table. 
The patient should be withdrawn from the study 
drug(s) associated with the infusion-related 
reaction. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.  
(NCI-CTCAE) 
After the infusion rate has been decreased by 50% or suspended due to an infusion-related 
reaction, it must remain decreased for all subsequent infusions.  If the patient has a second 
infusion-related reaction (≥ Grade 2) on the slower infusion rate, the infusion should be 
discontinued and the patient should be withdrawn from the assigned study drugs.  
NCI-CTCAE Grade 1 or 2 infusion reactions: Proper medical management should be 
instituted, as indicated per the type of reaction.  This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and, if considered indicated, oral or intravenous glucocorticoids, epinephrine, bronchodilators, 
and oxygen.  In the next cycle, the patient should receive oral premedication with an 
antihistamine (eg, diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or 
equivalent), and the patient should be closely monitored for clinical signs and symptoms of an 
infusion reaction. 


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NCI-CTCAE Grade 3 or 4 infusion reactions: Proper medical management should be 
instituted immediately, as indicated per type and severity of the reaction.  This includes but is not 
limited to oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms 
If a hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) 
(Soar et al 2008).  Patients should be instructed to report any delayed reactions to the investigator 
immediately. 
If a systemic anaphylactic/anaphylactoid reaction occurs, the infusion must be stopped 
immediately and the patient discontinued from the study treatment.  Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes after the administration 
of the drug/antigen, are characterized by respiratory distress, laryngeal edema, and/or intense 
bronchospasm, and are often followed by vascular collapse or shock without antecedent 
respiratory difficulty; cutaneous manifestations such as pruritus and urticaria with/without 
edema; and gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, 
and diarrhea. 
Epinephrine injection and dexamethasone infusion will be administered to patients if a 
hypersensitivity reaction is observed, and then the patient should be placed on monitor 
immediately and an Intensive Care Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of a 
nonsteroidal anti-inflammatory drug (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion.  
Alternative treatments for fever (ie, paracetamol) may be administered to the patient at the 
discretion of the investigator. 
8.7.3. 
Immune-Mediated Adverse Events 
Immune-mediated AEs are of special interest in this study.  If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, PD, or other neoplastic causes) with appropriate diagnostic 
tests that may include but are not limited to serologic, immunologic, and histologic (biopsy) data.  
If alternative causes have been ruled out, the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy and is consistent with an immune-mediated 
mechanism of action, the imAE indicator on the eCRF AE page should be checked. 
A list of potential imAEs is shown below in Table 8.  All conditions similar to those listed 
should be evaluated in patients to determine whether they are immune-mediated. 
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017; Brahmer et al 2018) and common immune-mediated toxicities are 
detailed in Appendix 6. For any AEs not included in Appendix 6, refer to the ASCO Clinical 


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Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation and 
management of immune-mediated toxicities. 
Table 8: 
Immune-Mediated Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase 
(ALT/AST) elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism (eg, fatigue, weakness, weight gain); insulin-dependent 
diabetes mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis; myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Neurologic 
encephalitis, meningitis, meningoradiculitis, meningoencephalitis 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 6. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drugs should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
8.7.4. 
Adverse Events of Special Interest Related to BAT1706 
Adverse events of special interest for BAT1706 are as follows: 
• Grade ≥ 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
• Severe cutaneous reactions (eg, Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
• Grade ≥ 3 hypertension 
• Grade ≥ 3 proteinuria 
• Any grade GI perforation, abscesses, or GI fistulae 


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• Grade ≥ 2 non-GI fistula or abscess 
• Tracheoesophageal fistula 
• Grade ≥ 3 wound-healing complication 
• Hemorrhage 
− Any grade CNS bleeding 
− Grade ≥ 2 hemoptysis 
− Other Grade ≥ 3 hemorrhagic event 
• Any arterial thromboembolic event 
• Grade ≥ 3 venous thromboembolic event 
• Any grade posterior reversible encephalopathy syndrome 
• Grade ≥ 3 congestive heart failure. 
For diagnosis and management of patients with AEs related to BAT1706, please refer to 
Appendix 7. 
8.7.5. 
Hepatic Function Abnormalities 
Patients with advanced HCC generally have underlying cirrhosis with decreased hepatic 
function.  Special attention is needed because they may also have a concomitant chronic viral 
infection.  Therefore, when a hepatic event, such as liver function laboratory abnormalities, is 
observed, the investigator must evaluate for re-activation of viral hepatitis, consider other drug-
related toxicities, and exclude PD involving the liver.  For diagnosis and management of patients 
with AST or ALT values ≤ Grade 1 at baseline, please see Section 8.7.3 and refer to Appendix 6.  
In patients with Grade 2 AST/ALT abnormalities at baseline, therapeutic interventions with a 
steroid treatment may be required with rising AST and ALT laboratory abnormalities while 
considering the total bilirubin (TBil) changes, when the AST or ALT elevation is suspected with 
immune-mediated nature.  The following algorithm is proposed for the use of steroid treatment 
and actions with immune checkpoint inhibitors: 
• If AST or ALT increases but is still within Grade 2, continue the study treatment and 
monitor AST/ALT within 1-2 weeks.  In case total bilirubin > 1.5x ULN, the 
monitoring should be more frequent. 
• If AST or ALT increases to 5-8x ULN and TBil ≤ 3x ULN, temporarily hold the 
immune checkpoint inhibitors and monitor AST/ALT within 1 week.  In case of TBil 
>1.5xULN, the monitoring should be more frequent.  If AST/ALT improves, 
continue, or resume the immune checkpoint inhibitors.  If AST/ALT doesn’t improve, 
initiate oral prednisone at 0.2-0.5 mg/kg/day or equivalent.  If AST/ALT improves, 
taper the corticosteroid over 4 weeks and resume the immune checkpoint inhibitors 
when AST/ALT elevation returns to Grade 1 or baseline.  Otherwise, it should be 
managed as AST or ALT with 8-20x ULN.  Note: in case of TBil > 3x ULN, consider 
permanent discontinuation of immune checkpoint inhibitors. 


