Clinical trial NCT04047862
Conditions: Locally Advanced and Metastatic Solid Tumors
Keywords: BGB-A1217 Anti-TIGIT antibody Tislelizumab anti-PD-1 antibody Ociperlimab
Sponsor: BeiGene
Start date: 2019-08-15; Completion date: 2024-08-07
Enrollment: 446 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study were: to assess the safety and tolerability, to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to determine the recommended Phase 2 dose (RP2D) of BGB-A1217 (known as ociperlimab) in combination with tislelizumab in participants with advanced solid tumors in phase 1.

Primary objective of Phase 1b was to assess overall response rate (ORR) determined by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v).1.1 for patients in each dose-expansion cohort.

Detailed description:

Arms: arm 1: Participants received ociperlimab 50 milligrams (mg) intravenous (IV) infusion on Day 1 of each cycle (cycle 1= 28 days) and tislelizumab 200 mg IV infusion on Day 8 of Cycle 1. If tolerated, participants received ociperlimab and tislelizumab doses IV on Cycle 2 Day 1 (cycle 2 onwards = 21 days) and thereafter every 21 days (that is, \[i.e.\], every 3 weeks \[Q3W\]) until disease progression, adverse events (AEs), participant withdrew consent, lost to follow-up or death, whichever came first. arm 2: Participants received ociperlimab 150 mg IV infusion on Day 1 of each cycle (cycle 1= 28 days) and tislelizumab 200 mg IV infusion on Day 8 of Cycle 1. If tolerated, participants received ociperlimab and tislelizumab doses IV on Cycle 2 Day 1 (cycle 2 onwards = 21 days) and thereafter every 21 days (i.e. Q3W) until disease progression, intolerable toxicity, or withdrawal of consent. arm 3: Participants received ociperlimab 450 mg IV infusion on Day 1 of each cycle (cycle 1= 28 days) and tislelizumab 200 mg IV infusion on Day 8 of Cycle 1. If tolerated, participants received ociperlimab and tislelizumab doses IV on Cycle 2 Day 1 (cycle 2 onwards = 21 days) and thereafter every 21 days (i.e. Q3W) until disease progression, intolerable toxicity, or withdrawal of consent. arm 4: Participants received ociperlimab 900 mg IV infusion on Day 1 of each cycle (cycle 1= 28 days) and tislelizumab 200 mg IV infusion on Day 8 of Cycle 1. If tolerated, participants received ociperlimab and tislelizumab doses IV on Cycle 2 Day 1 (cycle 2 onwards = 21 days) and thereafter every 21 days (i.e. Q3W) until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 5: Participants received ociperlimab 1800 mg IV infusion on Day 1 of each cycle (cycle 1= 28 days) and tislelizumab 200 mg IV infusion on Day 8 of Cycle 1. If tolerated, participants received ociperlimab and tislelizumab doses IV on Cycle 2 Day 1 (cycle 2 onwards = 21 days) and thereafter every 21 days (i.e. Q3W) until disease progression, intolerable toxicity, or withdrawal of consent. arm 6: Participants received ociperlimab 900 mg as monotherapy IV infusion on Day 1 of each 21-day treatment cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 7: Participants received ociperlimab 900 mg as IV infusion on Day 1 of each 21-day treatment cycle and tislelizumab 200 mg IV infusion once every 21 days (i.e. Q3W) until disease progression, intolerable toxicity, or withdrawal of consent. arm 8: Participants with metastatic squamous non-small cell lung cancer (NSCLC) received treatment with ociperlimab 900 mg IV infusion along with tislelizumab 200 mg IV infusion on Day 1 of each 21-day cycle. Participants also received 4 to 6 cycles of chemotherapy with carboplatin at an area under the curve (AUC) 5 or 6 (Day 1) + paclitaxel 200 or 175 mg/m\^2 (Day 1) or nab paclitaxel 100 mg/m\^2 (Days 1, 8 and 15) Q3W p until disease progression, intolerable toxicity, or withdrawal of consent. arm 9: Participants with metastatic non-squamous NSCLC received treatment with ociperlimab 900 mg IV infusion and tislelizumab 200 mg IV infusion on Day 1 of each 21-day cycle. Participants also received cisplatin 75 mg/m\^2 or carboplatin (AUC 5) and pemetrexed 500 mg/m\^2 (on Day 1) Q3W for 4-6 cycles followed by ociperlimab 900 mg + tislelizumab 200 mg + pemetrexed 500 mg/m\^2 on Day 1 Q3W until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 10: Participants with metastatic NSCLC (programmed cell death protein-ligand 1 \[PD-L1\] positive, tumor cell \[TC\] \>=1%) were treated with ociperlimab 900 mg IV infusion and tislelizumab 200 mg IV infusion on Day 1 of each 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 11: Participants with extensive-stage small-cell lung cancer (SCLC) received treatment with ociperlimab 900 mg IV infusion, tislelizumab 200 mg IV infusion. Participants also received 4 cycles of etoposide 100 mg/m\^2 (on Days 1, 2, 3), and cisplatin 75 mg/m\^2 or carboplatin AUC 5 (Day 1) Q3W, followed by ociperlimab 900 mg (Day 1) + tislelizumab 200 mg (Day 1) Q3W until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 12: Checkpoint inhibitor (CPI)-experienced NSCLC participants received treatment with ociperlimab 900 mg IV infusion and tislelizumab 200 mg IV infusions on Day 1 of each 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 13: Participants with metastatic esophageal squamous cell carcinoma (ESCC) received treatment with 6 cycles of ociperlimab 900 mg (Day 1) IV infusion, tislelizumab 200 mg (Day 1) IV infusion, cisplatin 75 mg/m\^2 (Day 1), and 5-fluorouracil 750-800 mg/m\^2 (5-FU; Day 1 to Day 5) or paclitaxel 200 or 175 mg/m\^2 (Day 1) Q3W followed by ociperlimab 900 mg and tislelizumab 200 mg on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 14: Participants with metastatic esophageal adenocarcinoma (EAC) received treatment with 6 cycles of ociperlimab 900 mg (Day 1) IV infusion, tislelizumab 200 mg (Day 1) IV infusion, cisplatin 75 mg/m\^2 (Day 1), and 5-Fluorouracil 750-800 mg/m\^2 (5-FU; Day 1 to Day 5) or paclitaxel 200 or 175 mg/m\^2 (Day 1) Q3W followed by ociperlimab 900 mg and tislelizumab 200 mg on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 15: Participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC; PD-L1 positive, visually estimated Combined Positive Score \[vCPS\] \>= 1%) received treatment with ociperlimab 900 mg IV infusion and tislelizumab 200 mg IV infusions on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 16: Participants with unresectable, locally advanced, recurrent, or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma received treatment with 6 cycles of ociperlimab 900 mg (Day 1) IV infusion, tislelizumab 200 mg (Day 1) IV infusion, (oxaliplatin 1300 mg/m\^2 \[Day 1\] and capecitabine 1000 mg/m\^2 \[Day 1-14 twice daily\]), or (cisplatin 75 mg/m\^2 \[Day\], and 5-FU 750-800 mg/m\^2 \[Day 1-5\]) Q3W followed by ociperlimab 900 mg (Day 1), tislelizumab 200 mg (Day 1) + capecitabine 1000 mg/m\^2 twice daily (Day 1-14) Q3W until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 17: articipants with metastatic NSCLC (PD-L1 positive, TC \>= 1%) received treatment with ociperlimab 450 mg IV infusion and tislelizumab 200 mg IV infusion on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 18: Participants with metastatic NSCLC (PD-L1 positive, TC \>= 1%) received treatment with ociperlimab 900 mg IV infusion and tislelizumab 200 mg IV infusion on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first. arm 19: Participants with metastatic NSCLC (PD-L1 positive, TC \>= 1%) received treatment with ociperlimab 1800 mg IV infusion and tislelizumab 200 mg IV infusion on Day 1 of every 21-day cycle until disease progression, AEs, participant withdrew consent, lost to follow-up or death, whichever came first.
Interventions: intervention 1: Ociperlimab intervention 2: Tislelizumab intervention 3: Pemetrexed intervention 4: Paclitaxel intervention 5: Nab paclitaxel intervention 6: Carboplatin intervention 7: Cisplatin intervention 8: Etoposide intervention 9: 5fluorouracil intervention 10: Oxaliplatin intervention 11: Capecitabine
Intervention descriptions: intervention 1: Administered as an intravenous (IV) injection intervention 2: Administered as an IV injection intervention 3: Administered in accordance with local guidelines, prescribing information/summary of product intervention 4: Administered in accordance with local guidelines , prescribing information/summary of product intervention 5: Administered in accordance with local guidelines , prescribing information/summary of product intervention 6: Administered in accordance with local guidelines , prescribing information/summary of product intervention 7: Administered in accordance with local guidelines , prescribing information/summary of product intervention 8: Administered in accordance with local guidelines , prescribing information/summary of product intervention 9: Administered in accordance with local guidelines , prescribing information/summary of product intervention 10: Administered in accordance with local guidelines , prescribing information/summary of product intervention 11: Administered in accordance with local guidelines , prescribing information/summary of product

Protocol documents:
Prot_000.pdf: 
BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1/1b Study Investigating Safety, Tolerability, 
Pharmacokinetics and Preliminary Antitumor Activity of Anti-
TIGIT Monoclonal Antibody BGB-A1217 in Combination with 
Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) in 
Patients with Unresectable Locally Advanced or Metastatic 
Solid Tumors 
Protocol Number: 
BGB-900-105 (AdvanTIG-105) 
Phase: 
1/1b 
Investigational Products: 
Ociperlimab (BGB-A1217) and Tislelizumab (BGB-A317) 
Proposed Indication(s): 
Advanced Solid Tumors 
Sponsor: 
BeiGene, Ltd.  
c/o BeiGene USA, Inc. 
1840 Gateway Drive 
Third Floor 
San Mateo, California 94404, USA 
Sponsor Medical 
Monitor: 
Phone: 
Email: 
Original Protocol 
Version 0.0: 
25 April 2019 
Protocol Amendment 1.0: 30 April 2020 
Protocol Amendment 2.0: 22 January 2021 
Protocol Amendment 3.0 
14 January 2022 
Protocol Amendment 4.0 
12 August 2022 
Protocol Amendment 5.0 
10 November 2023 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
affiliates.  This document is for use by individuals and their designated representatives for their review, 
consideration, and/or participation in investigational trial(s).  This document may not be copied or 
distributed for review by any unauthorized individuals without the prior written authorization of 
BeiGene, Ltd., or one of its affiliates.  Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its affiliates. 
Approved Date
11/10/2023
NCT Number
NCT04047862


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 2 
FINAL PROTOCOL APPROVAL SHEET  
 
Phase 1/1b Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary 
Antitumor Activity of Anti-TIGIT Monoclonal Antibody BGB-A1217 in Combination with 
Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) in Patients with Unresectable 
Locally Advanced or Metastatic Solid Tumors 
BeiGene, Ltd., Approval: 
See electronic signature 
_______________________________________ 
Sponsor Medical Monitor 
See electronic signature 
________________________________ 
Date 
 
 
Approved Date
11/10/2023


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 3 
INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
Phase 1/1b Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Anti-TIGIT Monoclonal Antibody 
BGB-A1217 in Combination with Anti-PD-1 Monoclonal Antibody 
Tislelizumab (BGB-A317) in Patients with Unresectable Locally 
Advanced or Metastatic Solid Tumors 
 
Protocol Identifier: 
BGB-900-105 (AdvanTIG-105) 
 
This protocol is a confidential communication of BeiGene, Ltd., and its affiliates.  I confirm that 
I have read this protocol, I understand it, and I will work according to this protocol and the terms 
of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its affiliates. 
 
Instructions for Investigator: Please SIGN and DATE this signature page.  PRINT your 
name, title, and the name and address of the center in which the study will be conducted.  
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
Approved Date
11/10/2023


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 4 
TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
SYNOPSIS  ....................................................................................................................................13 
LIST OF ABBREVIATIONS AND TERMS ................................................................................23 
1. 
INTRODUCTION AND RATIONALES ..................................................................26 
1.1. 
Introduction .................................................................................................................26 
1.2. 
Ociperlimab as a TIGIT Inhibitor ...............................................................................26 
1.2.1. 
Nonclinical ..................................................................................................................29 
1.2.1.1. 
Pharmacology .............................................................................................................29 
1.2.1.2. 
Toxicology ..................................................................................................................29 
1.2.2. 
Clinical Experience .....................................................................................................31 
1.2.2.1. 
Preliminary Safety ......................................................................................................32 
1.2.2.2. 
Clinical Pharmacology ................................................................................................33 
1.2.2.3. 
Efficacy .......................................................................................................................33 
1.3. 
Tislelizumab as a PD-1 Inhibitor ................................................................................33 
1.3.1. 
Pharmacology .............................................................................................................33 
1.3.2. 
Toxicology ..................................................................................................................34 
1.3.3. 
Clinical Pharmacology ................................................................................................35 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................35 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................35 
1.3.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................37 
1.4. 
Study Rationale ...........................................................................................................40 
1.4.1. 
Rationale for the Choice of Doses ..............................................................................41 
1.4.1.1. 
Rationale for the Starting Dose of Ociperlimab .........................................................41 
1.4.1.2. 
Rationale for the Selection of Ociperlimab Doses in Cohort 10 ................................42 
1.4.1.3. 
Rationale for the Selection of Tislelizumab Dose ......................................................42 
1.4.2. 
Rationale for Combination of Ociperlimab and Tislelizumab in the 
Treatment of Advanced Solid Tumors .......................................................................43 
Approved Date
11/10/2023


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 5 
1.4.3. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Platinum-
based Doublet Chemotherapy in NSCLC (Phase 1b) .................................................46 
1.4.4. 
Rationale for Combination of Ociperlimab and Tislelizumab in NSCLC 
With PD-L1 Positive (Tumor Cell Expression ≥ 1%) Population (Phase 1b) ............48 
1.4.5. 
Rationale for Combination of Ociperlimab and Tislelizumab and 
Platinum-based Doublet Chemotherapy in SCLC (Phase 1b) ....................................48 
1.4.6. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Chemotherapy 
in Esophageal Cancer .................................................................................................49 
1.4.7. 
Rationale for Combination of Ociperlimab and Tislelizumab in Head and 
Neck Squamous Cell Carcinoma With PD-L1 Positive (vCPS ≥ 1%) 
Population ...................................................................................................................50 
1.4.8. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Chemotherapy 
in Gastric Cancer ........................................................................................................51 
1.4.9. 
Biomarker Strategy Rationale.....................................................................................51 
1.5. 
Benefit-Risk Assessment ............................................................................................52 
1.6. 
Study Conduct ............................................................................................................53 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................54 
2.1. 
Study Objectives for Dose Escalation ........................................................................54 
2.1.1. 
Primary Objectives .....................................................................................................54 
2.1.2. 
Secondary Objectives .................................................................................................54 
2.1.3. 
Exploratory Objectives ...............................................................................................54 
2.2. 
Study Objectives for Dose Expansion ........................................................................54 
2.2.1. 
Primary Objective .......................................................................................................54 
2.2.2. 
Secondary Objectives .................................................................................................54 
2.2.3. 
Exploratory Objectives ...............................................................................................55 
2.3. 
Study Endpoints for Dose Escalation .........................................................................55 
2.3.1. 
Primary Endpoints ......................................................................................................55 
2.3.2. 
Secondary Endpoints ..................................................................................................55 
2.3.3. 
Exploratory Endpoints ................................................................................................55 
2.4. 
Study Endpoints for Dose Expansion .........................................................................55 
2.4.1. 
Primary Endpoint ........................................................................................................55 
2.4.2. 
Secondary Endpoints ..................................................................................................56 
2.4.3. 
Exploratory Endpoints ................................................................................................56 
3. 
STUDY DESIGN .......................................................................................................57 
Approved Date
11/10/2023


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 6 
3.1. 
Summary of Study Design ..........................................................................................57 
3.2. 
Details of Phase 1 .......................................................................................................64 
3.2.1. 
Phase 1 (Dose Escalation in Australia) .......................................................................64 
3.2.1.1. 
Starting Dose and Dose Escalation Approach ............................................................64 
3.2.1.2. 
Rules for Dose Escalation ...........................................................................................65 
3.2.1.3. 
Assessment of Dose-Limiting Toxicity ......................................................................66 
3.2.1.4. 
Dose-Limiting Toxicity Definition .............................................................................66 
3.2.1.5. 
RP2D Determination ..................................................................................................68 
3.2.2. 
RP2D Confirmation in Chinese Patients Phase 1 (Dose Verification in 
China) .........................................................................................................................68 
3.2.2.1. 
Dose-Limiting Toxicity Definition .............................................................................69 
3.3. 
Details of Phase 1b .....................................................................................................69 
4. 
STUDY POPULATION .............................................................................................71 
4.1. 
Inclusion Criteria ........................................................................................................71 
4.1.1. 
Inclusion Criteria for Phase 1 .....................................................................................71 
4.1.2. 
Inclusion Criteria for Phase 1b ...................................................................................72 
4.2. 
Exclusion Criteria .......................................................................................................74 
4.2.1. 
Exclusion Criteria for Phase 1 ....................................................................................74 
4.2.2. 
Exclusion Criteria for Phase 1b ..................................................................................76 
5. 
STUDY TREATMENT ..............................................................................................80 
5.1. 
Formulation, Packaging, and Handling ......................................................................80 
5.1.1. 
Ociperlimab ................................................................................................................80 
5.1.2. 
Tislelizumab ...............................................................................................................80 
5.1.3. 
Chemotherapy Agents ................................................................................................80 
5.2. 
Dosage, Administration, and Compliance ..................................................................80 
5.2.1. 
Ociperlimab and Tislelizumab Combination Dose Escalation ...................................81 
5.2.2. 
Dose Verification in China .........................................................................................82 
5.2.3. 
Ociperlimab and Tislelizumab Combination With or Without Chemotherapy 
for Phase 1b ................................................................................................................83 
5.2.3.1. 
Tislelizumab Plus Ociperlimab...................................................................................86 
5.2.3.2. 
Ociperlimab plus Tislelizumab Plus Chemotherapy ..................................................87 
5.3. 
Incorrect Administration or Overdose ........................................................................89 
5.4. 
Dose Delay or Modification .......................................................................................89 
Approved Date
11/10/2023


BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 7 
5.4.1. 
Dose Interruption or Delay for Ociperlimab and Tislelizumab ..................................90 
5.4.2. 
Dose Modifications for Ociperlimab and Tislelizumab .............................................91 
5.4.3. 
Dose Modifications of Chemotherapy ........................................................................91 
5.4.4. 
Criteria for Discontinuing Chemotherapy Regimens .................................................92 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................93 
6.1. 
Prior Therapy ..............................................................................................................93 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................93 
6.2.1. 
Systemic Corticosteroids ............................................................................................93 
6.2.2. 
Hepatitis B Treatment .................................................................................................93 
6.2.3. 
Radiation Therapy ......................................................................................................94 
6.3. 
Prohibited Concomitant Medications/Procedures ......................................................94 
6.4. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................95 
7. 
STUDY PERIODS, VISITS, OR PROCEDURES ....................................................97 
7.1. 
Screening Period .........................................................................................................97 
7.1.1. 
Informed Consent and Screening Log ........................................................................97 
7.2. 
Enrollment ..................................................................................................................97 
7.3. 
Treatment Period ........................................................................................................97 
7.4. 
Follow-up Periods .......................................................................................................98 
7.4.1. 
End-of-Treatment/+30-day Safety Follow-up Visit ...................................................98 
7.4.2. 
Efficacy Follow-up Period ..........................................................................................98 
7.4.3. 
Survival Follow-up (Phase 1b) ...................................................................................98 
7.4.4. 
Lost to Follow-up .......................................................................................................98 
7.5. 
Discontinuation From Study Treatment or From the Study .......................................99 
7.5.1. 
Patient Discontinuation From Study Treatment .........................................................99 
7.5.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ........................................................................................................................99 
7.6. 
End of Study .............................................................................................................100 
8. 
STUDY ASSESSMENTS ........................................................................................101 
8.1. 
Screening Assessments .............................................................................................101 
8.1.1. 
Pulmonary Function Tests ........................................................................................101 
8.2. 
Safety Assessments ...................................................................................................102 
8.2.1. 
Vital Signs ................................................................................................................102 
Approved Date
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BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 8 
8.2.2. 
Physical Examinations ..............................................................................................102 
8.2.3. 
Eastern Cooperative Oncology Group Performance Status ......................................102 
8.2.4. 
Laboratory Safety Tests ............................................................................................102 
8.2.4.1. 
Cardiac Enzyme Monitoring .....................................................................................103 
8.2.5. 
Electrocardiograms ...................................................................................................103 
8.2.6. 
Adverse Events .........................................................................................................103 
8.2.7. 
Hepatitis B and C Testing .........................................................................................103 
8.3. 
Pharmacokinetic Assessment and Antidrug Antibody Testing ................................104 
8.4. 
Biomarkers ................................................................................................................104 
8.5. 
Tumor and Response Evaluations ............................................................................105 
8.6. 
Visit Windows ..........................................................................................................107 
8.7. 
Unscheduled Visits ...................................................................................................107 
9. 
SAFETY MONITORING AND REPORTING .......................................................109 
9.1. 
Risks Associated With Study Drugs .........................................................................109 
9.1.1. 
Risks Associated With Ociperlimab and Tislelizumab ............................................109 
9.1.2. 
Risks Associated With Chemotherapeutic Agents ...................................................109 
9.2. 
General Plan to Manage Safety Concerns ................................................................110 
9.2.1. 
Eligibility Criteria .....................................................................................................110 
9.2.2. 
Abnormal Liver Function Tests ................................................................................111 
9.2.3. 
Safety Monitoring Plan .............................................................................................111 
9.3. 
Adverse Events .........................................................................................................111 
9.3.1. 
Definitions and Reporting .........................................................................................111 
9.3.2. 
Assessment of Severity .............................................................................................112 
9.3.3. 
Assessment of Causality ...........................................................................................112 
9.3.4. 
Following Adverse Events ........................................................................................113 
9.3.5. 
Laboratory Test Abnormalities .................................................................................114 
9.4. 
Definition of a Serious Adverse Event .....................................................................114 
9.5. 
Suspected Unexpected Serious Adverse Reaction ...................................................115 
9.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events .........................................................................................................115 
9.6.1. 
Adverse Event Reporting Period ..............................................................................115 
9.6.2. 
Reporting Serious Adverse Events ...........................................................................116 
9.6.2.1. 
Prompt Reporting of Serious Adverse Events ..........................................................116 
Approved Date
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BGB-900-105 (AdvanTIG-105) 
BeiGene 
Protocol Amendment 5.0 
10 November 2023 
 
CONFIDENTIAL 
Page 9 
9.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ......................117 
9.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events ...........................117 
9.6.3. 
Eliciting Adverse Events ..........................................................................................117 
9.6.4. 
Progressive Disease ..................................................................................................118 
9.6.5. 
Deaths .......................................................................................................................118 
9.6.6. 
Recording Pregnancies .............................................................................................118 
9.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ..............................................118 
9.6.8. 
Assessing and Recording Immune-Mediated Adverse Events .................................119 
9.6.9. 
Recording Infusion-Related Reactions .....................................................................119 
9.7. 
Management of Adverse Events of Special Interest .................................................119 
9.7.1. 
Infusion-Related Reactions .......................................................................................120 
9.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms ...................................121 
9.7.3. 
Immune-Mediated Adverse Events ..........................................................................121 
9.7.4. 
Management of Immune-Mediated AEs in Patients With Pre-Existing Renal 
Dysfunction ...............................................................................................................122 
10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...............124 
10.1. 
Statistical Analysis ....................................................................................................124 
10.1.1. 
Analysis Sets .............................................................................................................124 
10.1.2. 
Patient Disposition ....................................................................................................124 
10.1.3. 
Demographic and Other Baseline Characteristics ....................................................125 
10.1.4. 
Prior and Concomitant Medications .........................................................................125 
10.2. 
Efficacy Analyses .....................................................................................................125 
10.2.1. 
Secondary Efficacy Analysis in Phase 1 ..................................................................126 
10.2.2. 
Primary Efficacy Analysis in Phase 1b ....................................................................126 
10.2.3. 
Secondary Efficacy Analysis in Phase 1b ................................................................126 
10.2.4. 
Exploratory Efficacy Analysis ..................................................................................126 
10.3. 
Safety Analyses ........................................................................................................126 
10.3.1. 
Extent of Exposure ...................................................................................................127 
10.3.2. 
Adverse Events .........................................................................................................127 
10.3.3. 
Laboratory Analyses .................................................................................................128 
10.3.4. 
Vital Signs ................................................................................................................128 
10.3.5. 
Ophthalmologic Examination ...................................................................................128 
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10.4. 
Pharmacokinetic Analyses ........................................................................................128 
10.5. 
Immunogenicity Analyses ........................................................................................128 
10.6. 
Other Exploratory Analyses .....................................................................................129 
10.7. 
Sample Size Consideration .......................................................................................129 
10.8. 
Interim Analyses .......................................................................................................130 
11. 
STUDY COMMITTEES ..........................................................................................131 
11.1. 
Safety Monitoring Committee ..................................................................................131 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................132 
12.1. 
Access to Information for Monitoring ......................................................................132 
12.2. 
Access to Information for Auditing or Inspections ..................................................132 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................133 
13.1. 
Regulatory Authority Approval ................................................................................133 
13.2. 
Quality Assurance .....................................................................................................133 
13.3. 
Study Site Inspections...............................................................................................133 
13.4. 
Drug Accountability .................................................................................................133 
14. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................135 
14.1. 
Ethical Standard ........................................................................................................135 
14.2. 
Institutional Review Board/Independent Ethics Committee ....................................135 
14.2.1. 
Protocol Amendments ..............................................................................................135 
14.3. 
Informed Consent .....................................................................................................136 
14.4. 
Patient and Data Confidentiality ...............................................................................136 
14.5. 
Financial Disclosure .................................................................................................138 
15. 
DATA HANDLING AND RECORD KEEPING ....................................................139 
15.1. 
Data Collection and Management Responsibilities ..................................................139 
15.1.1. 
Data Entry in the Electronic Case Report Form .......................................................139 
15.1.2. 
Data Collection .........................................................................................................139 
15.1.3. 
Data Management/Coding ........................................................................................139 
15.2. 
Study Records Retention ..........................................................................................140 
15.3. 
Protocol Deviations ..................................................................................................141 
15.4. 
Study Report and Publications..................................................................................141 
15.5. 
Study and Study Center Closure ...............................................................................142 
15.6. 
Information Disclosure and Inventions ....................................................................142 
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16. 
REFERENCES .........................................................................................................144 
17. 
APPENDICES ..........................................................................................................152 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................153 
APPENDIX 1A. PHASE 1 (DOSE ESCALATION IN AUSTRALIA AND DOSE 
VERIFICATION IN CHINA) SCHEDULE OF ASSESSMENTS .........................154 
APPENDIX 1B. PHASE 1B SCHEDULE OF ASSESSMENTS ............................................161 
APPENDIX 1C. PHASE 1 PHARMACOKINETIC AND IMMUNOGENICITY 
SAMPLING SCHEDULE FOR OCIPERLIMAB AND TISLELIZUMAB ...........167 
APPENDIX 1D. PHASE 1B PHARMACOKINETIC AND IMMUNOGENICITY 
SAMPLING FOR OCIPERLIMAB AND TISLELIZUMAB WITH OR 
WITHOUT CHEMOTHERAPY FOR COHORTS 1 TO 9 .....................................171 
APPENDIX 1E. PHASE 1B COHORT 10 PHARMACOKINETIC AND 
IMMUNOGENICITY SAMPLING FOR OCIPERLIMAB AND 
TISLELIZUMAB .....................................................................................................172 
APPENDIX 1F. PHASE 1 BLOOD AND TISSUE BIOMARKER ANALYSIS....................174 
APPENDIX 1G. PHASE 1B BLOOD AND TISSUE BIOMARKER ANALYSIS ................176 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................178 
APPENDIX 3. ECOG PERFORMANCE STATUS .................................................................179 
APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................180 
APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................181 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................183 
APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................184 
APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................185 
APPENDIX 9. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................195 
APPENDIX 10. CHILD-PUGH CLASSIFICATION SCORING SYSTEM ...........................204 
APPENDIX 11. DOSE MODIFICATION OF CHEMOTHERAPY .......................................205 
APPENDIX 12. NUTRITIONAL RISK INDEX ......................................................................208 
APPENDIX 13. COCKCROFT-GAULT FORMULA AND CALVERT FORMULA ...........209 
 
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LIST OF TABLES  
Table 1: 
Safety and Efficacy Summary of Pembrolizumab With Chemotherapy in 
First-line NSCLC ........................................................................................................47 
Table 2: 
Safety and Efficacy Summary of Atezolizumab and Durvalumab With 
Chemotherapy in First-Line Extensive-Stage SCLC ..................................................48 
Table 3: 
Planned Dose Levels for Ociperlimab and Tislelizumab for Dose Escalation ...........81 
Table 4: 
Administration of Ociperlimab and Tislelizumab and Monitoring Time for 
Dose Escalation ..........................................................................................................82 
Table 5: 
Planned Dose Levels and Dosing Frequency for Ociperlimab as 
Monotherapy and in Combination With Tislelizumab for Dose Verification ............82 
Table 6: 
Administration of Ociperlimab as Monotherapy or in Combination With 
Tislelizumab ...............................................................................................................83 
Table 7: 
Dose, Frequency of Administration, and Route of Administration for Each 
Study Drug ..................................................................................................................85 
Table 8: 
Administration of Ociperlimab, Tislelizumab With or Without 
Chemotherapy and Monitoring Time for Dose Expansion .........................................86 
Table 9: 
Summary of the Common and Specific Reported Toxicities of the 
Chemotherapeutic Agents .........................................................................................110 
Table 10:  Guidance for Duration of Recording New or Worsening Adverse Events in 
All Cohorts................................................................................................................116 
Table 11: Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee ...........................................................................117 
Table 12: Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs ..............................................................................................................120 
Table 13: Immune-Mediated Adverse Events ..........................................................................122 
 
LIST OF FIGURES  
Figure 1: 
Combined Blockade of TIGIT and PD-1 with Ociperlimab and Tislelizumab 
(BGB-A317) Enhances IFN-γ secretion in Mixed Lymphocyte Reaction .................44 
Figure 2: 
The Combination of Anti-TIGIT and Anti-PD-1 Treatment Is More 
Effective Than Anti-PD-1 Inhibitors Alone ...............................................................45 
Figure 3: 
Study Schema for Phase 1 (Dose Escalation in Australia) .........................................60 
Figure 4: 
Study Schema for Phase 1 (Dose Verification in China) ...........................................61 
Figure 5: 
Study Schema for Phase 1b ........................................................................................62 
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SYNOPSIS  
Name of 
Sponsor/Company: 
BeiGene, Ltd. 
Investigational 
Product(s):  
Ociperlimab (also known as BGB-A1217) and Tislelizumab (also known as 
BGB-A317)  
Title of Study: 
Phase 1/1b Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activity of Anti-TIGIT Monoclonal Antibody 
BGB-A1217 in Combination with Anti-PD-1 Monoclonal Antibody 
Tislelizumab (BGB-A317) in Patients with Unresectable Locally Advanced or 
Metastatic Solid Tumors 
Protocol Identifier: 
BGB-900-105 (AdvanTIG-105) 
Phase of 
Development: 
1/1b 
Number of 
Patients: 
Approximately 294 to 564 evaluable patients may be enrolled 
Phase 1: Approximately 44 to 64 patients 
Phase 1b: Approximately 250 to 500 evaluable patients in 10 prespecified 
cohorts (20 to 40 evaluable patients each for Cohorts 1 to 8, 30 to 60 evaluable 
patients for Cohort 9, and 60 to 120 evaluable patients for Cohort 10 [3 arms, 
with 20 to 40 evaluable patients per arm]) 
Study Centers: 
Phase 1: Up to 10 centers (Australia and China) 
Phase 1b: Up to 85 centers globally 
Study Objectives: 
 
Phase 1 
Primary: 
• 
To assess the safety and tolerability of ociperlimab in combination with tislelizumab in 
patients with advanced solid tumors 
• 
To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) 
of ociperlimab in combination with tislelizumab 
• 
To determine the recommended Phase 2 dose (RP2D) of ociperlimab in combination with 
tislelizumab 
Secondary: 
• 
To assess the preliminary anticancer activity of ociperlimab in combination with 
tislelizumab 
• 
To characterize the pharmacokinetics (PK) of ociperlimab in combination with 
tislelizumab 
• 
To assess host immunogenicity to ociperlimab in combination with tislelizumab 
Exploratory: 
• 
To assess predictive, prognostic, and/or pharmacodynamic biomarkers including any 
association with response to ociperlimab treatment, exposure levels, and mechanism(s) of 
resistance 
 
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Phase 1b 
Primary: 
• 
To assess overall response rate (ORR) determined by investigator per Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for patients in each dose-expansion 
cohort   
Secondary: 
• 
To evaluate disease control rate (DCR), duration of response (DOR), and progression-free 
survival (PFS) determined by investigator per RECIST v1.1 for patients in each 
dose-expansion cohort 
• 
To further characterize the safety and tolerability of ociperlimab in combination with 
tislelizumab with or without chemotherapy 
• 
To further characterize the PK of ociperlimab in combination with tislelizumab with or 
without chemotherapy 
• 
To further assess host immunogenicity to ociperlimab in combination with tislelizumab 
with or without chemotherapy 
• 
To evaluate the association of PD-L1 and TIGIT expression level with clinical efficacy 
Exploratory: 
• 
To assess overall survival (OS) for each tumor expansion cohort 
• 
To further assess predictive, prognostic, and/or pharmacodynamic biomarkers, including 
any association with response to ociperlimab in combination with tislelizumab with or 
without chemotherapy and/or mechanism(s) of resistance 
Study Endpoints: 
 
Phase 1 
Primary Endpoints: 
• 
Adverse events (AEs) and serious AEs (SAEs) as characterized by type, frequency, 
severity (as graded by National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 5.0 [NCI-CTCAE v5.0]), timing, seriousness, and relationship to 
study drugs; physical examinations, electrocardiograms (ECGs), and laboratory 
assessments as needed; and AEs meeting protocol-defined dose-limiting toxicity (DLT) 
criteria 
• 
MTD or MAD, as defined as the highest dose at which less than one-third of patients 
experienced a DLT or the highest dose administered, respectively 
• 
RP2D of ociperlimab monotherapy and/or in combination with tislelizumab, determined 
by MTD or MAD, as well as long-term tolerability, PK, efficacy, and any other relevant 
data as available 
Secondary Endpoints: 
• 
ORR, DOR, and DCR, as assessed using RECIST v1.1 (as described in Section 10.2)   
• 
Serum concentrations at specified timepoints and PK parameters of ociperlimab and 
tislelizumab   
• 
Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection 
of antidrug antibodies (ADAs) 
 
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Exploratory Endpoints: 
• 
Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivative) 
samples obtained before, during, and/or after treatment with ociperlimab and their 
association with clinical efficacy.  Biomarkers may include, but not limited to, expression 
of TIGIT, CD226, CD155, CD112, and PD-L1 in tumor tissues, tumor mutation burden, 
microsatellite instability (MSI) status, and gene mutations in tissue and blood, immune 
cell subpopulations and gene expression profiling on peripheral blood and/or tumor 
tissues, and concentrations of cytokines and soluble proteins in plasma or serum 
Phase 1b 
Primary Endpoints: 
• 
ORR, as determined from investigator derived tumor assessments per RECIST v1.1 for 
each tumor expansion cohort (described in Section 10.2.2) 
Secondary Endpoints: 
• 
PFS, DOR, and DCR, as determined from investigator-derived tumor assessments per 
RECIST v1.1 for each tumor expansion cohort (described in Section 10.2.3) 
• 
AEs and SAEs as characterized by type, frequency, severity (as graded by NCI-CTCAE 
v 5.0), timing, seriousness, and relationship to study drugs; physical examinations, ECGs, 
and laboratory assessments as needed for each tumor expansion cohort 
• 
Serum ociperlimab and tislelizumab concentrations at specified timepoints with or without 
chemotherapy 
• 
Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection 
of ADAs with or without chemotherapy 
• 
PD-L1 and TIGIT expression as the predictive biomarker for efficacy (including but not 
limited to ORR and PFS) 
Exploratory Endpoints: 
• 
Overall survival-defined as the date of the first dose of study drug to the date of death due 
to any cause (as described in Section 10.2.4). 
• 
Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivatives) 
samples obtained before, during and/or after treatment with ociperlimab in combination 
with tislelizumab with or without chemotherapy and their association with clinical 
efficacy.  Biomarkers may include but not limited to expression of CD226, CD155, and 
CD112 in tumor tissues, tumor mutation burden, MSI status and gene mutations in tissue 
and blood, Epstein-Barr virus (EBV) status, immune cell subpopulations and gene 
expression profiling on peripheral blood and/or tumor tissues, and concentrations of 
cytokines and soluble proteins in plasma or serum. 
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Study Design 
This is an open-label, multicenter, Phase 1 and Phase 1b study to evaluate the safety and preliminary 
antitumor activity of ociperlimab in combination with tislelizumab in patients with unresectable locally 
advanced or metastatic solid tumors.  
• 
Dose Escalation: A modified 3+3 scheme will be used for sequential cohorts of approximately 
4 increasing dose levels of ociperlimab, evaluated in combination with 200 mg of tislelizumab, to 
determine the MTD or MAD, RP2D, safety, PK, and other key endpoints for ociperlimab in 
combination with tislelizumab.  
• 
The combination RP2D will be determined primarily from the Phase 1 safety, tolerability and PK 
data analyzed in its entirety, but may also consider any available efficacy and/or exploratory data.    
• 
Dose verification in China: Before Chinese patients join the Phase 1b study, safety and tolerability 
of ociperlimab (RP2D) will be assessed as a monotherapy, and in combination with tislelizumab 
(200 mg once every 3 weeks [Q3W]) in Chinese patients.  The Safety Monitoring Committee 
(SMC) will define the RP2D for Chinese patients based on the safety data from ociperlimab, 
combined with tislelizumab 200 mg, before Chinese patients join the Phase 1b study. 
• 
Dose Expansion: Approximately 190 to 380 evaluable patients in 9 prespecified tumor-type 
cohorts will receive ociperlimab (900 mg) in combination with tislelizumab (200 mg Q3W) with 
or without chemotherapy.  An interim analysis will be conducted on approximately the first 
20 patients in Cohorts 1 to 8 who had ≥1 evaluable postbaseline tumor assessment.  Based on the 
interim analysis for a given cohort, up to 40 evaluable patients with ≥ 1 evaluable postbaseline 
tumor assessment may be enrolled for Cohorts 1 to 8.  An interim analysis will be conducted 
based on approximately the first 30 patients in Cohort 9 who had ≥ 1 evaluable postbaseline tumor 
assessment.  Up to 60 evaluable patients in total may be enrolled based on interim analysis for 
Cohort 9. 
• 
Cohort 10: Approximately 60 to 120 evaluable patients with metastatic non-small cell lung cancer 
(NSCLC) (3 arms, with approximately 20 to 40 patients per arm) will be randomized in an 
open-label setting to ociperlimab 450 mg, 900 mg, or 1800 mg in combination with tislelizumab 
200 mg Q3W. 
Patients will receive study drug until they meet a study treatment discontinuation criterion (see 
Section 7.5).  
 