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• If AST or ALT increases to 8-20 x ULN, initiate prednisone immediately at 0.5-1 
mg/kg/day via oral or intravenous route depending on general condition, presence of 
liver decompensation and expected patient compliance.  If no further improvement 
within 4-7 days is observed, consider prednisolone pulses or mycophenolate mofetil.  
Monitor every 2-3 days, particularly if TBil is > 1.5x ULN.  If AST/ALT improves, 
taper the corticosteroid over 4 weeks and resume the immune checkpoint inhibitors 
when AST/ALT returns to Grade 1 or baseline, after discussion with the medical 
monitor.  In case of TBil > 2x ULN, AST/ALT > 10x ULN for > 2 weeks or 
AST/ALT > 15x ULN, consider permanent discontinuation of immune checkpoint 
inhibitors. 
• If any ALT or AST increases meet Grade 4 criteria, initiate steroid or 
immunosuppressant therapy promptly per Appendix 6.  Study drug(s) will be 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released.  Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan (SAP).  
9.1. 
Statistical Analysis 
The following descriptive statistics will be used to summarize the trial data on the basis of 
their nature unless otherwise specified: 
• Continuous variables: number of non-missing observations, mean, standard deviation, 
median, minimum, and maximum  
• Categorical variables: frequencies and percentages 
• Time-to-event variables: number of non-missing observations (N), median, minimum, 
and maximum.  Kaplan-Meier event-free rates may also be provided if applicable for 
specific time-to-event variables 
9.1.1. 
Analysis Sets 
The Safety Analysis Set (SAS) includes all patients who received ≥ 1 dose of study drugs, and 
will be the primary analysis set for the safety analyses. 
The Intent-to-Treat (ITT) Analysis Set includes all randomized patients.  Patients will be 
analyzed according to their randomized treatment arm (ie, Arm A or Arm B).  This will be the 
primary analysis set for all efficacy analyses. 
The Efficacy Evaluable Analysis Set (EAS) includes all patients in the ITT Analysis Set without 
critical protocol deviations who had measurable disease at baseline and ≥ 1 evaluable 
postbaseline tumor response assessment unless discontinued due to any clinical PD or death 
within 7 weeks after the first dose date.  This analysis set will be used for sensitivity analysis of 
the primary efficacy endpoint ORR. 
The DLT Evaluable Analysis Set includes patients enrolled during the safety run-in period who  
• received ≥ 80% of scheduled ociperlimab (if applicable), ≥ 80% of scheduled 
tislelizumab, and ≥ 80% of scheduled BAT1706 administration during the DLT 
assessment window (ie, within 21 days of the first dose of study drugs), remained on 
study during  the DLT observation period, and had sufficient safety evaluation 
performed. 
OR 
• experienced a DLT within the DLT observation period.  
The PK Analysis Set includes all patients who receive ≥ 1 dose of any component of study drugs 
per the protocol, and for whom any postdose PK data are available.  
The Immunogenicity Analysis Set includes all patients who receive ≥ 1 dose of any component 
of study drugs and for whom both baseline ADA and ≥1 postbaseline ADA result are available. 


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9.1.2. 
Patient Disposition 
The number of patients randomized, treated, and discontinued from study drugs and/or study and 
those with critical protocol deviations will be counted.  The primary reason for study drug and/or 
study discontinuation will be summarized according to the categories in the eCRF.  The 
end‑of‑study status (alive, dead, withdrew consent or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF. 
Critical protocol deviations will be summarized and listed by each category. 
9.1.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the ITT Analysis Set.  
Continuous variables include age, weight, vital signs, time since initial cancer diagnosis, time 
since advanced/metastatic disease diagnosis, etc.  
Categorical variables include gender, ECOG PS, geographical region, country, race, histological 
subtype, disease stage, metastatic site, tobacco use, etc.  
9.1.4. 
Prior and Concomitant Medications 
Prior medications will be defined as medications that stopped before randomization.  
Concomitant medications will be defined as medications that 1) started before randomization and 
were continuing at the time of randomization, or 2) started on or after the date of randomization 
up to 30 days after the patient’s last dose (as of the on-site Safety Follow-up Visit).   
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
drug codes and further coded to the appropriate Anatomical Therapeutic Chemical code 
indicating therapeutic classification.  Prior and concomitant medications will be summarized and 
listed by drug and drug class in the Clinical Study Report (CSR) for this protocol.   
9.2. 
Efficacy Analyses 
9.2.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is ORR as determined by investigator based on RECIST v1.1, in 
Arm A and Arm B.  
ORR is defined as the proportion of patients achieving confirmed BOR of CR or PR. BORs is 
defined as the best response recorded from the first dose of study drug until data cutoff or the 
initiation of new anticancer treatment, whichever occurs earlier.  Patients with no postbaseline 
response assessment (due to any reason) will be considered as nonresponders for BOR.  The 
proportion of patients in each response category will be presented. 
ORR will be summarized in the ITT Analysis Set with a Clopper-Pearson 95% CI constructed to 
assess the precision of the point estimate.  
The primary efficacy analysis will be conducted when ORR data are mature, which is 7.5 months 
(approximately 5 tumor assessments) after the last patient receives the first dose of study drug 
and will be based on the ITT Analysis Set.  


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The sensitivity analysis of ORR will be carried out in the Efficacy Evaluable Analysis Set. 
9.2.2. 
Secondary Efficacy Analysis  
Other efficacy endpoints with necessary tumor assessments (ie, DOR, PFS, TTR, DCR and CBR), 
as well as OS, will be summarized for the secondary efficacy analysis.  The secondary efficacy 
analysis will be conducted in the ITT Analysis Set assessed by investigator (if applicable) in 
Arm A and Arm B.  
Disease Control Rate (DCR) 
The DCR is defined as the proportion of patients who achieve CR, PR, or stable disease.  
The DCR will be summarized similarly as ORR in the ITT Analysis Set and also in Efficacy 
Evaluable Analysis Set for sensitivity analysis. 
Clinical Benefit Rate (CBR) 
The CBR is defined as the proportion of patients who achieve CR, PR, or durable stable disease 
(stable disease ≥ 24 weeks). 
The CBR will be summarized similarly as ORR in the ITT Analysis Set and also in the Efficacy 
Evaluable Analysis Set for sensitivity analysis.   
Duration of Response (DOR) 
The DOR is defined as the time from the first confirmed objective response to disease 
progression documented after treatment initiation or death, whichever occurs first.  
The DOR will be analyzed among the responders in the ITT Analysis Set.  The median and other 
quartiles of DOR will be estimated using the Kaplan-Meier method.  The 2-sided 95% CIs will 
be constructed with the generalized Brookmeyer and Crowley method (Brookmeyer and 
Crowley 1982).  Event-free rates at selected timepoints for DOR will be estimated using the 
Kaplan-Meier method with the corresponding 95% CI constructed using Greenwood’s formula 
(Greenwood 1926).  The DOR censoring rule will follow the US Food and Drug Administration 
(FDA) Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (US FDA 2018).   
More details, including the censoring rules, will be provided in the SAP.  
Progression-Free Survival (PFS) 
The PFS is defined as the time from treatment initiation to disease progression or death due to 
any cause, whichever occurs first.  
The PFS will be analyzed in the ITT Analysis Set using methods similar to those described for 
the DOR.  The PFS censoring rule will follow the same as that followed for the DOR.  The PFS 
rates at 3 months, 6 months, 9 months, and 12 months will be calculated based on the Kaplan-
Meier method. 
Overall Survival (OS) 
The OS is defined as the time from treatment initiation to death due to any cause. 