Study Assessments: 
Tables of scheduled study assessments for Phase 1 and Phase 1b are provided in Appendix 1, 
respectively.  Patients will be closely monitored for safety and tolerability throughout the study. 
Dose Limiting Toxicity Definition and Assessment 
All AEs will be graded according to NCI-CTCAE v5.0.  The occurrence of any of the following AEs 
will be considered a DLT if they occur within 28 days of receiving ociperlimab on Cycle 1 Day 1 and 
are deemed to be related to ociperlimab and/or tislelizumab. 
Definition of DLT 
Hematologic: 
1. Grade 4 neutropenia lasting > 7 days 
2. ≥ Grade 3 febrile neutropenia 
3. Grade 3 thrombocytopenia with clinically significant bleeding 
4. Grade 4 thrombocytopenia lasting > 7 days 
5. ≥ Grade 4 anemia 
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Non-hematologic: 
1. ≥ Grade 4 toxicity 
2. Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 7 days of initiating 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 nausea, vomiting, or diarrhea lasting for ≤ 72 hours with adequate antiemetic 
and/or other supportive care 
• Grade 3 fatigue lasting for ≤ 7 days 
• Grade 3 or higher electrolyte abnormality that lasts for ≤ 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions 
Patients will be considered not evaluable for DLTs, if they 1) withdraw from the study during the DLT 
assessment window, 2) did not receive ≥ 80% of each scheduled study drug administration during the 
DLT assessment window and/or 3) received supportive care during the DLT assessment window that 
confounds the evaluation of DLTs (not including supportive care described as part of the DLT 
definition).  Patients who are not DLT evaluable must be replaced, if needed. 
Clinically important or persistent AEs that are not part of the DLT criteria may also be considered a 
DLT following review by the sponsor in consultation with the investigators.  All AEs should be 
considered potentially related to the study drug regardless of investigator/sponsor causality assessment, 
excluding toxicities clearly related to disease progression or intercurrent illness.  Additionally, any 
clinically significant AEs that occur after the DLT assessment window (eg, late immune-mediated AE 
[imAE]) for a given dose level, may be considered regarding subsequent dose escalation decisions.  In 
such cases where patients have been safely dosed at the next dose level, additional dose escalation 
criteria (eg, increased minimum number of patients or expanded DLT assessment window) for 
subsequent dose levels will be considered by the sponsor in consultation with participating 
investigators.  Every DLT will be discussed in SMC to help the determination of RP2D.  
Dose Verification in China 
Before Chinese patients join the Phase 1b study, ociperlimab (RP2D; determined from the dose-
escalation stage) as a monotherapy (Cohort 1A) and in combination with tislelizumab (200 mg Q3W) 
(Cohort 1B) will be assessed.  For each cohort, 6 to 10 Chinese patients will be enrolled to assess the 
safety and tolerability of the combination RP2D similar to the Phase 1 as outlined in Section 3.2.2.  
The assessment period will be 21 days, with ociperlimab RP2D administered on Cycle 1 Day 1 alone 
in Cohort 1A, and in combination with tislelizumab 200 mg administered on Cycle 1 Day 1 in 
Cohort 1B.  De-escalation will be performed if excessive DLTs were observed, and a lower dose will 
be assessed in Cohort 2A (monotherapy) and Cohort 2B (in combination with tislelizumab) as 
specified in Section 3.2.2.  All available safety data, including AEs and laboratory assessments, will be 
reviewed by the sponsor’s medical monitor and study team members from Pharmacovigilance/Drug 
Safety, and Biostatistics with input from other members as appropriate.  The SMC will recommend the 
RP2D for Chinese patients based on the safety data of ociperlimab combined with tislelizumab 200 mg 
before they join the Phase 1b study. 
Tumor Assessments 
Tumor imaging will be performed ≤ 28 days before the first dose of study drugs.  During the study, 
tumor imaging will be performed approximately every 6 weeks (± 7 days) for the first 54 weeks, then 
every 12 weeks (± 7 days) thereafter. 
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Response will be assessed by investigators using RECIST v1.1.  If radiographic progressive disease 
(PD) is suspected by the investigator to reflect pseudoprogression, patients may continue treatment 
with study drugs as long as the patient meets criteria below and until PD is confirmed by repeated 
imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from the date of initial documentation of PD).  
At the investigator’s discretion, if a patient could continue to benefit from ociperlimab and tislelizumab 
after PD per RECIST v1.1 criteria, the patient may continue ociperlimab and tislelizumab.  The 
following criteria must be met in order to treat patients with suspected pseudoprogression or who may 
continue to benefit from study treatment beyond radiologic 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  
(Appendix 3)  
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) that requires urgent alternative medical intervention 
• 
Investigators must obtain written informed consent for treatment after PD confirmation 
and inform patients that this practice is not considered standard in the treatment of cancer. 
The decision to continue study drugs beyond initial investigator-assessed progression must be agreed 
by the medical monitor and documented in the study records.  Patients who receive study treatment 
beyond progression will have tumor assessments performed according to the original schedule until 
study treatment discontinuation (Section 8.5). 
A patient who discontinues study drugs early for reasons other than PD (eg, toxicity) will continue to 
undergo tumor assessments following the original plan until the patient meets one of the 
discontinuation criteria (see Section 7.5). 
Duration of Patient Participation: 
This study will consist of 5 periods: 
1. Screening Period will be performed ≤ 28 days before first dose of ociperlimab.  
2. Treatment Period starts with the first study drug administration and ends when the patient is 
discontinued from study treatment for any reason. 
3. End-of-Treatment/Safety Follow-up Period: Patients who permanently discontinue study 
drugs will be asked to return to the clinic for the End-of-Treatment (EOT) which is required to 
be conducted ± 7 days after EOT decision and the Safety Follow-up Visit which is required to 
be conducted 30 days (± 7 days) after the last dose of study drugs unless otherwise specified or 
before the initiation of subsequent anticancer therapy, whichever occurs first.  In addition, 
telephone contacts with patients should be conducted to assess imAEs and concomitant 
medications (if appropriate, ie, associated with an imAE or is a subsequent anticancer therapy) 
at 60 and 90 days (± 14 days) after the last dose of study drugs regardless of whether or not 
patients started a subsequent anticancer therapy.  If patients report a suspected imAE at a 
telephone follow-up contact, the investigator should arrange an unscheduled visit if further 
assessment is indicated. 
4. Efficacy Follow-up Period: Patients who discontinue study drugs for reasons other than PD 
(eg, toxicity) will continue to undergo tumor assessments following the original tumor 
assessment schedule until the patient experiences PD, withdraws consent, dies, or starts 
subsequent anticancer therapy, or for any other reason listed in Section 7.5.2, whichever occurs 
first. 
5. Survival Follow-up (Phase 1b): In Phase 1b, patients will be followed for survival and to 
obtain information on subsequent anticancer therapy information after discontinuation of study 
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treatment 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:  
Phase 1: Patients with histologically or cytologically confirmed unresectable locally advanced or 
metastatic solid tumors previously treated with standard systemic therapy or for which treatment is not 
available or not tolerated, and who have not received prior therapy targeting TIGIT.   
Phase 1b: Patients with histologically or cytologically confirmed tumor types based on the disease 
cohorts as below:   
• 
Cohort 1: Patients with metastatic squamous NSCLC  
• 
Cohort 2: Patients with metastatic non-squamous NSCLC 
• 
Cohort 3: Patients with metastatic NSCLC (PD-L1 positive, tumor cell expression [TC] 
≥ 1%) 
• 
Cohort 4: Patients with extensive-stage small cell lung cancer (ES-SCLC) 
• 
Cohort 5: Checkpoint inhibitor (CPI)-experienced NSCLC patients who have received 1 
or 2 prior therapies, including an anti-PD-(L)1 in the most recent line of treatment, and 
progressed after a best response of complete response (CR), partial response (PR), or 
stable disease (SD) 
• 
Cohort 6: Patients with metastatic esophageal squamous cell carcinoma (ESCC)  
• 
Cohort 7: Patients with metastatic esophageal adenocarcinoma (EAC) 
• 
Cohort 8: Patients with recurrent or metastatic head and neck squamous cell carcinoma 
(HNSCC) (PD-L1 positive, visually-estimated Combined Positive Score [vCPS] ≥ 1%) 
• 
Cohort 9: Patients with metastatic gastric or gastroesophageal junction (G/GEJ) 
adenocarcinoma 
• 
Cohort 10: Patients with metastatic NSCLC (PD-L1 positive, TC ≥ 1%) 
Key Eligibility Criteria: 
Adult patients (≥ 18 years of age or the legal age of consent, at the time of voluntarily signing of 
informed consent) with histologically or cytologically confirmed tumor type based on the disease 
cohorts (metastatic squamous NSCLC; metastatic non-squamous NSCLC; metastatic NSCLC with 
PD-L1 positive; extensive-stage SCLC; CPI-experienced NSCLC; metastatic ESCC; metastatic EAC; 
recurrent or metastatic HNSCC with PD-L1 positive; metastatic G/GEJ adenocarcinoma).  All patients 
are also required to demonstrate an ECOG Performance Status score of ≤ 1 and adequate organ 
function. 
Investigational Product, Dose, and Mode of Administration: 
Phase 1 
Dose Escalation in Australia:  
For dose escalation, a 28-day DLT observation period will be utilized in the first cycle.  A flat dose of 
ociperlimab will be administered intravenously as a single agent on Day 1 of each cycle followed by a 
200 mg tislelizumab administered intravenously on Day 8.  To be DLT evaluable, patients must 
receive ociperlimab alone on Day 1 of Cycle 1, followed by tislelizumab alone on Cycle 1 Day 8 
(+ 2 days).  Refer to Section 5.4.1 and Section 5.4.2 regarding continued treatment of patients who are 
unable to receive tislelizumab on Cycle 1 Day 8 (+2 days).  If no DLT(s) are observed thereafter and 
through the completion of the initial 28-day cycle, patients will receive ociperlimab and tislelizumab 
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on Day 29 and every 21 days (ie, Q3W) thereafter, as outlined in Section 5.2.1 and Appendix 1, until 
patients meet a treatment discontinuation criterion.  Except for the dose escalation DLT period, a 
21-day treatment cycle is planned for all cycles.   
The starting ociperlimab dose level (50 mg) will initially be evaluated in 1 patient (sentinel patient), 
whereas the second ociperlimab dose level (150 mg) will be evaluated in 3 or more patients.  
Escalation from the first ociperlimab dose level will proceed if no DLT is observed in the DLT 
evaluable patient.  If a DLT is observed in this sentinel patient, the dose will be further explored 
following the 3+3 rules.  Starting with the 150 mg ociperlimab dose level, escalation of the ociperlimab 
dose level will proceed if no DLT is observed during the DLT period in a minimum of 3 evaluable 
patients.   
However, if a DLT occurs within the DLT observation period for a given dose level, enrollment for 
that dose level and dose finding decisions will proceed per the 3+3 design rules as follows: 
a. ociperlimab dose escalation will advance if the first cycle DLT rate < 33%; 
b. ociperlimab dose escalation will stop if the first cycle DLT rate is ≥ 33%.  A minimum of 
6 patients will be enrolled to the current dose level of ociperlimab if DLT rate is 33% (eg, 1/3) 
or the next lower dose level if DLT rate is >33% (eg, 2/3 or 3/3); 
c. The MTD dose level is defined as the highest dose level at which < 33% of the patients 
experience a DLT. 
For dose escalation decisions, only DLTs occurring within 28 days of Cycle 1 Day 1 for the 
corresponding dose level will be evaluated.  However, as noted below and in Section 3.2.1.4, 
additional considerations may be taken into account if clinically significant toxicity(ies) is observed, 
regardless of when it occurred. 
Based upon emerging clinical data, lower, intermediate and/or higher dose levels and/or alternative 
dosing intervals of ociperlimab may also be evaluated.  However, the dosing regimen of tislelizumab 
will remain fixed for each different ociperlimab dose level evaluated. 
The combination RP2D will be determined primarily from the Phase 1 safety, tolerability and PK data 
analyzed in its entirety, but may also consider any available efficacy and/or exploratory data, from a 
minimum of 6 patients.   
Dose Verification in China: 
Before Chinese patients join the Phase 1b study, safety and tolerability of ociperlimab (RP2D) will be 
assessed as a monotherapy, and in combination with tislelizumab (200 mg Q3W) in Chinese patients.  
The SMC will define the RP2D for Chinese patients based on the safety data from ociperlimab, 
combined with tislelizumab 200 mg, before Chinese patients join the Phase 1b study. 
Phase 1b 
For dose expansion, tislelizumab (200 mg) in combination with ociperlimab (RP2D) with or without 
chemotherapy will be administered Q3W starting on Cycle 1 Day 1. 
For Cohort 10, tislelizumab (200 mg) in combination with ociperlimab 450 mg, 900 mg, or 1800 mg 
will be administered Q3W starting on Cycle 1 Day 1 in the 3 arms. 
Statistical Methods: 
Descriptive statistics will be mainly used in describing the safety, tolerability, and the anticancer 
activities of the ociperlimab as monotherapy and in combination with tislelizumab.  The safety and 
efficacy data will be presented by study phase.  Data from Phase 1 will be summarized by dose except 
that data from dose verification in Chinese patients will be summarized as a separate part by cohort.  
Data from Phase 1b (dose expansion) will be summarized by tumor type.  For Cohort 10, data will be 
summarized by treatment arm and total.  The sample sizes are mainly determined following 3+3 design 
for dose escalation and two-stage design based on Bayesian predictive probability for dose expansion.  
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Analysis Sets: 
• 
Safety Analysis Set includes all patients who received ≥ 1 dose of study drugs.  This will be 
the analysis set for the safety analyses. 
• 
Efficacy Evaluable Analysis Set includes all patients who received ≥ 1 dose of study drugs, 
have evaluable disease at baseline, and ≥ 1 evaluable postbaseline tumor response assessment 
unless any clinical PD or death occurred before the first postbaseline tumor assessment. 
• 
DLT Evaluable Analysis Set includes patients who received ≥ 80% each of the assigned doses 
ociperlimab and tislelizumab according to the treatment schedule, remained on study during 
the DLT observation period, and had sufficient safety evaluation or patients who experienced a 
DLT within the DLT observation period. 
• 
The PK Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have ≥ 1 
derivable PK parameter. 
• 
The ADA Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have 
both baseline ADA and ≥ 1 postbaseline ADA results. 
 
Efficacy Analyses: 
Primary and/or secondary efficacy endpoints will be based upon investigators’ tumor assessments per 
RECIST v1.1 and will be summarized as follows to evaluate the preliminary antitumor activity of 
ociperlimab in combination with tislelizumab with or without chemotherapy: 
• 
ORR is defined as the proportion of patients who had CR or PR. 
• 
DOR is defined as the time from the first determination of an overall response per RECIST 
v1.1, until the first documentation of progression or death, whichever comes first. 
• 
DCR is defined as the proportion of patients with best overall response (BOR) of CR, PR, or 
SD. 
• 
PFS is defined as the time from the date of the first dose of study drugs to the date of the first 
documentation of PD assessed by the investigator using RECIST v1.1 or death, whichever 
occurs first. 
• 
OS is defined as time from the first dose of study drugs to the date of death due to any cause. 
PFS and DOR will be estimated using the Kaplan-Meier method.  Waterfall plots of maximum tumor 
shrinkage per patient will be presented. 
 
Safety Analyses: 
Safety will be determined by the spontaneous reporting of AEs and by laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis).  Vital signs, physical examinations, and ECG findings 
will also be used in determining the safety profile.  The severity of AEs will be graded according to the 
NCI-CTCAE v5.0.  The incidence of DLTs 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, maximum for continuous variables; n [%] for categorical 
variables) and changes from baseline, will be determined for laboratory parameters and vital signs. 
 
Pharmacokinetic Analyses: 
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Noncompartmental analysis will be carried out for ociperlimab and tislelizumab serum concentrations.  
The PK analyses will include patients with sufficient data to enable estimation of key parameters, and 
the parameters such as Cmax, Cmin, Tmax, AUC0-21d, CL, and Vss (as appropriate for data collected) may 
be derived and summarized with descriptive statistics (mean, standard deviation, and coefficient of 
variation). 
Individual and mean serum ociperlimab and tislelizumab concentration versus time data will be 
tabulated and plotted by dose level except that the data from dose verification in Chinese patients will 
be tabulated and plotted separately by cohort. 
Additional PK analyses may be conducted as appropriate. 
 
Sample Size Consideration: 
The study may enroll up to approximately 294 to 564 evaluable patients: 
• 
Phase 1: Approximately 44 to 64 patients 
• 
Phase 1b: Approximately 250 to 500 evaluable patients 
For dose escalation in Phase 1, 32 patients should be sufficient to evaluate the safety and tolerability of 
increasing dose levels of ociperlimab in combination with tislelizumab per the modified 3+3 design 
rules with extra patients on R2PD for further evaluation.  An extra 12 to 32 Chinese patients will 
receive ociperlimab as monotherapy or in combination with tislelizumab as dose verification.  Overall, 
44 to 64 patients will be enrolled in Phase 1. 
For dose expansion in Phase 1b, 10 cohorts are planned, with approximately 20 to 40 evaluable 
patients for Cohorts 1 to 8, and 30 to 60 evaluable patients for Cohort 9.  For Cohort 10, approximately 
60 to 120 evaluable patients (20 to 40 patients for each of the 3 arms) will be enrolled.  A two-stage 
design based on Bayesian predictive probability (Lee and Liu 2008) will be implemented for these 
cohorts.  The predictive probability of achieving a potential target ORR will be calculated in the 
interim analysis for Cohorts 1 to 8 after approximately 20 evaluable patients have completed ≥ 1 
postbaseline tumor assessment, for Cohort 9 after approximately 30 evaluable patients have completed 
≥ 1 postbaseline tumor assessment, and for Cohort 10 after approximately 20 evaluable patients in each 
arm have completed ≥ 1 postbaseline tumor assessment.  The interim analysis will be carried out in a 
timely manner as soon as data becomes available.  The enrollment beyond 20 evaluable patients for 
Cohorts 1 to 8, 30 evaluable patients for Cohort 9, and 20 evaluable patients for each arm of Cohort 10 
may be allowed before the assessment is performed.  The potential target ORR can be chosen based on 
historical rate and may be further updated with the study conduct when relative emerging information 
becomes available.  If the predictive probability is less than 0.2 for the first 20 evaluable patients in 
Cohorts 1 to 8, for the first 30 evaluable patients in Cohort 9, and the first 20 evaluable patients in each 
arm of Cohort 10, enrollment will stop.  If the predictive probability is larger than 0.8, enrollment may 
stop with high confidence of achieving potential target ORR.  If the predictive probability is between 
0.2 and 0.8, extra 20 evaluable patients for Cohorts 1 to 8, extra 30 evaluable patients for Cohort 9, and 
extra 20 evaluable patients for each arm of Cohort 10 may be enrolled to evaluate the anticancer 
activities. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADAs 
antidrug antibodies 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BOR 
best overall response 
CD 
cluster of differentiation 
CK 
creatine kinase 
CK-MB 
creatine kinase-muscle/brain 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum observed plasma concentration 
CPI 
Checkpoint inhibitor 
CPS 
Combined Positive Score 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EAC 
esophageal adenocarcinoma 
EDC 
electronic data capture (system) 
EOT 
End-of-Treatment (Visit) 
ESCC 
esophageal squamous cell carcinoma 
ES-SCLC 
extensive-stage small cell lung cancer 
FDG 
fluorine-18 [F-18] fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin embedded 
GCP 
Good Clinical Practice 
GC 
Gastric cancer 
G/GEJ 
Gastric or gastroesophageal junction  
GEP 
gene expression profiling 
GFR 
glomerular filtration rate 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBV 
hepatitis B virus 
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Abbreviation 
Definition 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HNSCC 
head and neck squamous cell carcinoma 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IgG1 
immunoglobulin G1 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITIM 
immunoreceptor tyrosine-based inhibitory motif 
ITT 
immunoreceptor tail tyrosine 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect level 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
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 
PVR 
Poliovirus receptor 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QT 
measure of the time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCLC 
small cell lung cancer 
SMC 
Safety Monitoring Committee 
T3 
triiodothyronine 
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Abbreviation 
Definition 
T4 
Thyroxine 
TEAE 
treatment-emergent adverse event 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
TIM-3 
T cell immunoglobulin and mucin-domain containing-3 
tislelizumab 
BGB-A317 
TIL 
tumor-infiltrating lymphocyte 
tmax 
time to maximum plasma concentration 
TPS 
tumor proportion score 
TMB 
tumor mutation burden 
ULN 
upper limit of normal 
vCPS 
visually-estimated Combined Positive Score 
 