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The OS will be analyzed in the ITT Analysis Set using similar methods to those described for the 
DOR, except for censoring rules.  For OS, patients will be censored either at the date that the 
patient was last known to be alive or the date of data cutoff, whichever comes earlier, in the 
absence of death.  The OS rates at 3 months, 6 months, 9 months, and 12 months will be 
calculated based on the Kaplan-Meier method. 
Time to Response (TTR) 
The TTR is defined as the time from treatment initiation to the first documented response.  
The TTR will be analyzed in the ITT Analysis Set using sample statistics such as mean, median, 
and standard deviation for patients who have achieved an objective response.  
Waterfall plots of maximum tumor shrinkage per patient will be presented.  
9.2.3. 
Subgroup Analysis  
Subgroup analysis on key efficacy endpoints (ORR, OS, etc.) will be conducted to explore the 
consistency of efficacy across a variety of subgroups, as appropriate.  Subgroup variables may 
include but are not limited to age, gender, ECOG PS, hepatitis viral status, BCLC stage at study 
entry, prior loco-regional therapy, baseline AFP level, MVI and/or EHS, and PD-L1 expression. 
9.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording of AEs and 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 v 5.0.  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 (SOC) and PT. 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 and by arm. 
9.3.1. 
Extent of Exposure 
Extent of exposure to a study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure, cumulative total dose 
received per patient (mg), dose intensity (mg/day) and relative dose intensity (%). 
The number (and percentage) of patients with a dose reduction, dose delay, treatment 
interruption, or study drug discontinuation will be summarized with the respective reasons. 
Patient data listings will be provided for all dosing.  
9.3.2. 
Adverse Events 
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified 
into standardized medical terminology using the MedDRA®.  AEs will be coded to the MedDRA 
lowest level term closest to the verbatim term, preferred term, and primary SOC. 


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DLTs will be summarized for the safety run-in period. 
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 last dose of study 
drug(s), or initiation of new anticancer therapy, whichever occurs first.  The TEAE classification 
also applies to imAEs that are recorded up to 90 days after the last dose of tislelizumab and 
ociperlimab, regardless of whether or not the patient starts a new anticancer therapy.  All SAEs 
considered related to the study drug(s) that are brought to the attention of the investigator should 
be reported regardless of the time since the last dose of study drug.  Only those AEs that were 
treatment-emergent will be included in summary tables.  All AEs, treatment-emergent or 
otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT A patient will be counted only once by the highest severity grade per NCI-CTCAE 
v 5.0 within a SOC and PT, even if the patient experienced > 1 TEAE within a specific SOC and 
PT.  
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug(s).  Treatment-related TEAEs include those events considered by the investigator to 
be related to study drug or with missing assessment of the causal relationship. 
All TEAEs, SAEs, deaths, ≥ Grade 3 TEAEs, imAEs, AEs of special interest  related to 
BAT1706 (see Section 8.7.4), treatment-related TEAEs, and TEAEs that led to treatment 
discontinuation and dose modification (interruption/delay/reduction, as appropriate) will be 
summarized.  
9.3.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, clinical chemistry, coagulation, 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 included in the CSR for this protocol.  Descriptive 
summary statistics (eg, n, mean, standard deviation, median, minimum, and 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 change. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 or higher will be summarized by 
NCI-CTCAE grade.  In the summary of laboratory parameters by NCI-CTCAE grade, 
parameters with NCI-CTCAE grading in both high and low directions (eg, calcium, glucose, 
magnesium, potassium, and sodium) will be summarized separately. 
9.3.4. 
Vital Signs 
Descriptive statistics for vital sign parameters (body temperature, pulse rate, respiratory rate, and 
blood pressure [systolic and diastolic]) and weight and their changes from baseline will be 
presented by visit.  
9.3.5. 
Physical examination  
Physical examination parameters will be listed by visit, as appropriate. 


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9.3.6. 
Electrocardiograms 
ECG will be performed at the baseline and multiple time points after the start of treatment.  
Clinically significant abnormalities on ECG findings will be presented in a frequency table by 
visit and arm as appropriate. 
9.3.7. 
Eastern Cooperative Oncology Group Performance Status 
A shift table from baseline to worst postbaseline in ECOG PS will be summarized by arm.  
ECOG PS scores will be summarized by visit and arm, as appropriate. 
9.3.8. 
Ophthalmologic examination 
Ophthalmologic examination results will be listed by patient, if necessary. 
9.4. 
Pharmacokinetic Analyses 
PK samples will be collected in this study as outlined in Appendix 1. 
The ociperlimab, tislelizumab, and BAT1706 serum concentration data will be tabulated and 
summarized by visit/cycle at which these concentrations are collected.  Descriptive statistics will 
include means, medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses, including population PK analyses and exposure-response analyses 
(efficacy or safety endpoints), may be conducted as appropriate and the results of such analyses 
may be reported separately from the CSR. 
9.5. 
Immunogenicity Analyses 
Samples to assess anti-ociperlimab, anti-BAT1706, and anti-tislelizumab antibodies will be 
collected only in patients who receive study drugs and at sites that are able to adequately perform 
sampling, handling, and processing as outlined in the laboratory manual. 
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 allows. 
9.6. 
Other Exploratory Analyses 
Summary statistics might be provided for exploratory biomarkers including expression of PD-L1 
and TIGIT pathway-related proteins (TIGIT, poliovirus receptor/PVR and nectin cell adhesion 
molecule 2/nectin-2), TMB/DNA mutation, bTMB/ctDNA monitoring/DNA mutation, AFP and 
GEP.  
The association of biomarkers with disease status, response/resistance to tislelizumab plus 
BAT1706 with or without ociperlimab will be explored, when appropriate. 


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9.7. 
Sample Size Consideration 
This study plans to enroll approximately 90 patients, with 2:1 randomization to 
− Arm A (60 patients): tislelizumab + BAT1706 + ociperlimab 
− Arm B (30 patients): tislelizumab + BAT1706  
These patients will be enrolled to evaluate the preliminary efficacy of tislelizumab plus 
BAT1706 with or without ociperlimab.  
No formal hypothesis testing is planned in the efficacy evaluation. 


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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Safety Monitoring Committee 
A SMC will be established and include both the sponsor (including the medical monitor and 
study team members from Pharmacovigilance/Drug Safety, Clinical Pharmacology, and 
Biostatistics with other members as appropriate) and investigators.  The SMC will review all 
available safety, PK, and exploratory data and make recommendations on dose modification, and 
dose selection to ensure that the study treatment is tolerable and that patients are adequately 
monitored.   
The SMC will evaluate the safety and tolerability of the 2 combination therapies and will review 
the safety data including, but not limited, to DLTs, all TEAEs, and laboratory abnormalities 
when all patients enrolled in the safety run-in stage have completed 21 days of treatment or when 
≥ 2 DLTs occur. 
The SMC will make recommendations on safety management (including resumption of 
enrollment, or de-escalation of BAT1706, or termination of enrollment, etc) and will assess 
whether it is suitable to expand the cohorts. 
The SMC may also be called upon by the sponsor on an ad hoc basis where applicable to the 
conduct of the study.  The details of SMC membership, responsibilities, and meeting schedule 
are outlined in a separate SMC Charter. 
10.2. 
Communication 
When the CSR is completed, the sponsor will provide the major findings of the study to the 
investigator. 
The sponsor will not routinely inform the investigator or patient of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will be undetermined at such an early stage of research. 


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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented.  Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals.  In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation 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 to representatives of a regulatory agency or the 
sponsor 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 either obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements or file the 
protocol to the appropriate regulatory agency before the study is initiated at a study center in that 
country. 
12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit.  Regulatory agencies may also conduct a regulatory inspection 
of this study.  Such audits/inspections can occur at any time during or after completion of the 
study.  If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines.  
Site audits may be 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 drugs.  This includes acknowledgment of receipt of each shipment 
of study drugs (quantity and condition), patient drug dispensation records, and returned or 
destroyed study drugs.  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 requirements of the sponsor 
specified in the Pharmacy Manual.  At appropriate timepoints during the conduct of the study or 
at the end of the study after the final drug inventory reconciliation by the medical 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 periodically reviewed and verified by the 
study monitor over the course of the study. 