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1. 
INTRODUCTION AND RATIONALES  
1.1. Introduction  
Immune surveillance plays a critical role in preventing progression and metastasis.  However, 
tumors have developed resistance mechanisms to suppress and/or escape the host immune 
system, thereby enabling tumorigenesis to proceed unchecked (Schreiber et al 2011; 
Swann and Smyth 2007).  One such resistance mechanism involves upregulation of immune 
checkpoint receptors expressed on immune cells (eg, effector T cells), such as programmed cell 
death protein-1 (PD-1) and T cell immunoglobulin and immunoreceptor tyrosine-based 
inhibitory motif (ITIM) domain (TIGIT) (Johnston et al 2014; Chauvin et al 2015).  
Blocking antibodies targeting PD-1/programmed cell death protein-ligand 1 (PD-L1) have 
achieved remarkable results in the treatment of many types of tumors, but it is also worth noting 
that this therapeutic strategy typically achieves a < 30% overall response rate (ORR) as a 
monotherapy in patients whose tumors exhibit low positive PD-L1 expression and/or are 
microsatellite stable (Chen and Han 2015; Gong et al 2018; Vanella et al 2017).  In addition, 
dual PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade further 
improved clinical outcome in melanoma patients (Wolchok et al 2013).  It is therefore expected 
that targeting multiple immune inhibitory pathways in the tumor microenvironment will prove 
useful for more patients with advanced cancers.  For example, the inhibitory activity of TIGIT 
has been shown to be dependent on expression levels of its costimulatory counterpart CD226 
(DNAX accessory molecule-1 or DNAM-1), either through competition for a common ligand or 
via direct interaction (Yu et al 2009; Johnston et al 2014).  Subgroup analysis of patients with the 
highest TIGIT/CD226 ratio that were treated with anti-PD-1 and/or anti–CTLA-4 agents showed 
a significantly worse progression free survival of 2 months versus 12 months (p = 0.039) 
(Fourcade et al 2018).  The combination of anti-PD-1/anti–PD-L1 with anti-TIGIT therapies has 
also shown significant synergistic antitumor effects and increased immune activation relative to 
anti–PD-1 monotherapy in both colon and glioblastoma mouse models (Johnston et al 2014; 
Hung et al 2018).  Based upon this, the following combination of drugs will be evaluated in 
patients with advanced malignancies. 
Ociperlimab (also known as BGB-A1217) is a humanized, immunoglobulin G1-wild type 
monoclonal antibody against TIGIT.  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies. 
1.2. Ociperlimab as a TIGIT Inhibitor  
TIGIT (also known as VSIG9, VSTM3, or WUCAM) is a 26 kDa type I transmembrane 
glycoprotein and an immune checkpoint receptor, a 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 cDNAs coding for TIGIT were cloned 
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and characterized in mouse and human (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 1-120, and the transmembrane domain and cytoplasmic 
C-terminal tail comprises residues 121-223. 
TIGIT-deficient mice (TIGIT-/-) showed increased susceptibility to an experimental autoimmune 
model (Joller et al 2014).  TIGIT overexpressing natural killer (NK) cells produced less 
interferon-gamma (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- and IL-17 by antigen-restimulated splenocytes and antigen-specific 
proliferation.  Consistent with these observations, blockade of 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).  All 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, all of which could be rescued by TIGIT blocking antibodies or TIGIT expression 
knockdown (Chauvin et al 2015; Joller et al 2014; Lozano et al 2012).  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 Tregs, with higher expression of effector molecules, 
such as IL-10, granzymes, and Fgl2 (Joller et al 2014).  A high TIGIT/CD226 ratio in Tregs 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 poliovirus receptor–related 2 (PVR-L2) (CD112, or 
nectin-2).  These ligands are primarily expressed on antigen-presenting cells and tumor cells 
(Casado et al 2009; Levin et al 2011; Stanietsky et al 2009; Yu et al 2009).  The binding affinity 
of TIGIT to PVR (equilibrium dissociation constant [KD]: ~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: ~100nM) 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 (ITT) 
like motif.  In NK cells, TIGIT engagement induces the phosphorylation of tyrosine residues in 
its ITIM and ITT-like motifs through the Src kinases Fyn and Lck.  Then the phosphorylations of 
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TIGIT would lead to binding of Grb2 and β-arrestin 2 and subsequently recruitment of SHIP-1 
and SHP-2 to terminate PI3K and NK-κB signaling in the NK cells (Liu et al 2013; Stanietsky et 
al 2009).  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 tumor-infiltrating lymphocytes (TILs) has been reported in 
many types of cancers, such as lung (Tassi et al 2017), stomach (He et al 2017), breast (Gandara 
et al 2018; Gil Del Alcazar et al 2017), esophageal (Xie et al 2016), brain (Hung et al 2018), 
acute myeloid leukemia (Kong et al 2016), and melanoma (Mahnke et al 2016).  Interestingly, 
TIGIT expression appears to be minimally expressed by peripheral effector cells while 
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 (Yin et al 2018; Chauvin et al 2015).  Blockade of 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 CT26.WT mouse colon cancer model, anti-mouse TIGIT antibody of mIgG2a isotype 
(antibody-dependent cellular cytotoxicity enabling) demonstrated potent antitumor activity either 
in monotherapy or 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 activity (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 the 
interaction of anti-TIGIT with FcγR on antigen-presenting cells enhanced antigen-specific T cell 
responses and antitumor activity. 
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.  Blocking 
antibodies targeting the PD-1/PD-L1 pathway have achieved remarkable results in the treatment 
of many different tumor types.  However, based upon the rate of primary and secondary 
resistance to PD-1 blockade, it is apparent that additional immuno-regulatory mechanism(s) 
underlie tumor immune escape.  Indeed, research shows that the TIGIT pathway cooperates with 
PD-1 to maximize the suppression of effector TILs as well as 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 to a greater number of patients. 
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1.2.1. 
Nonclinical  
1.2.1.1. 
Pharmacology  
Ociperlimab binds to the extracellular domain of human TIGIT with high specificity and affinity 
(equilibrium dissociation constant [KD] = 0.135 nM), as demonstrated by target-binding assays 
and SPR characterization.  It competitively blocks TIGIT binding to PVR.  In in vitro cell-based 
assays, ociperlimab “in a dose dependent manner”: “consistently and dose-dependently enhances 
the functional activities of activated human peripheral blood mononuclear cells (PBMCs)”.  In 
addition, ociperlimab has shown antitumor activities in both the GL261 mouse glioma tumor 
model and the CT26.WT mouse colon cancer model in humanized TIGIT knock-in mice.  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 constant region of a wild-type human immunoglobulin G1 (IgG1) to enable the 
Fc-mediated effector functions.  Ociperlimab has demonstrated competent binding to C1q and all 
FcγRs, including FcγRI, FcγRIIA, FcγRIIB, and FcγRIIIA, in in vitro binding assays, and 
induces antibody-dependent cellular cytotoxicity against TIGIT overexpressing cell line, but no 
antibody-dependent cellular cytotoxicity 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. 
1.2.1.2. 
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 are the most 
relevant species based on the homology sequence of TIGIT, though it demonstrates a relatively 
lower ociperlimab binding affinity compared to human TIGIT (with EC50 756-fold weaker).  
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 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 repeat dose 
toxicology study in humanized TIGIT knock-in mice and a 13-week repeat dose toxicology 
study in cynomolgus monkeys.  These toxicity studies were conducted following Good 
Laboratory Practice regulations.  Furthermore, ociperlimab was evaluated in a 4-week repeat 
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 upon the target sequence homology and 
cross-species TIGIT binding activities of ociperlimab.  The tissue cross reactivity was evaluated 
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in the normal frozen tissues from humans.  The cytokine release responses were 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 following repeated dosing at 10, 30, or 
100 mg/kg once every 2 weeks (Q2W) 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 gender 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 one animal with strong ADA response at 5 mg/kg 
dose, most of these animals showed weak ADA signal or were proved to be false positives.  In 
monkeys, positive ADAs against ociperlimab were observed in 6/10, 3/10, and 4/10 animals 
during the dosing period, and 3/4, 2/4, and 2/4 during the recovery period, at 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. 
The tissue cross reactivity of ociperlimab was evaluated in normal human frozen tissues using an 
immunohistochemistry (IHC) method, with 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 IHC method. 
No significant increase in cytokine release was observed from an in vitro cytokine release assay 
following treatment of non-activated PBMCs with ociperlimab when compared to human IgG.  
The results suggested that ociperlimab had potentially low risks of causing acute cytokine release 
syndrome. 
Overall, no apparent toxicity was noted in the monkey or transgenic mice toxicity studies.  No 
unexpected tissue cross reactivity was found in human or monkey tissues.  The toxicokinetic 
profile was well characterized with dose proportional increases in systemic exposure without 
apparent accumulation or sex difference.  Immunogenicity was observed without apparent 
immunotoxicity 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. 
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1.2.2. 
Clinical Experience  
To date, first-in-human Phase 1-2 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. 
Clinical data has been released for Merck’s MK-7684 (Golan et al 2018) and OncoMed’s 
OMP-313M32 (Sharma et al 2018).  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, with doses ranging from 2.1 mg to 700 mg.  Merck’s MK-7684 
enrolled patients with metastatic solid tumors that failed standard treatment options, measurable 
disease, and Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 for the Phase 
1 dose escalation.  The preliminary results showed that MK-7684 was well tolerated in the dose 
escalation phase of the study, with no dose-limiting toxicity (DLT).  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.  Further, 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, 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, 
linear pharmacokinetics (PK) were reported at doses 200 mg and above of MK-7684. 
A total of 18 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.  Oncomed’s OMP-313M32 
enrolled patients with advanced solid tumors into either a Phase 1a single-agent portion (dose 
escalation in all comers + expansion in selected tumor types) or a Phase 1b combination 
[PD-(L)1 refractory] portion with nivolumab (dose escalation).  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%).  Of the 
18 patients treated with OMP-313M32 alone, there were no responses, yet a 38.9% DCR was 
observed.  Based upon the established safety as a 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 microsatellite instability-high (MSI-H) tumors 
(NCT03119428).  In addition, there are several ongoing Phase 2 and Phase 3 studies of 
anti-TIGIT antibodies evaluating the efficacy and tolerability in the non-small cell lung cancer 
(NSCLC) (NCT03563716, NCT04294810, NCT04165070 and NCT04262856) and 
extensive-stage small cell lung cancer (ES-SCLC) (NCT04256421). 
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The Phase 1 study data of tiragolumab was released in 2020 American Association for Cancer 
Research (AACR).  No objective responses occurred in 23 patients treated with tiragolumab 
monotherapy in Phase 1a.  However, 11% patients had achieved PR in 44 patients treated with 
tiragolumab combined with atezolizumab in Phase 1b (Bendell et al 2020).  A total of 
135 patients with previously untreated PD-L1–selected NSCLC have been treated with 
tiragolumab 600 mg IV Q3W plus atezolizumab 1200 mg IV Q3W (n = 67) or atezolizumab 
1200 mg IV Q3W plus placebo IV Q3W (n = 68) in a Phase 2 study (CITYSCAPE) sponsored 
by Genentech/Roche (Rodriguez-Abreu et al 2020).  Patients were randomly assigned to one of 
these treatment groups and were stratified by tumor proportion score (TPS) (1% to 49% or 
≥ 50%), histology (squamous versus non-squamous), and tobacco use (yes or no).  Preliminary 
efficacy results showed a clinically meaningful improvement in ORR and median 
progression-free survival (mPFS) in patients treated with tiragolumab plus atezolizumab (ORR 
31%; mPFS 5.42 months) compared with those treated with atezolizumab plus placebo (ORR 
16%; mPFS 3.58 months).  This improvement was still observed 6 months later: tiragolumab 
plus atezolizumab (ORR 37%; mPFS 5.55 months) compared with atezolizumab plus placebo 
(ORR 21%; mPFS 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%).  Based on 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). 
All of these findings support further development of anti-TIGIT antibody in combination with 
existing therapeutic modalities. 
1.2.2.1. 
Preliminary Safety  
As of the data cutoff date of 28 July 2021, a total of 133 patients received ociperlimab treatment 
in Study AdvanTIG-105 and Study AdvanTIG-202.  In Study AdvanTIG-105, 900 mg 
ociperlimab was administered as monotherapy in 9 patients in Cohort 1A (dose verification in 
China).  Seventy-six patients have been enrolled and treated with ociperlimab at doses of 50, 
150, 450, 900, or 1800 mg in combination with tislelizumab 200 mg and have cleared the DLT 
period without DLTs in the Phase 1 dose-escalation part of the study.  Twenty-five patients from 
the dose-expansion Cohorts 1, 2, 4, 6, 7, and 9 were treated with ociperlimab in combination 
with tislelizumab 200 mg and chemotherapies.  In Study AdvanTIG-202, 23 patients have been 
treated with ociperlimab at a flat dose of 900 mg in combination with tislelizumab 200 mg in 
Cohort 1.  Ociperlimab continues to appear to be safe and well-tolerated up to and including the 
900 mg dose level. 
As of the data cutoff date of 28 July 2021, of the 133 patients in the Safety Analysis Set, 
117  (88%) experienced ≥ 1 treatment-emergent adverse event (TEAE) and 77 patients (57.9%) 
experienced ≥ 1 TEAE related to ociperlimab.  TEAEs ≥ Grade 3 in severity were experienced 
by 53 of 133 patients (39.8%), and 8 patients (6.0%) experienced ≥ Grade 3 TEAE related to 
ociperlimab.  Forty-seven patients (35.3%) had serious TEAEs, 7 (5.3%) of these were 
considered related to ociperlimab.  Nine patients (6.8%) experienced TEAEs that led to 
discontinuation of ociperlimab.  Six patients (4.5%) experienced TEAE that led to death, but 
none of them were assessed as related to ociperlimab.  No TEAEs were considered to be DLT. 
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Please refer to the Ociperlimab Investigator’s Brochure for detailed safety information. 
1.2.2.2. 
Clinical Pharmacology  
The first-in-human study AdvanTIG-105 evaluating safety and tolerability of ociperlimab in 
combination with tislelizumab in advanced solid tumors is still ongoing.  Preliminary PK data 
are available from a total of 51 patients treated with ociperlimab 50 mg, 150 mg, 450 mg, 
900 mg, and 1800 mg dose levels in combination with tislelizumab 200 mg in the 
dose-escalation and dose-verification portions of Study AdvanTIG-105.  Serum concentrations 
of ociperlimab decreased in biexponential manner after administration.  The mean elimination 
half-life ranged from 7.1 to 10.5 days.  In Cycle 1, ociperlimab exposures (AUC and Cmax) 
increased approximately dose proportionally from the 50 mg to the 1800 mg dose.  Postdose PK 
sampling duration may not be sufficient for robust characterization of elimination half-life using 
noncompartmental analysis (NCA); hence, the reported half-life values should be interpreted 
with caution.   
The TIGIT receptor occupancy data were available as of 23 July 2021 for 32 enrolled patients 
treated with ociperlimab at the 50 mg (n = 1), 150 mg (n = 3), 450 mg (n = 6), 900 mg (n = 16), 
and 1800 mg (n = 6) dose levels in Study AdvanTIG-105.  Complete TIGIT receptor occupancy 
(100%) was observed on CD8+ and CD4+ T cells, and regulatory T cells in peripheral blood at 
all the tested dose levels. 
Please refer to the Ociperlimab Investigator’s Brochure for detailed Clinical Pharmacology 
information. 
1.2.2.3. 
Efficacy  
The first-in-human Study AdvanTIG-105 evaluating efficacy of ociperlimab in combination with 
tislelizumab in advanced solid tumors is still ongoing. Efficacy data from Study AdvanTIG-105 
(as of the data cutoff date of 21 February 2021) were presented at the 2021 meeting of the 
American Society of Clinical Oncology.  A total of 26 evaluable patients received ociperlimab 
(dose range: 50 to 900 mg) in combination with tislelizumab 200 mg.  One patient was treated 
with ociperlimab 50 mg, 3 patients were treated with ociperlimab 150 mg, 6 patients were treated 
with ociperlimab 450 mg, and 16 patients were treated with ociperlimab 900 mg.  PR was 
observed in 2 patients (1 receiving ociperlimab 450 mg, and 1 receiving ociperlimab 900 mg).  
Stable disease was observed in 9 patients (1 receiving ociperlimab 150 mg, 3 receiving 
ociperlimab 450 mg, and 5 receiving ociperlimab 900 mg).  The longest duration of stable 
disease (SD) was 54 weeks (1 patient receiving ociperlimab 150 mg).  Three patients (2 
receiving ociperlimab 450 mg and 1 receiving ociperlimab 900 mg) had a > 30% reduction in 
target lesions.  More follow-up data will be updated in further updates to the Investigator’s 
Brochure (IB). 
1.3. Tislelizumab as a PD-1 Inhibitor  
1.3.1. 
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. 
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Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD] = 0.15 nM).  It competitively blocks binding 
efforts by both programmed cell death protein ligand-1 (PD-L1) and programmed cell death 
protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T cells.  In in vitro 
cell-based assays, tislelizumab was observed to consistently and dose-dependently enhance the 
functional activity of human T cells and pre-activated, primary peripheral blood mononuclear 
cells.  Tislelizumab has demonstrated in-vivo antitumor activity in several allogeneic xenograft 
models, in which peripheral blood mononuclear cells 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 gamma fragment crystallizable region (Fc) receptors 
(FcγR) such as FcγRI and FcγRIIIA, and it has very low binding affinity to Complement 1q 
(C1q), a subunit of complement 1.  In vitro assays with tislelizumab suggest either low or no 
antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis 
(ADCP), or complement-dependent cytotoxicity (CDC) effects in humans (Labrijn et al 2009).  
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. 
1.3.2. 
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.  Tissue cross-reactivity was evaluated in normal frozen tissues from both 
humans and monkeys.  The cytokine release assays were conducted using fresh human whole 
blood cells.  The pivotal toxicology studies were conducted following Good Laboratory Practice 
(GLP) regulations.  The single-dosing regimens spanned from the intended human doses to 
10-fold higher than the maximum of the intended human doses, and the repeat-dosing regimens 
spanned to 3-fold higher than the maximum of the intended human doses.  Cynomolgus monkey 
was the only relevant species based on the target sequence homology and binding activity. 
Overall, no apparent toxicity was noted in mice 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.  The safety profile of tislelizumab is 
considered adequate to support the current study, Study AdvanTIG-105. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
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1.3.3. 
Clinical Pharmacology  
Based on pooled data from 2596 patients across 12 clinical studies, the PK of tislelizumab was 
best characterized using a 3-compartmental linear population PK model with linear clearance 
mechanisms.  No time-varying clearance was observed in tislelizumab PK.  The Cmax and AUC 
increased in a nearly dose-proportional manner from 0.5 to 10 mg/kg.  The terminal t1/2 was 
estimated to be approximately 23.8 days, and the steady state is expected to be reached in 
12 weeks.  Tislelizumab PK was generally similar between Chinese patients and patients of other 
ethnic groups and across tumor types.  Please refer to the Tislelizumab Investigator’s Brochure 
for more detailed information on the clinical pharmacology of tislelizumab. 
1.3.4. 
Prior Clinical Experience of Tislelizumab  
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. 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
As of 20 May 2021, 1992 patients with solid tumors had been treated with tislelizumab 
monotherapy in 7 clinical studies. 
A pooled monotherapy analysis was conducted to provide a comprehensive review of the 
tislelizumab safety profile.  Patients included in this analysis (N = 1992) had a median age of 
60.0 years with 72.1% of them being male.  Median treatment exposure duration was 4.1 months 
(range: 0.1 to 41.5) and median study follow-up duration was 11.5 months (range: 0.1 to 58.9). 
Overall, there were 2150 patients in the pooled monotherapy studies: 1992 patients treated in 
7 solid tumor studies and 158 patients treated in 3 hematologic malignancy studies.   
Solid tumor studies included the following: BGB-A317_Study_001 (Phase 1a/1b advanced solid 
tumors), BGB-A317-102 (Phase 1/2 advanced solid tumors), BGB-A317-204 (Phase 2 locally 
advanced or metastatic urothelial bladder cancer), BGB-A317-208 (Phase 2 previously-treated 
unresectable hepatocellular carcinoma), BGB-A317-209 (Previously-treated locally advanced 
unresectable or metastatic MSI-H or Mismatch Repair Deficient [dMMR] Solid Tumors), 
BGB-A317-302 (Phase 3 advanced unresectable/metastatic esophageal squamous cell 
carcinoma), and BGB-A317-303 (Phase 3 non−small cell lung cancer).   
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1.3.4.1.1. Treatment-Emergent Adverse Events Assessed as Related to Tislelizumab  
Of the 1992 patients with solid tumors treated with tislelizumab monotherapy, 1391 (69.8%) 
experienced ≥ 1 treatment-related TEAE.  The most commonly occurring TEAEs (≥ 5% of 
patients) assessed as related to tislelizumab irrespective of grade were aspartate aminotransferase 
(AST) increased (250 patients, 12.6%), ALT increased (242 patients, 12.1%), hypothyroidism 
(197 patients, 9.9%), anaemia (186 patients, 9.3%), rash (159 patients, 8.0%), pruritus 
(142 patients, 7.1%), fatigue (138 patients, 6.9%), decreased appetite (115 patients, 5.8%), blood 
bilirubin increased (111 patients, 5.6%), and diarrhoea (103 patients, 5.2%). 
Two hundred sixty-nine patients (13.5%) 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 (25 patients, 1.3%), and ALT increased and anaemia (20 patients 
each, 1.0%). 
1.3.4.1.2. Treatment-Emergent Serious Adverse Events  
Of the 1992 patients with solid tumors treated with tislelizumab monotherapy, 706 patients 
(35.4%) experienced ≥ 1 treatment-emergent SAE.  The most commonly occurring 
treatment-emergent SAEs (irrespective of relationship to study drug) were pneumonia 
(95 patients, 4.8%), pneumonitis (33 patients, 1.7%), dysphagia (23 patients, 1.2%), and pleural 
effusion and pyrexia (20 patients each, 1.0%). 
Two hundred and nine patients (10.5%) experienced ≥ 1 tislelizumab-related treatment-emergent 
SAE.  The most common treatment-emergent SAEs deemed related to tislelizumab were 
pneumonitis (31 patients, 1.6%).  All other tislelizumab-related treatment-emergent SAEs 
occurred in less than 1% of patients. 
1.3.4.1.3. Immune-Mediated Adverse Events  
Anti-PD-1 therapies are known to cause immune-mediated adverse events (imAEs) in some 
patients and therefore have been defined as AEs of special interest (AESI) in tislelizumab 
clinical studies and as such are being monitored closely. 
The imAEs are consistent with an immune-related mechanism or immune-related component for 
which noninflammatory etiologies (eg, infection or tumor progression) have been ruled out.  The 
imAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity.  There is a potential temporal relationship between the initiation of treatment with 
tislelizumab and the onset of an imAE that spans a window of days to several months. 
All imAEs presented here are assessed as related to study drug by the investigator and 
categorized and adjudicated by the BeiGene Safety/Pharmacovigilance Team.  Certain imAEs 
have multiple Medical Dictionary for Regulatory Activities (MedDRA) terms associated with the 
same category.  Special categories have been created to group patients experiencing these events. 
Of the 1912 patients with solid tumors included in the pooled analysis of imAEs, 286 patients 
(15.0%) experienced ≥ 1 imAE of any grade.  The most commonly occurring imAEs of any 
grade were hypothyroidism (115 patients, 6.0%), pneumonitis (41 patients, 2.1%), 
immune-mediated lung disease (14 patients, 0.7%), rash (13 patients, 0.7%), and ALT increased 
and hyperthyroidism (12 patients each, 0.6%). Analysis of the patients with ≥ 1 imAE that was 
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also ≥ Grade 3 in severity showed that 73 patients (3.8%) experienced such events.  The most 
commonly occurring imAEs that were ≥ Grade 3 in severity were pneumonitis (15 patients, 
0.8%) and interstitial lung disease (7 patients, 0.4%). 
1.3.4.1.4. Infusion-Related Reactions  
Infusion-related reactions, including high-grade hypersensitivity reactions, following the 
administration of tislelizumab are uncommon.  Of the 1992 patients treated with tislelizumab 
monotherapy, 58 patients (2.9%) experienced ≥ 1 infusion-related reaction of any grade.  The 
most commonly occurring infusion-related reactions of any grade were infusion-related reactions 
(28 patients, 1.4%); pyrexia (17 patients, 0.9%); rash (5 patients, 0.3%); and hypotension, 
nausea, and pruritus (3 patients each, 0.2%).  There were 5 patients (0.3%) with ≥ Grade 3 
infusion-related reactions. The most common ≥ Grade 3 IRRs was infusion-related reaction 
(2 patients, 0.1%).  All other ≥ Grade 3 IRRs occurred in single patients. 
1.3.4.1.5. Liver Laboratory Abnormalities  
Of the 1743 patients in the solid tumor group (excluding Study BGB-A317-208) of pooled 
monotherapy studies, 32 patients (1.8%) experienced ALT or AST levels > 3 x upper limit of 
normal (ULN) with a concurrent total bilirubin level > 2 x ULN.  Concurrent elevation of ALP 
(eg, ALP > 2 x ULN) was observed in 29 of these 32 patients.  Of the remaining 3 patients, none 
met the criteria for a Hy’s law case. 
The 3 patients in the solid tumor group (excluding Study BGB-A317-208) with liver laboratory 
abnormalities consistent with potential for Hy’s law were evaluated for the clinical cause of the 
observed changes.  One patient (BGB-A317-303-086007-033) met lab criteria for Hy’s law 
marginally based on a single occurrence of AST and bilirubin elevation at an unscheduled visit 
following Cycle 35.  These results were not considered clinically significant by the investigator.  
The levels returned to the normal range on Day 1 of Cycle 36.  Patients BGB-A317-001-45-207 
and BGB-A317-102-06-225 were females with advanced metastatic gastric or liver cancer with 
extensive hepatic involvement and confirmed hepatic disease progression at the time of the 
observed hepatic laboratory abnormalities.  Neither met the criteria for a Hy’s law case, which is 
based on laboratory criteria and a lack of an alternative medical cause for the observed changes. 
1.3.4.1.6. Fatal Adverse Events  
Out of 1992 patients in the solid tumor group of pooled monotherapy studies, 163 (8.2%) died 
≤ 30 days after their last dose of tislelizumab.  The causes of death for these patients were 
adverse events (54 patients, 2.7%), disease under study (52 patients, 2.6%), disease progression 
(50 patients, 2.5%), and other (7 patients, 0.4%).   
1.3.4.2. 
Efficacy Assessment of Tislelizumab  
As of 20 May 2021, efficacy data are available from 6 of the ongoing monotherapy studies in 
solid tumors, BGB-A317_Study_001, Study BGB-A317-102, Study BGB-A317-203, 
Study BGB-A317-204, Study BGB-A317-207, and Study BGB-A317-208 which are 
summarized below. 
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1.3.4.2.1. Study BGB-A317_Study_001  
Study BGB-A317_Study_001 was a Phase 1a/1b, open-label, multiple-dose, dose-escalation, and 
dose-expansion study to investigate the safety, PK, and antitumor activities of tislelizumab in 
patients with advanced tumors.  Phase 1a consisted of dose-escalation and dose-finding 
components.  Phase 1b investigated efficacy and safety in select tumor types.  The efficacy 
endpoints of the study included ORR, DCR, best overall response (BOR), and clinical benefit 
rate as assessed by the investigator per Response Evaluation Criteria in Solid Tumors Version 
1.1 (RECIST v1.1). 
In Phase 1a, patients received intravenous tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W; 2 or 5 mg/kg 
administered Q2W or Q3W; or 200 mg Q3W.  In Phase 1b, patients received intravenous 
tislelizumab 5 mg/kg Q3W.  
Of the 451 patients treated with tislelizumab in the study, BORs of complete response (CR) were 
reported in 6 patients (1.3%) and of PR in 54 patients (12.0%).  The resulting overall clinical 
response rate (CR + PR) was 13.3%.  Additionally, there were 141 patients (31.3%) with a BOR 
of SD. 
The greatest ORRs were seen in cholangiocarcinoma (31.3%), head and neck squamous cell 
carcinoma (29.4%), colorectal cancer (15.0%), gastric cancer (13.0%), and ovarian cancer 
(12.2%). 
1.3.4.2.2. Study BGB-A317-102  
Study BGB-A317-102 is a Phase 1/2 study investigating safety, tolerability, PK, and preliminary 
antitumor activities of tislelizumab in Chinese patients with advanced solid tumors.  Phase 1 
includes a dose-verification substudy and a substudy of PK evaluation of the products derived 
from 2 manufacturing processes and scales.  Phase 2 is an indication-expansion study.  The 
efficacy endpoints include ORR, DCR, and clinical benefit rate as assessed by the investigator 
per RECIST v1.1. 
Tumor responses were summarized for all disease cohorts composed of > 15 enrolled patients.  
These data represent 238 of 300 patients (79.3%) treated with ≥ 1 dose of tislelizumab in the 
study.  Tislelizumab (200 mg Q3W) demonstrated preliminary antitumor activity across multiple 
tumor types.  Of the presented indications, ORR was ≥ 15% in nasopharyngeal carcinoma (43%), 
MSI-H/dMMR solid tumors (19%), NSCLC (18%), gastric cancer (17%), hepatocellular 
carcinoma (HCC) (17%), and melanoma (15%).  The median duration of response (DOR) was 
only mature for the nasopharyngeal carcinoma cohort, which had a DOR of 8.3 months (range: 
3.9 months to not estimable) with a median follow-up of 4.8 months. 
1.3.4.2.3. Study BGB-A317-203  
Study BGB-A317-203 is a Phase 2, single-arm, multicenter study of tislelizumab monotherapy in 
patients with relapsed or refractory classical Hodgkin's lymphoma (cHL) in China.  The efficacy 
endpoints of the study include ORR, CR rate, and time to response assessed by the Independent 
Review Committee (IRC) per Lugano 2014 Classification.  
The Modified Safety Analysis Set consists of all patients treated with tislelizumab who had 
confirmed cHL.  Of the 70 patients in this analysis set, BORs of CR were reported in 47 patients 
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(67.1%) and of PR in 14 patients (20.0%).  The resulting overall clinical response rate was 
87.1%.  Additionally, there were 2 patients (2.9%) with a BOR of SD. 
1.3.4.2.4. Study BGB-A317-204  
Study BGB-A317-204 is a Phase 2, single-arm, multicenter study of tislelizumab monotherapy in 
patients with previously treated, PD-L1+, locally advanced or metastatic urothelial bladder 
cancer.  The efficacy endpoints of the study include ORR and DCR as assessed by the IRC per 
RECIST v1.1. 
The primary analysis set for this study is the Efficacy Evaluable Analysis Set (N = 104), which 
consists of all patients treated with tislelizumab who had ≥ 1 measurable baseline target lesion as 
assessed by the IRC per RECIST v1.1.  A summary of tumor responses is from a modified 
efficacy analysis set (N = 101) that excludes all patients who had prior platinum-compound 
intolerance (n = 3).  Of the 101 patients, BORs of CR were reported in 10 patients (9.9%) and of 
PR in 15 patients (14.9%).  The resulting overall clinical response rate was 24.8%.  Additionally, 
there were 14 patients (13.9%) with a BOR of SD. 
1.3.4.2.5. Study BGB-A317-207  
Study BGB-A317-207 is a Phase 2, open-label study of tislelizumab monotherapy in patients 
with relapsed or refractory mature T- and NK-cell neoplasms.  The efficacy endpoints of the 
study include ORR, DOR, progression-free survival (PFS), and overall survival (OS).   
The study consists of 3 disease cohorts: 
• Cohort 1: relapsed/refractory extranodal NK/T-cell lymphoma (nasal or non-nasal type) 
• Cohort 2: other relapsed/refractory mature T-cell neoplasms (limited to the following 
histologies: peripheral T-cell lymphoma [not otherwise specified], angioimmunoblastic 
T-cell lymphoma, or anaplastic large cell lymphoma) 
• Cohort 3: relapsed/refractory cutaneous T-cell lymphoma (limited to mycosis fungoides 
and Sézary syndrome) 
Efficacy data for patients in Cohort 1 (N = 22) and Cohort 2 (N = 44) (data cutoff 
11 October 2019) are summarized. Of the 22 patients in Cohort 1, ORR was 31.8%; BORs of CR 
were reported in 4 patients (18.2%) and of PR in 3 patients (13.6%).  Of the 44 patients in Cohort 
2, ORR was 20.5%; BORs of CR were reported in 3 patients (6.8%) and of PR in 6 patients 
(13.6%). 
1.3.4.2.6. Study BGB-A317-208  
Study BGB-A317-208 is a Phase 2 open-label, multicenter study of tislelizumab monotherapy in 
patients with previously treated unresectable HCC.  The primary endpoint of this study is ORR 
as assessed by the IRC per RECIST v1.1 in the Safety Analysis Set.  The Safety Analysis Set 
consists of patients who have received any dose of tislelizumab. 
Of the 249 patients in the Safety Analysis Set, ORR was 13.3%; BORs of CR were reported in 
3 patients (1.2%) and of PR in 30 patients (12.0%). 
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1.4. Study Rationale  
As described earlier, despite the wealth of evidence supporting TIGIT’s role 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 (Section 1.2).  
Therefore, the clinical development of ociperlimab focuses on rational combinations, such as 
with tislelizumab.  Taking this into account, the dose escalation study was designed to minimize 
a patient’s exposure to ociperlimab monotherapy and therefore maximize the patient’s potential 
therapeutic benefit while simultaneously achieving the clinical objective of characterizing the 
safety and efficacy of ociperlimab in combination with tislelizumab. 
The appropriateness of the study design is also based upon the following data, which suggest the 
combination of ociperlimab + tislelizumab will be safe and tolerable with a manageable safety 
profile: 
1. Based upon the ociperlimab animal toxicology data, which showed no toxicity at the 
maximal allowed dose (Section 1.2.1.2), and confirmed clinically by 2 other anti-TIGIT 
therapies (Golan et al 2018; Sharma et al 2018), ociperlimab/TIGIT blockade is expected to 
be safe and well tolerated; 
2. The starting dose of ociperlimab is predicted to have an 82-fold exposure margin based on 
toxicology data (Section 1.4.1.1); 
3. Tislelizumab and/or other anti-PD-1 therapies have shown to be safe and tolerable, both as a 
monotherapy and in combination with other effector T-cell stimulating immune-oncology 
agents (Section 1.3 [Wang et al 2017; Esin et al 2017; Boutros et al 2016; Naing et al 2018]); 
4. The combination of anti-TIGIT and anti-PD-1 was publicly reported to be well tolerated in 
patients resulting in commencement of the dose expansion (Merck Inc 2018; Oncomed 
Pharmaceuticals, Inc 2018); 
5. An extensive clinical, laboratory and electrocardiogram (ECG) monitoring plan has been 
established to closely monitor patient safety so as to identify and address immune-mediated 
toxicities as early as possible (Appendix 1); 
6. A comprehensive and effective algorithm based upon guidelines from the European Society 
for Medical Oncology or American Society for Clinical Oncology has been established to 
monitor, diagnose and manage immune-mediated toxicities (Appendix 8); 
7. For reasons described in Section 1.2, there is no intention to clinically evaluate, characterize 
and/or develop ociperlimab for use as a monotherapy. 
It is important to emphasize the safety experience gained from prior clinical studies whereby 
anti-PD-1 has been evaluated in combination with another effector T-cell activating 
immune-oncology agent.  In general, the combinations lead to similar AEs compared to 
anti-PD-1 alone, although in some cases with greater frequency, severity and/or earlier onset but 
ultimately shown to be safe, tolerable and if necessary, manageable with standard of care 
(Section 1.3, [Wang et al 2017, Esin et al 2017, Boutros et al 2016, Naing et al 2018]).  
However, TIGIT and PD-1 have overlapping immuno-regulatory functions and in the absence of 
activation, peripheral effector T-cells typically do not express TIGIT, thereby limiting the 
potential for peripheral immune autoreactivity (Johnston et al 2014).  Therefore, there is a 
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distinct possibility that the combination of ociperlimab and tislelizumab will result in a safety 
profile (type, frequency, severity, timing, etc.) that is similar to tislelizumab alone.  Regardless, 
an effective diagnostic and treatment algorithm is available to address immune mediated 
toxicities related to PD-1 blockade alone or the combined blockade of multiple 
immune-regulatory pathways. 
The dosing schema during the DLT assessment window was designed based upon the following 
rationales: 1) allows for the evaluation of acute toxicities related to ociperlimab alone (eg, 
immediate and/or non-immediate hypersensitivity reactions, cytokine release syndrome, delayed 
infusion reactions, etc [Baldo 2013; Picard 2017]) as well as early onset immune mediated 
toxicities related to the combination of ociperlimab and tislelizumab; 2) based upon the projected 
half-life and trough levels of ociperlimab, the chosen dosing schema also provides sufficient 
exposure throughout the DLT assessment period that is estimated to achieve approximately 90% 
TIGIT receptor occupancy in PBMCs, which is necessary to fully and consistently evaluate the 
safety of ociperlimab alone or in combination with tislelizumab; 3) based upon the time to event 
profile of immune mediated toxicities related to checkpoint therapies, it is unlikely that the 
toxicity profile of ociperlimab monotherapy will differ significantly for a 3-week versus 1-week 
observation period thereby negating the benefit of evaluating ociperlimab alone for the first 
Cycle while only serving to delay optimal treatment of cancer patients with advanced disease; 4) 
all toxicities regardless of when they occur will be taken into consideration regarding dosing 
decisions; 5) if unexpected toxicity is observed, the protocol does allow for immediate 
implementation of additional dose escalation criteria (eg, extension of the DLT period) as 
described in Section 3.2.1. 
Another important consideration is that the safety profile of tislelizumab has been characterized 
in over 2150 patients (Tislelizumab Investigator’s Brochure), thereby serving as a safety 
reference when evaluating and/or characterizing the safety of ociperlimab in combination with 
tislelizumab.  Finally, the sponsor has in place a multi-layered process for ensuring patient safety 
in part through close collaboration between study investigators and the sponsor study team.  The 
study will also utilize the sponsor’s established processes for the continuous collection, review, 
and aggregate analyses of all safety data. 
In summary, the current dose escalation study design allows patients, most of whom have failed 
multiple prior lines of therapy and/or experiencing rapid disease progression typical for a Phase 1 
study, the opportunity to obtain maximal therapeutic benefit without compromising patient safety 
or clinical objectives. 
1.4.1. 
Rationale for the Choice of Doses  
1.4.1.1. 
Rationale for the Starting Dose of Ociperlimab  
A starting dose of 50 mg Q3W is proposed in this first-in-human study for ociperlimab.  The 
selection of this starting dose was based on the tumor growth inhibition (TGI) data from the 
efficacy of ociperlimab in the GL261 murine glioma tumor model in humanized TIGIT knock-in 
mice.  The maximum drug concentration of ociperlimab after the first dose (Cmax, the first dose) 
or AUC1-168h was correlated with the percent TGI observed in GL261 mouse tumor model.  The 
EC50 (and EC90) parameters were estimated as 3.7 μg/mL (12.9 μg/mL) for Cmax, the first dose 
and 14.2 μg/day/mL (70 μg/day/mL) for the AUC1-168h variables.  By achieving the same EC90 
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for AUC1-168h or Cmax, the first dose in humans as those in the transgenic mice, the human starting 
dose for ociperlimab was estimated to be 50 mg.  Ociperlimab non-clinical safety data and 
clinical experience from competitor anti-TIGIT monoclonal antibodies justifies the proposed 
dose.  The proposed dosing interval of every 3 weeks is supported by PK evaluations and allows 
for a convenient integration with tislelizumab dosing regimen and other common 
chemotherapeutic regimens. 
The highest non–severely toxic dose or NOAEL from the 3-month repeated dose toxicology 
study in monkeys was determined to be 100 mg/kg (Ociperlimab Investigator‘s Brochure, 
Section 4.1.1.5), with the one-sixth highest non–severely toxic dose calculated as 16.7 mg/kg 
(body-weight based) or 9.8 mg/kg (exposure-based); this provides a wide safety margin at the 
proposed starting dose.  Based on the steady-state AUC and Cmax at 100 mg/kg NOAEL dose in 
the 3-month toxicity study in monkeys (Ociperlimab Investigator‘s Brochure), the projected 
safety margins at the proposed starting dose of 50 mg are 82 and 115, respectively, which 
reflects favorably on the safety profile of ociperlimab.   
Furthermore, clinical experience with similar anti-TIGIT monoclonal antibodies, OMP-313M32 
(OncoMed Pharmaceuticals) and MK-7684 (Merck), suggest that the anti-TIGIT antibodies can 
be administered safely either as monotherapy or in combination with anti–PD 1 antibody in 
patients.  The OMP 313M32 doses were escalated up to 20 mg/kg every 2 weeks as monotherapy 
and MK-7684 doses were escalated up to 700 mg Q3W both as monotherapy and in combination 
with 200 mg pembrolizumab Q3W without any DLTs (Golan et al 2018; Sharma et al 2018).  
Ociperlimab is also an IgG1 antibody similar to OMP 313M32 and MK-7684, and these clinical 
findings may be applicable.   
1.4.1.2. 
Rationale for the Selection of Ociperlimab Doses in Cohort 10  
Three dose levels of ociperlimab 450 mg, 900 mg, and 1800 mg in combination with 
tislelizumab 200 mg in patients with metastatic NSCLC (PD-L1 positive, tumor cell expression 
[TC] ≥ 1%) have been selected for Cohort 10.  The choice of the doses will provide wide 
exposure range and thus allowing for conducting exposure-response analyses of data from a 
specific tumor type. 
1.4.1.3. 
Rationale for the Selection of Tislelizumab Dose  
The PK, safety, and efficacy data obtained from the first-in-human study BGB-A317_Study_001 
(Desai et al 2020) as well as other clinical study data, were analyzed in aggregate to determine 
the recommended dose for pivotal studies of tislelizumab.  The dose of 200 mg intravenously 
Q3W was selected for further evaluation. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
Q2W and Q3W were comparable, suggesting no clear dose-dependence across these regimens.  
Similarly, confirmed ORRs in patients treated with tislelizumab 2 mg/kg and 5 mg/kg Q2W 
ranged between 10% and 15%, compared to a range of 15% to 38% for patients treated at 
2 mg/kg and 5 mg/kg Q3W. 
According to PK data from BGB-A317_Study_001(Desai et al 2020), Phase 1a, the clearance of 
tislelizumab was found to be independent of body weight, ethnicity, and gender, and the 
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observed serum exposure of a 200-mg dose fell between serum exposure observed after 2 mg/kg 
and 5 mg/kg doses (dose range with comparable safety and efficacy rates). 
Additionally, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts.  Of 
the evaluable patients treated (n = 13), 3 patients (23%) had a BOR of PR, 4 patients (31%) had a 
BOR of SD, and 6 patients (46%) had a BOR of progressive disease (PD).  Therefore, clinical 
activity with a manageable and tolerable safety profile is expected to be maintained in patients 
receiving tislelizumab 200 mg Q3W. 
Therefore, the recommended dose for pivotal studies for tislelizumab of 200 mg Q3W will be 
utilized for the combination with ociperlimab; however, alternate doses or dose schedules may 
be evaluated based on emerging clinical data. 
1.4.2. 
Rationale for Combination of Ociperlimab and Tislelizumab in the Treatment of 
Advanced Solid Tumors  
Blocking antibodies targeting PD-1 have achieved remarkable results in the treatment of many 
types of tumors.  However, it is also worth noting that this therapeutic strategy typically achieves 
a < 30% ORR as a monotherapy in patients whose tumors exhibit low positive PD-L1 expression 
and/or are microsatellite stable (Chen and Han 2015). 
TIGIT and PD-1 function as immune checkpoint receptors in the overlapping regulation of 
immune tolerance.  As noted above, TIGIT and PD-1 have been shown to be overexpressed on 
the TILs from patient samples of various solid tumors including, but not limited to NSCLC, head 
and neck squamous cell carcinoma, gastric carcinoma, ovarian cancer, and triple-negative breast 
cancer.  Subsequently, the activation of TIGIT and PD-1 represent TILs from both patients or 
animals across solid tumor types with the most exhausted immunophenotype (ie, cytokine 
expression, proliferation etc.), which can be reversed with combined blockade of TIGIT and 
PD-1.  Interestingly, TIGIT expression on effector T-cells is strongly correlated with PD-1 
expression and the expression both of which is upregulated following effector activation 
(Johnston et al 2014).  As such, immune escape via PD-1 will be sustained in patients with 
PD-L1 positive tumors thereby negating TIGIT blockade alone. 
The overlap in expression and function indicates that TIGIT and PD-1 cooperate to promote 
effector cell exhaustion which may impede an effective antitumor immune response.  Indeed, the 
combined blockade of TIGIT and PD-1 significantly increased IFN- production in vitro relative 
to the increase seen for TIGIT or PD-1 blockade alone, thus demonstrating that the combined 
blockade of TIGIT and PD-1 can mitigate effector cell exhaustion following activation and 
chronic antigen stimulation (Figure 1).   
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Figure 1: 
Combined Blockade of TIGIT and PD-1 with Ociperlimab and Tislelizumab 
(BGB-A317) Enhances IFN-γ secretion in Mixed Lymphocyte Reaction 
 
Abbreviations: Conc., concentration; IFN- interferon-gamma. 
A conventional mixed lymphocyte reaction assay was performed. In brief, "stimulator PBMCs" from a healthy 
donor were pre-treated with OKT3 (40 ng/mL, eBioscience) and co-cultured with a mixture of "responder” 
A549/OS8-PD-L1 and A549/PD-L1 cells in complete RPMI1640 media plus ociperlimab and/or 
tislelizumab/BGB-A317 (100 ng/mL) in a 96-well flat-bottom plates for 18 hours.  The secretion of IFN-γ into the 
cell culture was performed using an IFN- ELISA kit (eBioscience) and analyzed as a readout of T-cell function. All 
conditions were performed in duplicates and results are shown as mean ± SD.   
Further, combined blockade of TIGIT and PD-L1 resulted in a greater antitumor effect in vivo 
compared to either TIGIT or PD-L1 blockade alone as observed in a CT26 colorectal tumor 
model (Figure 2 [a, b]).  Importantly, mice that achieved a CR on treatment with the combination 
of anti-TIGIT and anti-PD-L1 were able to mount a protective antitumor response when re-
inoculated with CT26 tumor cells but not syngeneic EMT6 breast cancer cells  
(Figure 2 [c]).  The ability to reject a secondary inoculation with CT26 cells suggests an 
induction of tumor antigen-specific immunity in the mice previously treated with the 
combination (Johnston et al 2014). 
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Figure 2: 
The Combination of Anti-TIGIT and Anti-PD-1 Treatment Is More Effective 
Than Anti-PD-1 Inhibitors Alone 
 
Figure 2A: Groups of BALB/c mice (n = 10) were inoculated subcutaneously in the right thoracic flank with 1x105 
CT26 colon carcinoma cells.  After 2 weeks tumors reach 150-200mm3, mice were randomized into treatment 
groups and treated intraperitoneally with either control (cIg), anti-PD-L1 (10mg/kg), anti-TIGIT (25 mg/kg) or their 
combination (35 mg/kg) 3 times per week for 3 weeks. Tumor were measured 2 times per week by caliper and 
volumes calculated by modified ellipsoid formula. Animals whose tumors shrank to 32mm3 or smaller were 
considered to be CR, while those whose tumors grew to larger than 2000mm3 were considered to have progressed 
and euthanized. The median (left) and individual (right) tumor volumes for treatment groups are shown. 
Figure 2B: Survival time for mice in 2A. 
Figure 2C: Approximately 60 days after inoculation with CT26 cells, BALB/c treated with the combination of 
anti-PD-L1 and anti-TIGIT that reached CR, along with naïve control mice, were re-inoculated with CT26 cells in 
the left thoracic flank or inoculated with EMT6 breast carcinoma cells in their mammary fat pads and followed for 
tumor growth (n=7-10). 
Based upon the overlapping expression profiles and immuno-regulatory functions, the improved 
in vivo antitumor effects, as well as the potential for TIGIT-mediated adaptive resistance, there is 
strong scientific rationale to evaluate the antitumor effects derived from the combined blockade 
of TIGIT and PD-1 in advanced solid tumors. 
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1.4.3. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Platinum-based 
Doublet Chemotherapy in NSCLC (Phase 1b)  
Upregulation of TIGIT expression in tumor infiltrating lymphocytes (TILs) has been reported in 
NSCLC (Tassi et al 2017).  Blockade of 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).  Preclinical 
studies have also indicated that platinum-based chemotherapy elicits tumor CD8 + T-cell 
infiltration and sensitized tumors to immune checkpoint blockade therapy, which results in a 
durable control of cancer (Pfirschke et al 2016). 
The results from the pivotal Phase 3 study (Lu et al 2020) support tislelizumab in combination 
with platinum and pemetrexed as a potential new standard for first-line treatment of advanced 
non-squamous NSCLC.  The addition of tislelizumab resulted in significantly improved PFS by 
IRC (9.7 months versus 7.6 months; p = 0.0044, hazard ratio [HR] = 0.30 [95% CI: 0.462 to 
0.902]) as well as higher ORR by IRC and longer DOR by IRC than observed with 
chemotherapy alone in relevant patients.  No new safety signals were identified with the addition 
of tislelizumab to standard chemotherapy.  The safety profile of tislelizumab in combination with 
platinum and pemetrexed was consistent with the known risks of each study treatment 
component.  Most AEs were mild or moderate in severity and were manageable. 
The robust results were also observed in another Phase 3 study (Wang et al 2020) for first-line 
treatment of advanced squamous NSCLC, irrespective of PD-L1 expression.  Both tislelizumab 
in combination with carboplatin + paclitaxel/nab-paclitaxel demonstrated statistically significant 
prolonged PFS as compared with paclitaxel + carboplatin treatment arm (HR 0.524 with median 
7.6 months [95% CI: 5.95 to 9.79] versus 5.5 months [95% CI: 4.21 to 5.65] and HR 0.478 with 
median 7.6 month [95% CI: 5.75 to 11.01] versus 5.5 months [95% CI: 4.21 to 5.65]), 
respectively.  The ORR assessed by IRC was higher for tislelizumab in combination with 
paclitaxel + carboplatin (72.5%) and higher for tislelizumab in combination with nab-paclitaxel 
+ carboplatin (74.8%) than with chemotherapy alone (49.6%).  The DOR by IRC was also longer 
in paclitaxel + carboplatin (8.2 months) with HR 0.461 and nab-paclitaxel + carboplatin 
(8.6 months) with HR 0.446 than in paclitaxel + carboplatin (4.2 months).  These findings further 
validated the benefit of adding tislelizumab to platinum-based chemotherapy.  The safety profile 
of tislelizumab in combination with carboplatin and paclitaxel or nab-paclitaxel was 
well-tolerated.  And the safety profile exhibited in this study was in line with the known 
chemotherapy agents, tislelizumab, and underlying NSCLC.  Most AEs were reported to be mild 
or moderate in severity and manageable. 
The consistent clinical benefit and safety profile of other anti-PD-1/PD-L1 antibodies combined 
with platinum-doublet chemotherapy is observed in first-line NSCLC setting, shown in Table 1.  
Keynote-189 study showed pembrolizumab plus pemetrexed-carboplatin or cisplatin has superior 
OS and PFS over pemetrexed-carboplatin or cisplatin in metastatic non-squamous NSCLC 
(Gadgeel et al 2020), while Keynote-407 study showed pembrolizumab plus paclitaxel or 
nab-paclitaxel-carboplatin has superior OS and PFS over paclitaxel or nab-paclitaxel-carboplatin 
in metastatic squamous NSCLC(Paz-Ares et al 2018).  US Food and Drug Administration (FDA) 
has approved pembrolizumab combined with platinum-doublet chemotherapy in first-line 
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NSCLC with squamous and non-squamous histology regardless of PD-L1 expression based upon 
the two studies.  Atezolizumab has been approved by the FDA in metastatic non-squamous 
NSCLC in first-line with the combination with nab-paclitaxel-carboplatin which had superior OS 
over nab-paclitaxel-carboplatin regardless of PD-L1 expression (West et al 2019). 
Table 1: 
Safety and Efficacy Summary of Pembrolizumab With Chemotherapy in 
First-line NSCLC 
 