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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will also comply with the 
requirements of the ICH E2A guideline (ICH E2A 1994). 
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/other information and 
the approved amended ICF/other information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC.  Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments.  In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC.  Investigators may receive written 
Investigational New Drug Safety Reports or other safety-related communications from the 
sponsor.  Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments 
Any protocol amendments will be prepared by the sponsor.  All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements.  Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the 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 be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study.  For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality 
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study.  This 
approach ensures that patients’ names are not included in any data set transmitted to any sponsor 
location. 
Patient medical information obtained during this study is confidential and may be disclosed to 
third parties only 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 the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principal investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable data privacy 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. 
Data generated during this study must be available for inspection upon request by representatives 
of the China National Medical Products Administration and all other national and local health 
authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  The investigator agrees that all information 
received from the sponsor, including but not limited to the Ociperlimab Investigator’s Brochure, 


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Tislelizumab Investigator’s Brochure, BAT1706  Investigator’s Brochure, this protocol, eCRFs, 
the information on the investigational new drugs, and any other study information, remain the 
sole and exclusive property of the sponsor during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor.  The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.  
If a written contract for the conduct of the study that includes confidentiality provisions 
inconsistent with this section is executed, that contract’s provisions shall apply to the extent they 
are inconsistent with this section. 
13.5. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of clinical investigators and/or disclose those financial 
interests, as required, to the appropriate health authorities.  This is intended to ensure that 
financial interests and arrangements of 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 is 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 electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The 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 prior 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 course of the study, a study monitor will make site visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the 
study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.  Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study.  Direct access to source data is also required for inspections 
and audits and will be carried out, giving due consideration to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA.  AEs will be coded to MedDRA by Lowest Level Term, PT, and primary SOC. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary.  
Concomitant diseases/medical history will be coded using MedDRA.  


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14.2. 
Data Integrity and In-house Blinding 
Due to the open-label design of the study, access to the unblinded patient level clinical data in 
the EDC system will only be assigned to predefined study personnel.  Functions/persons with 
access to the EDC system shall be prohibited from using the EDC system to generate 
unnecessary listings/summaries that may introduce unwanted bias, or share such outputs or the 
unblinded data from the EDC system with other functions/persons who do not have access to the 
EDC.  Although the study is open-label, analyses or summaries generated by treatment 
assignment and actual treatment received will be limited and documented. 
14.3. 
Study Records Retention 
The investigator must maintain adequate and accurate records so that the conduct of the study 
can be fully documented and the study data can be subsequently verified.  These documents 
should be classified into at least 1 of the following 2 categories: the investigator’s study file or 
the 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, but not be limited to, 
documents such as the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, pathology and 
special assessment reports, consultant letters, and screening and enrollment log, 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, 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 or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements including, 
but not limited to, the following: archival at an off-site facility or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 


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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 at a separate location so that they can be sealed and returned to 
the investigator in case of a regulatory audit.  When source documents are required for the 
continued care of the patient, appropriate copies should be made for storage outside of the site. 
At the conclusion of this study, biological samples may be retained as outlined in the agreement 
with the contract research organization managing the biological samples, for a period of up to 
10 years or as allowed by the 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 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.  In 
accordance with established IRB/IEC policies and procedures, the investigator must promptly 
report any important deviations that might impact patient safety and/or data integrity to the 
sponsor and to the IRB/IEC. 
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 ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3).  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.  For a multicenter study, the first publication or disclosure of 
study results shall be a complete, joint multicenter publication, or disclosure coordinated by the 
sponsor.  Thereafter, any secondary publications will reference the original publication(s).  
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors or stricter local 
criteria (International Committee of Medical Journal Editors 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 sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy.  Each investigator 
agrees that, in accordance with the terms of 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/provide all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drugs 
• 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 reasons.  
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 and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action.  If 
required by applicable regulations, the investigator must inform the 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 all unused study drugs in accordance with the applicable 
sponsor procedures for the study. 
Financial compensation to investigators and/or institutions will be made 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, expertise, 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: 
• 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, which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 


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15. 
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16. 
APPENDICES 
 






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Abbreviations: ADA, anti-drug antibodies; AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle isoenzyme; CT, 
computed tomography; EC, Ethics Committee; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EGD, 
esophagogastroduodenoscopy; EOT, end-of-treatment; FT3, free triiodothyronine; FT4, free thyroxine; HBcAb, hepatitis B core antibody; HBsAg, 
hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAb, hepatitis B surface antibody; imAE, immune-mediated 
adverse event; IRB, institutional review board; IRT, interactive response technology; MRI, magnetic resonance imaging; NCI-CTCAE, National 
Cancer Institute Common Terminology Criteria for Adverse Events; PD, progressive disease; PET, positron emission tomography; PK, 
pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; TSH, thyroid stimulating hormone; v, 
version. 
 
a Written informed consent is required before performing any study-specific tests or procedures.  Results of standard-of-care tests or examinations 
performed before obtaining informed consent and within 28 days of randomization may be used for Screening assessments rather than repeating 
such tests. 
b The EOT Visit is conducted when the investigator determines that one or more of the study drugs, ie, ociperlimab and tislelizumab in Arm A, 
tislelizumab in Arm B, or BAT1706 in both arms will no longer be used.  Optical coherence tomography, visual acuity test, CK and CK-MB, and 
thyroid function assessments are not required at the EOT Visit for BAT1706.  If routine laboratory tests (eg, hematology, serum chemistry) were 
completed within 7 days before the EOT Visit, the tests do not need to be repeated.  Tumor assessment is required at the EOT Visit if the 
investigator determines that the study drug(s) must be discontinued.  However, the tumor assessment may be omitted at the EOT visit provided 
that ≤ 6 weeks have passed since the last assessment.  Patients who discontinue all study drugs prior to disease progression will need to undergo 
tumor assessment. 
Patients who permanently discontinue tislelizumab and ociperlimab in Arm A, or tislelizumab in Arm B, will be asked to return to the clinic for 
the Safety Follow-up Visit, which is required to be conducted 30 (± 7) days after the last dose of the specific study drug(s), unless otherwise 
specified, or before the initiation of subsequent anticancer therapy, whichever occurs first.  
If the decision to end treatment is taken ≥ 23 days after the last dose of ociperlimab/tislelizumab in Arm A, or tislelizumab in Arm B, the EOT 
and the Safety follow-up visits should be conducted concurrently within 7 days of the end of treatment decision.  
Patients who discontinue ociperlimab/tislelizumab in Arm A or tislelizumab in Arm B will be asked to return to the clinic or will be contacted 
via telephone to assess imAEs and concomitant medications (if appropriate, ie, associated with an imAE) at 60 and 90 (± 14) days after the last 
dose of ociperlimab or tislelizumab, whichever is later, regardless of whether they started a subsequent anticancer therapy.  If patients report a 
suspected imAE at a follow-up visit or a telephone contact, the investigator should arrange an unscheduled visit if further assessment is 
indicated. 
c Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(± 14 days) after the Safety Follow-up Visit or as directed by the sponsor until death, loss to follow-up, withdrawal of consent, or study 
termination by the sponsor.  All patients will be followed up for survival and subsequent anticancer therapy information unless a patient requests 
to be withdrawn from follow-up. 