Pembrolizumab 
(KN-189) 
Pembrolizumab 
(KN-407) 
Atezolizumab 
(IMpower130) 
Treatment 
Pembro+Pem+Carbo/Cis 
vs Pem+Carbo/Cis  
Pembro+Carbo+nab-
Pac/Pac vs Carbo+nab-
Pac/Pac 
Atezo+Nab-Pac+Carbo 
vs Nab-Pac+Carbo   
Patient number 
405 vs 202 pts 
278 vs 280 pts 
451 vs 228 pts 
Histology  
NSQ 
SQ 
NSQ 
Median PFS, months 
ITT: 8.8 vs 4.9,  
HR = 0.52 
ITT: 6.4 vs 4.8,  
HR = 0.56 
ITT: 7.0 vs 5.5, 
HR = 0.64 
Median OS, 
Months  
ITT: NR vs 11.3, 
HR = 0.49 
15.9 vs 11.3,  
HR = 0.64 
ITT: 18.6 vs 13.9, 
HR = 0.79, p = 0.033 
ORR, % 
47 vs 18.9 
57.9 vs 38.4 
49.2 vs 31.9 
Median DOR, 
months 
11.2 vs 7.8  
7.7 vs 4.8  
8.4 vs 6.1 
Treatment-related 
AEs Gr 3-5, % 
69.8 vs 68.2 
Paclitaxel: 63.9 vs 59.3 
Nab-paclitaxel: 78.9 vs 
81.4 
75 vs 61 
Abbreviations: AEs, adverse events; Atezo, atezolizumab; Carbo, carboplatin; Cis, cisplatin; DOR, duration of 
response; HR, hazard ratio; ITT, intent-to-treat; Nab-Pac, nab-paclitaxel; NSQ, non-squamous non-small cell lung 
cancer; ORR, overall response rate; OS, overall survival; Pem, pemetrexed; Pembro, pembrolizumab; Pac, 
paclitaxel; PFS, progression-free survival; pts, patients; SQ, squamous non-small cell lung cancer; vs, versus 
The Cancer Genome Atlas (TCGA) dataset showed the upregulation of TIGIT and PVR 
expression in tumor samples compared with normal samples in both adenocarcinoma lung cancer 
and squamous cell lung cancer (TCGA).  The TCGA RNAseq dataset illustrated NSCLC patients 
with low expression of PVR have longer survival (p = 0.0082) (GEPIA2).  This is consistent 
with the important role of TIGIT/PVR signaling pathway in the immune tolerance to cancer 
(Section 1.2).  In addition, increased expression of TIGIT and PD-1 in human non-small cell 
lung cancer suggests potential synergy of combining of anti-TIGIT antibody and anti-PD-1 
antibody (Solomon and Garrido-Laguna 2018). 
Ociperlimab, tislelizumab, and platinum-based doublet chemotherapy have nonoverlapping 
anticancer mechanisms, and likely to have synergistic and/or added activity.  Both ociperlimab 
plus tislelizumab and tislelizumab plus chemotherapy are tolerable.  Adding ociperlimab to 
tislelizumab and platinum-based doublet chemotherapy will likely further enhance the overall 
clinical activity of tislelizumab plus platinum-based doublet chemotherapy and prevent 
progression/disease related death in stage IV NSCLC in the front line. 
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1.4.4. 
Rationale for Combination of Ociperlimab and Tislelizumab in NSCLC With 
PD-L1 Positive (Tumor Cell Expression ≥ 1%) Population (Phase 1b)  
Anti-PD-1 antibody monotherapy has been the new standard of care for patients with a PD-L1 
TPS of 1% or greater based on Keynote-042 study (Mok et al 2019).  In this study, 1274 patients 
with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n = 637) or chemotherapy 
(n = 637) and included in the Intention-to-Treat Population.  Overall survival was significantly 
longer in the pembrolizumab group than in the chemotherapy group in PD-L1 ≥ 1% with 16.7 
months versus 12.1 months (HR = 0.81, [95% CI: 0.71 to 0.93], p = 0.0018).  Treatment-related 
adverse events of Grade 3 or worse occurred in 18% treated patients in the pembrolizumab group 
and in 41% in the chemotherapy group and led to death in 2% and 2% patients, respectively. 
As described in the section of clinical experience (Section 1.2.2), anti-TIGIT antibody combined 
with anti-PD-1 showed good tolerability and preliminary efficacy in some solid tumors.  The 
increased expression of TIGIT and PD-1 suggested a synergy in combination of anti-TIGIT 
antibody and anti-PD-1 antibody in human NSCLC (Section 1.4.3).  Ociperlimab plus 
tislelizumab will more likely enhance the antitumor activity in the front-line NSCLC with PD-L1 
positive patients.  Study AdvanTIG-105 will evaluate clinical activity of ociperlimab and 
tislelizumab in PD-L1 positive (TC ≥ 1%) patients with stage IV NSCLC. 
1.4.5. 
Rationale for Combination of Ociperlimab and Tislelizumab and 
Platinum-based Doublet Chemotherapy in SCLC (Phase 1b)  
In a Phase 2 study of locally advanced or metastatic non-squamous NSCLC, squamous NSCLC, 
and extensive-stage SCLC, tislelizumab was evaluated in combination with first-line 
platinum-based doublet chemotherapy, respectively.  Seventeen patients with extensive-stage 
SCLC were treated with tislelizumab plus etoposide-cisplatin or carboplatin with ORR of 47.1%.  
Patients tolerated well with ≥ Grade 3 treatment-related AE of 76.5% and imAE of 23.5%.  The 
Phase 3 study of extensive-stage SCLC exploring tislelizumab in combination with 
etoposide-cisplatin or carboplatin is ongoing (BGB-A317-312). 
In addition, both atezolizumab plus carboplatin-etoposide and durvalumab plus 
etoposide-carboplatin/cisplatin have been approved as first-line treatment in extensive-stage 
SCLC with superior clinical efficacy over chemotherapy and good tolerability (shown in 
Table 2). 
Table 2: 
Safety and Efficacy Summary of Atezolizumab and Durvalumab With 
Chemotherapy in First-Line Extensive-Stage SCLC 
 