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d Patients will be randomized into either the ociperlimab + tislelizumab + BAT1706 arm (Arm A) or tislelizumab + BAT1706 arms (Arm B) via 
IRT.  All patients are required to receive the study drug(s) within 2 business days of randomization. 
e Includes age or date of birth, gender, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior medication, 
loco-regional treatment(s), and surgical treatment(s).  Information on radiographic studies performed prior to study entry may be collected for 
review by the investigator.  Pre-existing AEs at baseline should be recorded as medical history. 
 f Vital signs collected on study include temperature, pulse rate, respiratory rate and blood pressure (systolic and diastolic) while the patient is in a 
seated position after resting for 10 minutes.  The patient's vital signs should be examined up to 60 minutes before all study drug infusions.  For 
patients treated with BAT1706, vital signs will be measured at the end of BAT1706 infusion and 2 (± 1) hours after end of the infusion and 
during the study if clinically indicated. 
The dose of BAT1706 will be based on the baseline weight, defined as the weight of the patient (in kilograms) measured ≤ 14 days before the 
initiation of study drug, and will remain the same throughout the study unless there is a weight change of > 10%. If re-assessment of baseline 
weight is needed the latest baseline weight should always be used to calculate percent change in weight for all subsequent doses. 
 g A complete physical examination is required at Screening while subsequent visits entail limited, symptom-directed physical examinations.  
Investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during 
tislelizumab treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
h All patients must undergo an EGD and all size of varices (small to large) must be assessed and treated per local standard of care prior to 
enrollment. 
i The ECG recordings will be obtained during Screening, the EOT/Safety Follow-up visits, and as clinically indicated at other time points.  
Patients should be resting in a semi-recumbent supine position for ≥ 10 minutes prior to each ECG collection. 
j Eye exam, including visual acuity test and optical coherence tomography (or equivalent diagnostic test), will be assessed by an appropriate 
specialist at the Screening Visit.  Patients will undergo repeat assessments by an ophthalmologist approximately every 15 weeks (± 7 days) 
during study treatment and a final assessment during the  EOT Visit for ociperlimab and/or tislelizumab. 
k The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0.  All AEs will also be evaluated for seriousness.  After the informed 
consent form has been signed, but prior to the first administration of study drug, only SAEs should be recorded.  After initiation of study drug, all 
AEs and SAEs, regardless of relationship to study drug, will be reported until either 30 days after last dose of study drug(s) or initiation of new 
anticancer therapy, whichever occurs first.  The imAEs (serious or non-serious) should be reported until 90 days after the last dose of study 
drugs, regardless of whether the patient starts a new anticancer therapy.  All 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. 
l Review of AEs and concomitant medications may be conducted by telephone on Days 8 and 15. 
m Local laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will be 
collected.  If laboratory tests at Screening are not performed within 7 days of randomization, these tests should be repeated and reviewed before 
randomization.  Hematology and serum chemistry (including liver function tests) will be performed weekly for the first 3 cycles and then at the 


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beginning of each subsequent cycle.  After Cycle 1, the tests are to be performed and the results are to be reviewed within 48 hours before study 
drug administration.  Proteinuria must be < 2+ within 7 days of randomization.  Patients that have ≥ 2+ proteinuria on urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours.  Urinalysis is to be conducted for predose 
assessment at the beginning of each cycle.  
n All patients will have CK and CK-MB testing at Screening, and repeated at all scheduled visits during the first 3 treatment cycles, all predose 
assessments from Cycle 4 onwards, and at the EOT and Safety Follow-up visits.  If CK-MB fractionation is not available, troponin I and/or 
troponin T may be tested instead.  
o Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented with a negative result within 7 days of randomization.  Urine pregnancy tests will be performed at each visit prior to dosing, and at 
the EOT/Safety Follow-up visit.  A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
p Analysis of FT3, FT4, and TSH will be performed by a central laboratory or the local study site laboratory.  Thyroid function tests will be 
performed at Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, et cetera), and at the EOT/Safety Follow-up Visit. 
q Testing will be performed by a central laboratory and/or the local laboratory at Screening and will include HBV/HCV serology (HBsAg, HBsAb, 
HBcAb, and HCV antibody) and viral load assessment (HBV DNA and HCV RNA), which will be performed only when HBsAg or HCV 
antibody is positive, respectively.  Patients who have detectable HBV DNA or HCV RNA at Screening will undergo the respective viral load test 
every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc).  Blood samples will be collected on Day 1 of Cycle 1 before dosing of study drug, and stored 
and may be analyzed if patients develop hepatic AEs. 
r Patients who are suspected of having or known to have serious and/or severe respiratory conditions, exhibit significant respiratory symptoms 
unrelated to the underlying cancer, or have with a history of thoracic radiotherapy will undergo pulmonary function testing which may include, 
but is not limited to, spirometry and assessment of diffusion capacity done during the Screening period to assist the determination of suitability 
for the study. 
s Procedures for collection of PK samples are described in the Laboratory Manual.  Predose (within 60 minutes before starting infusion) samples 
are required to be collected on Day 1 of Cycles 1, 2, 5, 9 and 17.  A postdose (within 30 minutes after completing infusion) sample is required to 
be collected on Day 1 of Cycles 1 and 5.  For ociperlimab/tislelizumab, an additional PK sample is required to be collected at the Safety Follow- 
up Visit.  For BAT1706, an additional PK sample is required to be collected at the EOT Visit.  Should a patient present with any ≥ Grade 3 
imAE, an additional blood PK sample may be taken to determine the serum concentration of tislelizumab/ociperlimab/BAT1706.  These tests are 
required when allowed by local regulations/IRBs/ECs.  
t Blood samples used to test for ADAs should be collected within 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 5, 9, and 17;  
ADAs for ociperlimab/tislelizumab are required to be tested at the Safety Follow-up Visit.  For BAT1706, an additional ADA sample is required 
to be collected at the EOT Visit.  All samples should be drawn at the same time as blood collection for predose PK analysis.  These tests are 
required when allowed by local regulations/IRBs/ECs. 


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u Blood samples will be collected for all patients at baseline (predose on Cycle 1 Day 1, required), at the time of first tumor response (predose on 
Day 1 of the following cycle, optional), and at the time of PD (optional) [approximately 10 mL for each timepoint].  In addition, local laboratory 
assessment of alpha-fetoprotein is required at baseline (predose on Cycle 1 Day 1).  Written patient consent is required for blood sample 
collections. 
v Radiological images captured as standard-of-care before obtaining written informed consent and ≤ 28 days before randomization may be used 
rather than repeating tests.  All measurable and evaluable lesions are required to 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 imaging protocol for CT or MRI).  Bone scan or PET is required if clinically indicated.  During the study, 
tumor imaging will be performed every 6 weeks (± 7 days), from Day 1 of Cycle 1, for the first 48 weeks, and every 12 weeks (± 7 days) 
thereafter based on RECIST v1.1.   
Tumor assessments are required to be performed on schedule regardless of whether study drug(s) have been administered or held.  That is, they 
should not be adjusted for possible delays in cycles.  Tumor assessment should continue until study drug discontinuation.  Patients who 
discontinue study drugs early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments following the 
original plan until the patient begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to follow-up, 
or dies, or until the study terminates, whichever occurs first.  
w Archival tumor tissues (if available) must be sent to the central laboratory for PD-L1 detection during the screening period and for retrospective 
analysis of exploratory biomarkers.  If archival tumor tissues are not available during the screening period, a fresh tumor biopsy is mandatory.  
Optional fresh biopsies in patients who have confirmed PD will be collected during the study from accessible tumor sites.  Written patient 
consent is required for fresh tumor biopsies. 
For fresh biopsy, acceptable samples include core needle biopsies for nonsuperficial tumor tissue or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions.  Tumor tissue should be of good quality based on total and viable tumor content.  Fine-
needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. 
x Tislelizumab will be given intravenously on Day 1 of each 21-day cycle (once every 3 weeks).  Note: Tislelizumab must not be concurrently 
infused with any other drug.  
y For patients randomized to Arm A, ociperlimab will be given intravenously on Day 1 of each 21-day cycle (once every 3 weeks).  Note: 
Ociperlimab must always be prepared and administered separately from any other systemic medication including tislelizumab and BAT1706.  
Ociperlimab infusion must always occur after infusion of tislelizumab has been completed.  
z BAT1706 will be given intravenously on Day 1 of each 21-day cycle (once every 3 weeks).  


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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Hematocrit 
Prothrombin time 
pH 
ALT 
Hemoglobin 
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
Specific gravity 
AST 
Platelet counts 
International 
normalized ratio 
Glucose 
Albumin 
White blood cell count  
 
Protein 
Total bilirubin 
Neutrophil count 
 
Ketones 
Direct bilirubin 
Lymphocyte count 
 
Blood 
Blood urea nitrogen or 
urea 
 
 
24-hour proteina 
Potassium 
 
 
 
Sodium 
 
 
 
Calcium 
 
 
 
Phosphorus 
 
 
 
Magnesium  
 
 
 
Chloride 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Creatine kinase/CK-MB b  
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK-MB, creatine 
kinase-muscle/brain. 
a On routine urinalysis, if urine protein is ≥ 2+ then obtain a 24-hour urine sample for total protein or a random 
urine sample for total protein and creatinine to determine a protein-to-creatinine ratio. 
b Cardiac enzyme testing has been added to monitor for potential event of immune-mediated myocarditis.  If 
CK-MB fractionation is not available, assess troponin I and/or troponin T instead.  Investigators should make 
every effort to perform either CK-MB, troponin I and/or troponin T consistently at screening and at follow-up 
visits. 
 


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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, 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 4. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal). 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation: 
− oral 
− injectable 
− implantable  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study drug(s)). 
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patient’s usual and preferred lifestyle. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods), 
declaration of abstinence for the duration of exposure to study drugs, and withdrawal are 
not acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with another acceptable method listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 


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• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL 
Adapted from: Recommendations related to contraception and pregnancy testing in clinical trials 


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APPENDIX 5. 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 6. 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. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, PD, and adverse 
effects of concomitant drugs.  In addition to the results of these tests, the following factors 
should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of study drugs and the AE? 
• How did the patient respond to withdrawal of study drugs? 
• Did the event recur when study drugs was/were reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is PD 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 should be checked. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse Events 
Immune-Mediated Toxicity 
Diagnostic Evaluation Guideline 
Thyroid disorders 
Scheduled and repeat thyroid function tests (TSH and T4).   
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss, and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, 
such as an upper respiratory infection, new cough, shortness of breath or hypoxia 
should be assessed by high-resolution CT.  Consider pulmonary function test 
including DLCO. 
Radiographic appearance is often nonspecific.  Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered.  Consult with a respiratory medicine physician for cases of uncertain 
cause.   
Neurological toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications.  Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology.  Consider the need for brain/spine MRI/MRA and nerve conduction 
study for peripheral neuropathy.  Consult with a neurologist if there are abnormal 
findings. 


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Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse Events 
Immune-Mediated Toxicity 
Diagnostic Evaluation Guideline 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, 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 ≥ 3-4; every 2-3 days if Grade 2, until recovering).  
Review medications (eg, statins, antibiotics) and alcohol history.  Perform liver 
screen including hepatitis A/B/C serology, hepatitis E PCR and assess anti-
ANA/SMA/LKM/SLA/LP/LCI, iron studies.  Consider imaging (eg, ultrasound 
scan for metastases or thromboembolism).  Consult with a hepatologist and 
consider liver biopsy.   
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  
Consider renal ultrasound scan, protein assessment (dipstick/24-hour urine 
collection), or phase-contrast microscopy.  Refer to nephrology for further 
management assistance.   
Dermatology 
Consider other causes by conducting a physical examination; consider 
dermatology referral for skin biopsy. 
Joint or muscle inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin I and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, troponin I, and refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CNS, central nervous system; CRP, C-reactive protein; CT, computed 
tomography; DLCO, diffusing capacity for carbon monoxide; ECG, electrocardiogram; ESR, erythrocyte 
sedimentation rate; FBC, full blood count; 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. 
Treatment of Immune-mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study drug(s) interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention, as appropriate, 
with patients is required 


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• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drugs may be 
considered if there is evidence of a clinical response to study drug(s) after 
consultation with the medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks.  Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 
0.5 μg/kg/day).  Add oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Thyrotoxic patients 
require treatment with a beta blocker 
and may require carbimazole until 
thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  Initiate 
pulse IV methylprednisolone 1 mg/kg 
for patients with headache/visual 
disturbance due to pituitary 
inflammation.  Convert to oral 
prednisolone and taper over at least 
1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days. 
If appearance worsens, treat as 
Grade 2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over ≥ 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 
2 months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, 
vitamin D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-
1 mg/kg/day.  Taper over at least 
4 weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/diarrhea 
1 
Mild symptoms: < 3 liquid 
stools per day over 
baseline and feeling well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-
6 liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids over 
2-4 weeks, consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate IV methylprednisolone 1-
2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose monitoring, 
vitamin D/calcium supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg; if no perforation, 
sepsis, TB, hepatitis, NYHA 
Grade III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10%-30% of 
BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch.  Consider a 
short course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with substantial 
symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 
3 days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and taper 
over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment) 
Initiate IV methylprednisolone 1-
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3X 
ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours: 
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-
1 mg/kg/day for 3 days then taper 
over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.   
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤ 10 mg. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
ALT or AST 5-20X ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day.  When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 
4 weeks.   
Hold study treatment 
until improved to 
baseline grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X ULN 
Initiate IV methylprednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over ≥ 
6 weeks.   
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
If on oral prednisolone, change to pulsed IV methylprednisolone 
If on IV, add MMF 500-1000 mg twice a day 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection.  Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-
72 hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy.  If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg.  
Taper corticosteroids over at least 
4 weeks. 
Hold study treatment 
until the cause is 
investigated. 
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Diabetes/ 
hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; ULN 
to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 160-
250 mg/dL; 8.9-
13.9 mmol/L 
Obtain a repeat blood glucose level at 
least every week.  Manage according 
to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 250-
500 mg/dL; 13.9-27.8 
mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose value 
> 500 mg/dL; 
> 27.8 mmol/L 
Admit patient to hospital and institute 
local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior 
uveitis/panuveitis or 
significant symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
4 
Blindness (at least 20/200) 
in the affected eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.   
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.   
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental (fine 
motor) activities 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments, and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food 
and fluid intake, daily 
living activity limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency care.  
Consider IV corticosteroids if not 
contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2.   
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
3-4 
Severe weakness, limiting 
self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 1-
2 mg/kg/day maintenance for severe 
activity restriction or dysphagia.  If 
symptoms do not improve add 
immunosuppressant therapy.  Taper 
oral steroids over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1.  
Discontinue if any 
evidence of myocardial 
involvement. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant intraventricular 
conduction delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac symptoms or 
any increase in cardiac serum 
markers to the coronary care unit. 
Initiate oral prednisolone or IV 
(methyl)prednisolone at 1-
2 mg/kg/day.  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. 
Hold study treatment 
until completely 
resolved or myocarditis 
has been ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
has been excluded and 
symptoms have 
completely resolved. 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CK, creatine kinase; CK-MB, creatine kinase-muscle-brain; CHF, congestive heart failure; 
INR, international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; 
NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; 
TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 


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APPENDIX 7. MANAGEMENT GUIDELINES FOR ADVERSE EVENTS 
RELATED TO BAT1706 
The management guidelines for adverse events related to BAT1706 are listed in the table below.  
For cases which is not covered in the management guideline below or in BAT1706 Investigator's 
Brochures, patients should be managed as deemed appropriate by the investigator according to 
investigators' best medical judgment.  
If corticosteroids are used for treating adverse events related to BAT1706, they must be tapered 
to ≤ 10 mg/day oral prednisone or equivalent per institutional guidelines before tislelizumab or 
tislelizumab plus ociperlimab can be resumed. 
Tislelizumab or tislelizumab plus ociperlimab may be withheld for a period of time beyond 12 
weeks to allow for corticosteroids to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the sponsor medical monitor. 
Management Guidelines for Adverse Events Related to BAT1706 
Events 
Grade 
Action to Be taken 
Gastrointestinal events 
Gastrointestinal perforation 
Any grade 
• Discontinue BAT1706. 
• Initiate treatment per institutional guidelines. 
Bowel obstruction 
Grade 2 
• Hold BAT1706 for partial obstruction 
requiring medical intervention. 
• BAT1706 may be restarted upon complete 
resolution of event. 
Grade 3 - 4 
• Hold BAT1706 for complete obstruction. 
• If surgery is necessary, patient may restart 
BAT1706 after full recovery from surgery 
and at investigator's discretion. 
Hypertension 
Hypertension 
General 
• Grade 2 or above, start antihypertensive 
therapy. 
Grade 2 
• Hold BAT1706. 
• Once blood pressure < 150/100 mmHg, 
patient may continue BAT1706 therapy. 


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Events 
Grade 
Action to Be taken 
Grade 3 
• If blood pressure is not controlled to 150/100 
mmHg with medication, discontinue 
BAT1706. 
Grade 4 
(includes 
hypertensive 
encephalopathy) 
• Discontinue BAT1706. 
Congestive heart failure 
Congestive heart failure 
Grade 3- 4 
• Discontinue BAT1706. 
Hemorrhage 
Hemorrhage 
Grade 1-2 
• Patients who are also receiving full-dose 
anticoagulation will be discontinued from 
receiving BAT1706. 
• Hold BAT1706 for the other patients until 
the following criteria are met: the bleeding 
has resolved and hemoglobin is stable; no 
bleeding diathesis would increase the risk of 
therapy; and no anatomic or pathologic 
condition significantly increases the risk of 
hemorrhage recurrence. 
• After resumption of BAT1706, if the patient 
experiences another Grade 1 pulmonary or 
intracranial hemorrhagic event, BAT 1706 
should be discontinued. 
Grade 3-4  
• Discontinue BAT1706. 
Any grade 
cerebral 
hemorrhage 
• Discontinue BAT1706. 
Venous Thromboembolic Events 
Venous thromboembolic event Grade ≥ 3 
• For Grade 3 thromboembolic events, hold 
BAT1706 for > 3 weeks.  BAT1706 
treatment may be resumed during the period 
of therapeutic-dose anticoagulant therapy 


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Events 
Grade 
Action to Be taken 
once the level of anticoagulation therapy is 
stabilized. 
• Anticoagulant treatment should be 
administered per institutional guidelines. 
• After administration of BAT1706 is 
restarted, if the patient experiences another 
Grade ≥ 3 venous thromboembolic event, 
BAT1706 should be discontinued. 
• For Grade 4 thromboembolic events, 
discontinue BAT1706. 
Arterial Thromboembolic Events 
Arterial thromboembolic 
event 
Any grade 
• Discontinue BAT1706. 
Proteinuria 
Proteinuria first occurrence, 
no diagnosis of nephrosis 
proteinuria < 2+ 
• No BAT1706 dose interruptions. 
Proteinuria ≥ 2+ 
• Administer BAT1706 as planned and collect 
24-hour urine for determination of total 
protein within 3 days before next scheduled 
BAT1706 administration. 
• If 24-hour proteinuria ≤ 2 g, the next 
BAT1706 dose can be administered as 
scheduled. 
• If 24-hour proteinuria > 2 g, hold BAT1706 
treatment.  Continue to do 24-hour urine 
collections for determination of total protein 
within 3 days of each scheduled BAT1706 
dose and continue to hold scheduled 
BAT1706 until proteinuria has decreased to 
≤ 2 g/24 hours. 
• When proteinuria has decreased to ≤ 2 g/24 
hours, scheduled BAT1706 may be 
administered as planned.  However, continue 
to do 24-hour urine collections for 
determination of total protein within 3 days 
of each scheduled BAT1706 dose until 
proteinuria has improved to ≤ 1 g/24 hours. 


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Events 
Grade 
Action to Be taken 
Proteinuria second and 
subsequent occurrences, no 
diagnosis of nephrosis 
proteinuria < 3+ 
• No BAT1706 dose interruptions. 
Proteinuria ≥ 3+ 
• Administer BAT1706 as planned and collect 
24-hour urine for determination of total 
protein within 3 days before next scheduled 
BAT1706 administration. 
• If 24-hour proteinuria ≤ 2 g, the next 
BAT1706 dose can be administered as 
scheduled. 
• If 24-hour proteinuria > 2 g, hold BAT1706 
treatment.  Continue to do 24-hour urine 
collections for determination of total protein 
within 3 days of each scheduled BAT1706 
dose and continue to hold scheduled 
BAT1706 until proteinuria has decreased to 
≤ 2 g/24 hours. 
• When proteinuria has decreased to ≤ 2 g/24 
hours, scheduled BAT1706 may be 
administered as planned.  However, continue 
to do 24-hour urine collections for 
determination of total protein within 3 days 
of each scheduled BAT1706 dose until 
proteinuria has improved to ≤ 1 g/24 hours. 
Proteinuria with diagnosis of 
nephrosis 
Any grade 
• Discontinue BAT1706. 
Fistula 
Tracheoesophageal fistula 
Any grade 
• Discontinue BAT1706. 
Fistula (non-
tracheoesophageal) 
Grade 4 
• Discontinue BAT1706. 
Wound healing complications 
Wound dehiscence 
Any grade 
requiring medical 
or surgical 
therapy  
• Discontinue BAT1706. 


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Events 
Grade 
Action to Be taken 
Posterior Reversible Encephalopathy Syndrome (PRES)/Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) 
PRES/RPLS 
Any grade 
confirmed by 
MRI 
• Discontinue BAT1706. 
Abbreviations: MRI, magnetic resonance imaging; PRES, Posterior Reversible Encephalopathy Syndrome; RPLS, 
Reversible Posterior Leukoencephalopathy Syndrome. 
 


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APPENDIX 8. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference: Eisenhauer et al 2009. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 
• 10 mm caliper measurement by clinical examination (when superficial). 
• 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (CT/MRI scan slice 
thickness recommended to be ≥ 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 


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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT or MRI scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan, this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node which is reported as being 20 mm × 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with short axis 
≥ 10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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


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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 trials 
where recurrence following CR or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between 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 to differentiate between response (or stable disease) and PD. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• CR: Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) 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. 
• PD: At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note: the appearance of 1 or 
more new lesions is also considered progression). 
• Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  Case report recorded in a separate section where, to 
qualify for CR, each node must achieve a short axis < 10 mm.  For PR, stable disease, 


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and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions. 
• Target lesions that become “too small to measure.” While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.” 
• When this occurs, it is important that a value be recorded on the 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 non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon 
measurement error.  To reiterate, however, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing non-target lesions.  
(Note: the appearance of 1 or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of 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 
non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of stable disease or PR of target disease will therefore 
be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large,” an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point.  While 
it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must 
be substantial. 
New Lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important.  There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some “new” bone lesions may be simply 
healing or flare of pre-existing lesions).  This is particularly important when the patient’s 
baseline lesions show partial or complete response.  For example, necrosis of a liver lesion may 
be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD.  An example of this is the patient who has 
visceral disease at baseline and while on trial has a CT or MRI brain scan ordered that reveals 
metastases.  The patient’s brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 


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While fluorine-18 [F-18] 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 assessment of progression (particularly possible “new” disease).  New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion.   
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
Evaluation of Best Overall Response 
The BOR 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 BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in nonrandomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “BOR.” 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all timepoints (for example, a patient who has 
stable disease at first assessment, PR at second assessment, and PD on last assessment has a 
BOR of PR).  When stable disease is believed to be best response, it must also meet the protocol 
specified minimum time from baseline.  If the minimum time is not met when 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, PD at second and 
does not meet minimum duration for stable disease, will have a best response of PD.  The same 
patient lost to follow-up after the first stable disease assessment would be considered 
inevaluable. 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
Stable disease 
Non-PD or not all 
evaluated 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ timepoint assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with timepoint responses of PR-not 
evaluable-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document objective progression even after discontinuation of 
treatment.  Symptomatic deterioration is not a descriptor of an objective response: it is a reason 
for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of 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 false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 


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


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APPENDIX 9. CHILD-PUGH CLASSIFICATION SCORING SYSTEM 
The information presented here has been obtained from the Washington University Medical 
Center, with sources as follows: 
• Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list: a report of a national conference organized by the 
American Society of Transplant Physicians and the American Association for the 
Study of Liver Diseases.  Liver Transpl Surg. 1997;3(6):628-37. 
• Pugh RN, Murray-Lyon IN, Dawson DL, et al. Transection of the oesophagus for 
bleeding oesophageal varices.  Br J Surgery.  1973;60:646-9. 
• Trey C, Burns DG, Saunders SJ.  Treatment of hepatic coma by exchange blood 
transfusion.  N Engl J Med. 1966;274(9):473-81. 
Child-Pugh classification is either Grade A (mild: score 5 to 6 points), B (moderate: from 7 to 9 
points), or C (severe: from 10 to 15 points) and is determined by both clinical and biochemical 
parameters (as shown below). 
Clinical/Biochemical Parameter 
Score (Anomaly Severity) 
1 
2 
3 
Hepatic encephalopathy (NCI-CTCAE Grade)a 
0b 
1c or 2d 
3e or 4f 
Ascites (presence and severity) 
None 
Mild 
Moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prothrombin time (seconds prolonged) 
or 
(INRg) 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events. 
a. Trey C, Burns DG, Saunders SJ.  Treatment of hepatic coma by exchange blood transfusion. N Engl J Med. 
1966;274(9):473-81. 
b. Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c. Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5CPS waves. 
d. Grade 2: Lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e. Grade 3: Drowsiness, coma, orientation disorder, over-reflection, stiff/slow wave. 
f. Grade 4: Cannot wake up from coma, no independent personality/behavior, irrational, slow 2-3CPS Delta 
activity. 
g. Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant 
waiting list: a report of a national conference organized by the American Society of Transplant Physicians and 
the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997;3(6):628-37. 
 


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APPENDIX 10. BARCELONA CLINIC LIVER CANCER (BCLC) 
STAGING CLASSIFICATION 
The Barcelona Clinic Liver Cancer (BCLC) system has been widely validated and is the most 
commonly used staging system for HCC.  It determines cancer stage and patient prognosis based 
on tumor burden, severity of liver disease, and the patient’s ECOG Performance Status. 
The staging according to the BCLC classification assigns prognoses based on clinical and tumor 
parameters and is summarized as follows: 
BCLC Stagea, b 
Very early stage (0) 
Early stage (A) 
Intermediate 
stage (B) 
Advanced stage (C) Terminal stage (D) 
Single nodule < 2 
cm 
Carcinoma in situ 
Child–Pugh A, 
ECOG PS 0 
Single or 3 
nodules 
< 3 cm 
Child–Pugh A-B, 
ECOG PS 0 
Multinodular, 
Child–Pugh A-B, 
ECOG PS 0 
Portal invasion, 
Extrahepatic spread, 
Child–Pugh A-B, 
ECOG PS 1-2 
Child–Pugh C 
ECOG PS 3-4 
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group 
Performance Status. 
a. 
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with 
hepatocellular carcinoma.  Gastroenterology. 2016;150:835-53. 
b. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin 
Liver Dis 1999;19:329-38. 


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APPENDIX 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (Levey 2009) and the Modification of Diet in Renal Disease (MDRD) Study equation.  
The National Kidney Disease Education Program (NKDEP) calculators rely on creatinine 
determinations which are isotope dilution mass spectrometry (IDMS) traceable.  All laboratories 
should be using creatinine methods calibrated to be IDMS traceable. 
This CKD-EPI equation calculator should be used when serum creatinine (Scr) is reported in 
mg/dL.  This equation is recommended when eGFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for women and 0.9 for men, 
α is -0.329 for women and -0.411 for men, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: 
https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators 
 


Approval
04-Mar-2021 02:57:15 GMT+0000

SAP_001.pdf: 
NCT Number:
NCT04948697