IMpower 133 
(Atezolizumab+EP vs EP) 
Caspian 
(Durvalumab+EP vs EP) 
ORR, % 
60.2 vs 64.4 
67.9 vs 57.6 
DOR, months 
4.2 vs 3.9 
5.1 vs 5.1 
Median PFS, months 
5.2 vs 4.3 
5.1 vs 5.4 
Median OS, months  
12.3 vs 10.3  
(p = 0.0154) 
13.0 vs 10.3 
(p = 0.0047) 
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Treatment-related Grade 3-4 
AEs, % 
56.6 vs 56.1 
46 vs 52 
Abbreviations: AEs, adverse events; DOR, duration of response; EP, etoposide; ORR, overall response rate; PFS, 
progression-free survival 
The published data shows PVR is broadly expressed in SCLC cell lines and tumor tissues.  And 
high PVR expression was associated with poor prognosis, advanced tumor stage and large tumor 
size.  PVR expression may represent an important targeted immune checkpoint in lung cancer.  
The blockade of TIGIT pathway may represent a potent therapeutic strategy to combine different 
checkpoint blocking agents for SCLC therapy (Yu et al 2018).  In the Phase 1b stage of  
Study AdvanTIG-105, we will evaluate the clinical activity with the addition of ociperlimab to 
the combination of tislelizumab plus platinum-based doublet chemotherapy in first-line treatment 
of extensive-stage SCLC.  
1.4.6. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Chemotherapy in 
Esophageal Cancer  
In a Phase 2 study of locally advanced or metastatic esophageal squamous cell carcinoma 
(ESCC) and gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, tislelizumab was 
evaluated in combination with cisplatin and fluorouracil.  Fifteen patients with ESCC were 
treated with tislelizumab plus cisplatin and fluorouracil with confirmed ORR of 46.7% and DCR 
of 80%.  Patients tolerated well with ≥ Grade 3 TEAEs of 86.7% and ≥ Grade 1 imAEs of 80% 
(Xu et al 2020).  The Phase 3 study of first line tislelizumab in combination with chemotherapy 
for unresectable, locally advanced recurrent or metastatic ESCC is ongoing (BGB-A317-306). 
Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with 
advanced esophageal cancer has been evaluated in KEYNOTE-590, a Phase 3 global study 
(Kato et al 2020).  In this study, 749 patients were allocated to pembrolizumab plus 
chemotherapy (n = 373) or chemotherapy (n = 376) and included in the Intention-to-Treat 
Analysis Set.  Overall survival was significantly longer in the pembrolizumab plus chemotherapy 
group than that in the chemotherapy group with 12.4 months versus 9.8 months 
(HR = 0.73  [0.62 to 0.86], p < 0.0001).  PFS was superior in the pembrolizumab plus 
chemotherapy group than in the chemotherapy group with 6.3 months versus 5.8 months 
(HR = 0.65 [0.55 to 0.76], p < 0.0001).  Treatment-related adverse events of Grade 3 or worse 
occurred in 71.9% treated patients in the pembrolizumab plus chemotherapy group and in 67.6% 
in the chemotherapy group and led to death in 2.4% and 1.4% patients, respectively.  
Immune-mediated AE and infusion reactions occurred in 25.7% treated patients in 
pembrolizumab plus chemotherapy group and in 11.6% treated patients in chemotherapy group 
(Kato et al 2020).  
In the TCGA RNAseq dataset, TIGIT expression was significantly increased in esophageal 
cancer tissue (including ESCC and esophageal adenocarcinoma [EAC]) compared with normal 
tissue and highly correlated with PD1 expression (Spearman correlation r = 0.84, p < 0.001).  
PD-L1 was reported to be expressed on both tumor cells and immune cells in ESCC and EAC 
tumor tissue, with relatively higher PD-L1 positive prevalence in the former, indicating a 
relatively inflamed tumor macroenvironment favorable for immunotherapy.  About 40-50% 
PD-L1 positive prevalence by Combined Positive Score (CPS) ≥ 10, TC ≥ 1% or 
visually-estimated CPS (vCPS) ≥ 10% was reported in ESCC (Keynote-181/590, 
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ATTRACTION-3, ESCORT, BGB-A317-001/102).  A trend of higher TIGIT expression was 
also found in the PD-L1 vCPS high subgroup and a subgroup of non-responders showed 
numerically higher TIGIT expression level compared with the responder subgroup in ESCC 
patients in BGB-A317-102/001 study.  These data imply the potential synergistic effect of 
anti-TIGIT plus anti-PD-1 in esophageal cancer. 
1.4.7. 
Rationale for Combination of Ociperlimab and Tislelizumab in Head and Neck 
Squamous Cell Carcinoma With PD-L1 Positive (vCPS ≥ 1%) Population  
Anti-PD-1 antibody monotherapy has been the new standard of care for recurrent or metastasis 
HNSCC patients with a PD-L1 CPS of ≥ 1 based on Keynote-048 study (Burtness et al 2019).  In 
this study, 882 patients were allocated to pembrolizumab alone (n = 301), pembrolizumab with 
chemotherapy (n = 281) or cetuximab with chemotherapy (n = 300) and included in the 
Intention-to-Treat Population.  At the second interim analysis, pembrolizumab alone improved 
OS versus cetuximab with chemotherapy in the CPS of 20 or more population (median 
14.9 months versus 10.7 months, HR = 0.61 [95% CI: 0.45 to 0.83], p = 0.0007) and CPS of 1 or 
more population (12.3 months versus 10.3 months, HR=0.78 [0.64 to 0.96], p = 0.0086) and was 
non-inferior in the total population (11.6 months versus 10.7 months, HR = 0.85 [95% CI: 
0.71 to 1.03]).  At final analysis, ≥ Grade 3 worse all-cause adverse events occurred 55% in the 
pembrolizumab alone group, and 83% in the cetuximab with chemotherapy group.  Adverse 
events led to death in 8% of the pembrolizumab alone group and in 10% of the cetuximab with 
chemotherapy group, respectively (Burtness et al 2019). 
As described in the section of clinical experience (Section 1.2.2) anti-TIGIT antibody combined 
with anti-PD-1 showed good tolerability and preliminary efficacy in some solid tumors.  The 
increased expression of TIGIT and PD-1 suggested a synergy in combination of anti-TIGIT 
antibody and anti-PD-1 antibody in HNSCC.  Study AdvanTIG-105 will evaluate clinical 
activity of ociperlimab and tislelizumab in PD-L1 positive (vCPS ≥ 1%) patients with recurrent 
or metastatic HNSCC.  
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1.4.8. 
Rationale for Combination of Ociperlimab, Tislelizumab, and Chemotherapy in 
Gastric Cancer  
In a Phase 2 study of locally advanced or metastatic ESCC and G/GEJ adenocarcinoma, 
tislelizumab was evaluated in combination with oxaliplatin and oral capecitabine.  Fifteen 
patients of G/GEJ adenocarcinoma were treated with tislelizumab plus oxaliplatin and 
capecitabine with confirmed ORR of 46.7% and DCR of 80%.  Patients tolerated well with ≥ 
Grade 3 TEAEs of 66.7% and ≥ Grade 1 imAEs of 73.3% (Xu et al 2020).  The Phase 3 study of 
first-line tislelizumab in combination with chemotherapy for unresectable, locally advanced 
recurrent or metastatic gastric cancer is ongoing (BGB-A317-305).   
Nivolumab plus chemotherapy versus chemotherapy as first-line therapy in patients with 
advanced G/GEJ cancer/EAC has been evaluated in CheckMate 649, a Phase 3 global study 
(Moehler et al 2020).  In this study, 1581 patients were allocated to nivolumab plus 
chemotherapy (n=789) or chemotherapy (n=792) and included in the Intention-to-Treat 
population.  Overall survival was significantly longer in patients with tumors expressed PD-L1 
CPS ≥ 5 in the nivolumab plus chemotherapy group than in the chemotherapy group 
(14.4 months versus 11.1 months, HR = 0.71 [95% CI: 0.59 to 0.86], p<0.0001).  PFS was 
superior in patients with tumors expressed PD-L1 CPS ≥ 5 in the nivolumab plus chemotherapy 
group than in the chemotherapy group (7.7 months versus 6.0 months, HR = 0.68 [95% CI: 
0.56 to 0.81], p < 0.0001).  Serious treatment-related adverse events occurred in 22% of patients 
in the nivolumab plus chemotherapy group and in 12% of patients in the chemotherapy group, 
respectively.  Adverse events leading to death occurred in 2% of patients in the nivolumab plus 
chemotherapy group and in 1% of patients in the chemotherapy group, respectively 
(Moehler et al 2020). 
Additionally, enhanced nivolumab plus chemotherapy versus chemotherapy as first-line therapy 
in patients with advanced G/GEJ cancer has also been evaluated in ATTRACTION-4 study 
(Boku et al 2020).  It included patients from Japan, Korea and Taiwan.  In this study, 
724 patients were allocated to nivolumab plus chemotherapy (n = 362) or chemotherapy 
(n = 362) and included in the Intention-to-Treat Population.  PFS was superior in the nivolumab 
plus chemotherapy group than in the chemotherapy group (10.45 months versus 8.34 months 
HR = 0.68 [95% CI: 0.51 to 0.9], p = 0.0007).  Serious treatment-related AEs occurred in 24.5% 
of patients in the nivolumab plus chemotherapy group and in 14.2% of patients in the 
chemotherapy group, respectively.  Treatment-related AEs led to discontinuation occurred in 
6.1% of patients in the nivolumab plus chemotherapy group and in 4.7% of patients in the 
chemotherapy group, respectively. 
Additionally, TIGIT expression was observed to be highly expressed in gastric tumor tissue 
compared with normal tissue and highly correlated with PD1 expression in the TCGA RNAseq 
dataset. 
1.4.9. 
Biomarker Strategy Rationale  
Biomarker analyses will be performed to study the following aspects of ociperlimab and 
tislelizumab treatments: 1) target engagement (in Phase 1 only); 2) treatment effects induced in 
patients; 3) biomarkers predictive of response or resistance.  
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Ociperlimab TIGIT and tislelizumab PD-1 receptor occupancy on peripheral blood cells will be 
used to demonstrate TIGIT or PD-1 target engagement by the antibodies in Phase 1.  Blockade of 
TIGIT and PD-1 checkpoint pathways have shown to enhance the activation of T and NK cells 
(Johnston et al 2014; Chauvin et al 2015).  Treatment effects in patients will be studied with the 
main focus on T, NK cell activations (may include but not limited to activation/proliferation 
markers on these cells, activation signatures, cytokines secreted by activated T and NK cells) by 
comparing these cells in peripheral blood before, during and after treatment.   
Higher PD-L1 expression was reported to be associated with better clinical efficacy in 1L 
NSCLC treated with anti-TIGIT antibody tiragolumab plus Tecentriq in CITYSCAPE study.  
Superior ORR and PFS were observed in the PD-L1 ≥ 50% subgroup compared with PD-L1 
1-49% subgroup (Rodriguez-Abreu et al 2020).  TIGIT and PVR were reported to be mainly 
expressed on immune cells and tumor cell respectively in tumor tissue with varied expression 
levels across tumor types (Fourcade et al 2018; MacDonald et al 2016).  The association of 
TIGIT and PVR expression with clinical efficacy of anti-TIGIT combinational therapy is still to 
be explored.  Besides, other biomarkers including tumor mutational burden, microsatellite 
instability, abundance and location of TILs, and immune related gene expression profile are 
reported to be associated with response to immunotherapies including anti-PD-1 antibodies in 
different cancers (Vilain et al 2017; Goodman et al 2017; Gandara et al 2018; Jiang et al 2018).  
In melanoma patients, high TIGIT/CD226 ratio on Treg cells correlated with poor clinical 
outcome upon anti-PD1 or anti-PD-L1 antibody treatment.  This advised signaling through 
TIGIT pathway in tumor tissues might contribute to resistance to current immune checkpoint 
inhibitors targeting PD-1 or PD-L1 (Fourcade et al 2018).  Therefore, expression of TIGIT 
pathway molecules including TIGIT, CD226, CD155, CD112, as well as tumor PD-L1 
expression, tumor mutational burden, TILs and gene expression profile will be studied in 
relationship with clinical response to ociperlimab in combination with tislelizumab treatment to 
explore predictive biomarkers.  
1.5. Benefit-Risk Assessment  
The first-in-human Study AdvanTIG-105 evaluating safety, tolerability, and clinical benefit of 
ociperlimab in combination with tislelizumab in solid tumors is still ongoing.  As discussed 
above, there is extensive evidence supporting TIGIT’s role in regulating immune response as 
well as the interaction between the TIGIT and PD-1 pathways in promoting tumor immune 
escape (Section 1.2; Section 1.4.2).  Combined with the clinical efficacy that has been 
demonstrated for PD-1 blockade/tislelizumab (Section 1.3), the data strongly suggest that 
ociperlimab has the potential to improve and/or extend the therapeutic benefits of tislelizumab, 
both in the treatment-naïve as well as disease progression settings. 
As discussed earlier (Section 1.2.1.2, Section 1.2.2, Section 1.4.1, Section 1.4.2), based upon the 
mechanism(s) of action, nonclinical as well as clinical data, the combined blockade of TIGIT and 
PD-1 by ociperlimab and tislelizumab, respectively, is expected to result in immune mediated 
toxicities similar to what has been observed with tislelizumab alone.  Although there is the risk 
of observing an augmented safety signals as has been shown for other anti-PD-1 based 
immuno-oncology combinations, a comprehensive algorithm derived from the European Society 
for Medical Oncology and American Society for Clinical Oncology, has been established to 
monitor, diagnose as well as manage such immune-related toxicities (Appendix 8).  It is 
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important to note that peripheral effector T-cells typically do not express TIGIT, which is in 
contrast to TILs stimulated by the antigens in tumor microenvironment.  Therefore, the 
combination provides an opportunity to specifically augment the activity of effector T-cells in 
the tumor rather than periphery and/or nontumor tissue (Johnston et al 2014). 
Blockade of the PD-1 pathway has demonstrated strong antitumor efficacy either alone or in 
combination with standard of care in multiple cancer indications.  As discussed in Section 1.4.1, 
PD-1 blockade by tislelizumab has been evaluated in more than 1350 patients with a safety and 
efficacy profile similar to what has been reported for other anti-PD-(L)1 therapies. 
As shown in Appendix 1, a comprehensive monitoring plan will be utilized to monitor patient 
safety.  The subsequent safety data will be continuously analyzed by the sponsor’s study team 
and in consultation with investigator(s) as needed.  Refer to Section 1.4.1 and Section 9 for 
information regarding additional safeguards and considerations related to potential risk. 
In addition, available data from clinical trials of other anti-PD-1 antibodies, tislelizumab, 
nivolumab, and pembrolizumab, have demonstrated favorable benefit/risk ratio.  Available data 
indicates that combining standard treatment of chemotherapy and tislelizumab has a manageable 
safety profile and very promising antitumor activity when administered as first-line therapy in 
patients with advanced lung cancer (Section 1.4 ). 
RP2D will be determined after discussion with Safety Monitoring Committee (SMC) before the 
initiation of dose expansion (Phase 1b).  Phase 1b study is designed to include a safety run-in 
stage during which 6 patients will be treated with tislelizumab 200 mg plus ociperlimab 900 mg 
and standard chemotherapy regimen in the 6 cohorts (squamous NSCLC Cohort 1, 
non-squamous NSCLC Cohort 2, extensive-stage SCLC Cohort 4, ESCC Cohort 6, EAC 
Cohort 7, G/GEJ adenocarcinoma Cohort 9).  Safety data will be reviewed by a SMC after the 
6 patients in each cohort have completed ≥ 1 cycle of treatment (Section 3.3).  If there are no 
new unexpected safety signals detected, the enrollment will continue up to 20 to 40 evaluable 
patients for Cohort 1, 2, 4, 6, and 7, 30 to 60 evaluable patients for Cohort 9, and 20 to 
40 evaluable patients for each of the 3 arms in Cohort 10.  
To assure an ongoing favorable benefit-risk assessment for patients enrolled in 
Study AdvanTIG-105, significant safety events will be evaluated by the investigator and 
sponsor; in the event of unacceptable toxicity, such as treatment-related death or unexpected 
treatment-related Grade 4 toxicity, the study will be stopped with the concurrence of both the 
SMC and sponsor. 
In summary, there is strong scientific rationale that the combined blockade of the TIGIT pathway 
and PD-1 pathway with or without standard chemotherapy may result in enhanced antitumor 
activity and benefit bigger patient populations as compared to anti-PD-1 monotherapy without a 
major increase in the risk of immune-related toxicities. 
1.6. 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 for Dose Escalation  
2.1.1. 
Primary Objectives  
• To assess the safety and tolerability of ociperlimab in combination with tislelizumab in 
patients with advanced solid tumors 
• To determine the MTD or maximum administered dose (MAD) of ociperlimab in 
combination with tislelizumab 
• To determine the RP2D of ociperlimab in combination with tislelizumab 
2.1.2. 
Secondary Objectives  
• To assess the preliminary anticancer activity of ociperlimab in combination with 
tislelizumab 
• To characterize the PK of ociperlimab in combination with tislelizumab 
• To assess host immunogenicity to ociperlimab in combination with tislelizumab 
2.1.3. 
Exploratory Objectives  
• To assess predictive, prognostic, and/or pharmacodynamic biomarkers including any 
association with response to ociperlimab treatment, exposure levels, and mechanism(s) of 
resistance 
2.2. Study Objectives for Dose Expansion  
2.2.1. 
Primary Objective  
• To assess ORR determined by investigator per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST v1.1) for patients in each dose-expansion cohort   
2.2.2. 
Secondary Objectives  
• To evaluate DCR, DOR, and PFS determined by investigator per RECIST v1.1 for 
patients in each dose-expansion cohort 
• To further characterize the safety and tolerability of ociperlimab in combination with 
tislelizumab with or without chemotherapy 
• To further characterize the PK of ociperlimab in combination with tislelizumab with or 
without chemotherapy  
• To further assess host immunogenicity to ociperlimab in combination with tislelizumab 
with or without chemotherapy 
• To evaluate the association of PD-L1 and TIGIT expression with clinical efficacy 
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2.2.3. 
Exploratory Objectives  
• To assess OS for each tumor expansion cohort 
• To further assess predictive, prognostic, and/or pharmacodynamic biomarkers, including 
any association with response to ociperlimab in combination with tislelizumab with or 
without chemotherapy and/or mechanism(s) of resistance 
2.3. Study Endpoints for Dose Escalation  
2.3.1. 
Primary Endpoints  
• AEs and SAEs as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 
[NCI-CTCAE v5.0]), timing, seriousness, and relationship to study drugs; physical 
examinations, ECGs, and laboratory assessments as needed; and AEs meeting 
protocol-defined DLT criteria 
• MTD or MAD, as defined as the highest dose at which less than one-third of patients 
experienced a DLT or the highest dose administered, respectively 
• RP2D of ociperlimab monotherapy and/or in combination with tislelizumab, determined by 
MTD or MAD, as well as long-term tolerability, PK, efficacy, and any other relevant data 
as available 
2.3.2. 
Secondary Endpoints  
• ORR, DOR, and DCR, as assessed using RECIST v1.1 (as described in Section 10.2) 
• Serum concentrations at specified timepoints and PK parameters of ociperlimab and 
tislelizumab  
• Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection 
of ADAs 
2.3.3. 
Exploratory Endpoints  
• Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivative) 
samples obtained before, during, and/or after treatment with ociperlimab and their 
association with clinical efficacy.  Biomarkers may include, but not limited to, expression 
of TIGIT, CD226, CD155, CD112 and PD-L1 in tumor tissues, tumor mutation burden, 
MSI status and gene mutations in tissue and blood, immune cell subpopulations and gene 
expression profiling (GEP) on peripheral blood and/or tumor tissues, and concentrations 
of cytokines and soluble proteins in plasma or serum. 
2.4. Study Endpoints for Dose Expansion  
2.4.1. 
Primary Endpoint  
• ORR, as determined from investigator derived tumor assessments per RECIST v1.1 for 
each tumor expansion cohort (as described in Section 10.2.2)  
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2.4.2. 
Secondary Endpoints  
• PFS, DOR, and DCR as determined from investigator derived tumor assessments per 
RECIST v1.1 for each tumor expansion cohort (as described in Section 10.2.3)  
• AEs and SAEs as characterized by type, frequency, severity (as graded by NCI-CTCAE 
v5.0), timing, seriousness, and relationship to study drugs; physical examinations, ECGs, 
and laboratory assessments as needed for each tumor expansion cohort 
• Serum ociperlimab and tislelizumab concentrations at specified timepoints with or 
without chemotherapy 
• Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection 
of ADAs with or without chemotherapy  
• PD-L1 and TIGIT expression as the predictive biomarker for efficacy (including but not 
limited to ORR and PFS) 
2.4.3. 
Exploratory Endpoints  
• Overall survival-defined as the date of the first dose of study drug to the date of death due 
to any cause (as described in Section 10.2.4) 
• Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivatives) 
samples obtained before, during and/or after treatment with ociperlimab in combination 
with tislelizumab with or without chemotherapy and their association with clinical 
efficacy.  Biomarkers may include but are not limited to expression of CD226, CD155, 
CD112 in tumor tissues, tumor mutation burden, MSI status, and gene mutations in tissue 
and blood, Epstein-Barr virus (EBV) status, immune cell subpopulations and GEP on 
peripheral blood and/or tumor tissues, and concentrations of cytokines and soluble 
proteins in plasma or serum. 
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3. 
STUDY DESIGN  
3.1. Summary of Study Design  
This is an open-label, multicenter, Phase 1 and Phase 1b clinical trial to investigate safety, 
tolerability, pharmacokinetics and preliminary antitumor activity of anti-TIGIT monoclonal 
antibody ociperlimab in combination with anti-PD-1 monoclonal antibody tislelizumab 
(BGB-A317) with or without chemotherapy in patients with unresectable locally advanced or 
metastatic solid tumors.  The study designs for Phase 1 and Phase 1b are presented in Figure 3, 
Figure 4, and Figure 5, respectively.  
Approximately 44 to 64 patients will be enrolled in Phase 1 and 250 to 500 evaluable patients 
will be enrolled in Phase 1b.  Phase 1 will be conducted across up to 10 sites in Australia and 
China.  Phase 1b will be conducted across approximately up to 85 sites globally.  For all Phase 1 
and Phase 1b study assessments and procedures, see Section 8 and Appendix 1. 
Phase 1  
Dose Escalation in Australia: A flat dose of ociperlimab will be administered intravenously as 
a single agent on Day 1 of each cycle.  In the first cycle, 200 mg tislelizumab will be 
administered intravenously on Day 8.  Patients will be monitored for DLTs for 28 days following 
the first administration of ociperlimab.  If tolerated, patients will receive ociperlimab and 
tislelizumab on Day 29 and every 21 days (ie, Q3W) thereafter until they meet a discontinuation 
criterion (Section 7.5).  The doses of ociperlimab to be tested are 50, 150, 450, and 900 mg, 
while the dose level of tislelizumab will be fixed at 200 mg.  However, if warranted, different 
dose levels and/or dosing schedules of ociperlimab (eg, up to 1600 mg) and tislelizumab may be 
explored to confirm the optimal dosing regimen of ociperlimab and tislelizumab (Figure 3). 
Refer to Section 3.2.1 for the details of dose escalation study in Australia. 
RP2D will be determined after discussion with SMC before the initiation of dose expansion.  
Refer to Section 3.2.1.5 for the result of RP2D determination. 
Dose Verification in China: Before Chinese patients join the Phase 1b study, safety and 
tolerability of ociperlimab (RP2D) will be assessed as a monotherapy, and in combination with 
tislelizumab (200 mg Q3W) in Chinese patients.  The SMC will define the RP2D for Chinese 
patients based on the safety data from ociperlimab, combined with tislelizumab 200 mg, before 
Chinese patients join the Phase 1b study. 
Refer to Section 3.2.2 for the details of dose verification study in China.  
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Phase 1b 
Approximately 250 to 500 evaluable patients (having measurable disease at baseline and 
postdose) will be enrolled into 10 different disease cohorts, including: 
• Cohort 1 (n = 20 to 40): Patients with metastatic squamous NSCLC will be treated with 
ociperlimab plus tislelizumab plus paclitaxel/nab-paclitaxel plus carboplatin.  
• Cohort 2 (n = 20 to 40): Patients with metastatic non-squamous NSCLC will be treated 
with ociperlimab plus tislelizumab plus pemetrexed plus cisplatin/carboplatin.  
• Cohort 3 (n = 20 to 40): Patients with metastatic NSCLC (PD-L1 positive, TC ≥ 1%) 
will be treated with ociperlimab plus tislelizumab. 
• Cohort 4 (n = 20 to 40): Patients with extensive-stage SCLC will be treated with 
ociperlimab plus tislelizumab plus etoposide plus cisplatin/carboplatin.  
• Cohort 5 (n = 20 to 40): Checkpoint inhibitor (CPI)-experienced NSCLC patients will be 
treated with ociperlimab plus tislelizumab.  
• Cohort 6 (n = 20 to 40): Patients with metastatic ESCC will be treated with ociperlimab 
plus tislelizumab plus cisplatin plus 5-FU/paclitaxel.  
• Cohort 7 (n = 20 to 40): Patients with metastatic EAC will be treated with ociperlimab 
plus tislelizumab plus cisplatin plus 5-FU/paclitaxel. 
• Cohort 8 (n = 20 to 40): Patients with recurrent or metastatic HNSCC (PD-L1 positive, 
[vCPS] ≥ 1%) will be treated with ociperlimab plus tislelizumab. 
• Cohort 9 (n = 30 to 60): Patients with unresectable, locally advanced, recurrent or 
metastatic G/GEJ adenocarcinoma will be treated with ociperlimab plus tislelizumab plus 
oxaliplatin plus capecitabine or ociperlimab plus tislelizumab plus cisplatin plus 5-FU. 
• Cohort 10 (n = 20 to 40 per arm, 3 dose arms): Patients with metastatic NSCLC (PD-L1 
positive, TC ≥ 1%) will be treated with ociperlimab plus tislelizumab. 
Depending on the allocated cohort, Phase 1b will include different stages (Figure 5).  For 
Cohorts 1, 2, 4, 6, 7, and 9, patients will receive ociperlimab combined with tislelizumab and 
chemotherapy.  Phase 1b includes a safety run-in stage and a dose-expansion stage.  For Cohorts 
3, 5, and 8, patients will receive ociperlimab combined with tislelizumab.  Phase 1b includes 
dose-expansion stage.  For details of Phase 1b, please refer to Section 3.3.  
For Cohorts 1 to 8 and the 3 dose arms in Cohort 10, an interim analysis will be conducted based 
on approximately the first 20 patients who have had ≥ 1 on-study tumor assessment 
(Section 10.7).  Based upon the interim analysis for a given cohort, up to 40 evaluable patients 
may be enrolled for that cohort as described in Section 10.7.  For Cohort 9, the interim analysis 
will be conducted based on approximately the first 30 patients who have had ≥ 1 postbaseline 
tumor assessment.  Up to 60 evaluable patients in total may be enrolled based on the interim 
analysis for Cohort 9.  
Patients will receive study drug until they meet a study treatment discontinuation criterion 
(Section 7.5).  
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All patients will be closely monitored for AEs throughout the study and for ≥ 30 days after the 
last dose of study treatment or until initiation of another anticancer therapy, whichever occurs 
first.  AEs will be graded according to the NCI-CTCAE v5.0.  Refer to Section 9 for additional 
and specific information regarding AE monitoring and reporting. 
PK analysis will be performed for ociperlimab and tislelizumab with or without chemotherapy.  
Biomarker analysis will include, but not limited to, TIGIT, CD226, CD155, CD112, and PD-L1 
expression in tumors, TIL analysis, tumor mutation burden, MSI status and gene mutations in 
tissue and blood, EBV status, cytokine analysis in plasma, peripheral blood cell population 
analysis, and/or GEP in tissue and blood (Section 8.4). 
Preliminary anticancer activity will be evaluated by the investigator using RECIST v1.1, 
(Section 8.5 and/or Appendix 9).  
Patients may continue to receive ociperlimab and tislelizumab beyond the initial 
investigator-assessed PD, as defined by RECIST v1.1, provided that the patient has 
investigator-assessed clinical benefit and is tolerating study drugs.  Refer to Section 7.5 and 
Section 8.5 for additional considerations regarding treatment continuation and withdrawal.  
Patients who, at time of progression, have an ongoing AE that leads to treatment discontinuation 
and has completed the scheduled Safety Follow-up Visit will be followed until the event 
resolves, the investigator assesses the event as stable, the patient is lost to follow-up, or the 
patient starts a subsequent anticancer therapy.  If a patient discontinues study drugs due to 
reasons other than PD or death, tumor assessments should continue to be performed following 
the scheduled assessment plan until the start of subsequent anticancer therapy, PD, death, lost to 
follow-up, or withdrawal of consent for efficacy follow-up (Section 7.4.2). 
Patients who have discontinued study drugs should return to the site for an End-of-Treatment 
(EOT) Visit within ≤ 7 days as detailed in Section 7.4.1.  After the EOT Visit, patients will have 
scheduled follow-up visits for safety and, if applicable, for efficacy per the Schedule of 
Assessments (Appendix 1). 
Study procedures and assessments are further detailed in Section 7 and Section 8, respectively, 
and the Schedule of Assessments can be found in Appendix 1.  Specific details regarding Phase 1 
and Phase 1b are described in the following sections. 
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Figure 3: 
Study Schema for Phase 1 (Dose Escalation in Australia) 
 
Abbreviations: C, Cycle; D, day; DLT, dose-limiting toxicity; MAD, maxima administered dose; MTD, maximal tolerated dose; PK, pharmacokinetics; RP2D, 
recommended Phase 2 dose. 
 
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Figure 4: 
Study Schema for Phase 1 (Dose Verification in China) 
 
 
Abbreviations: DLT, dose-limiting toxicity; mono, monotherapy; pts, patients; RP2D, recommended Phase 2 dose. 
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Figure 5: 
Study Schema for Phase 1b 
 
 
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Abbreviations: 5-FU, 5-fluorouracil; Carbo, carboplatin; Cis, cisplatin; EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; G/GEJ, 
gastric or gastroesophageal junction; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death-1 ligand; Q3W, once every 3 weeks; ES-SCLC, 
extensive-stage small cell lung cancer; SMC, Safety Monitoring Committee. 
Note: For Cohort 9, capecitabine as optional maintenance therapy is for oxaliplatin + capecitabine regimen only. 
 
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3.2. Details of Phase 1  
3.2.1. 
Phase 1 (Dose Escalation in Australia)  
3.2.1.1. 
Starting Dose and Dose Escalation Approach  
A modified 3+3 scheme will be used for sequential cohorts of approximately 4 increasing dose 
levels of ociperlimab in combination with tislelizumab in patients with advanced solid tumors 
(Figure 3) to determine the MTD or MAD, RP2D, safety, PK, and other key endpoints for 
ociperlimab in combination with tislelizumab.   
Except for the dose escalation DLT period, a 21-day treatment cycle is planned for all cycles 
thereafter. 
For dose escalation, a 28-day DLT observation period will be utilized in the first cycle.  A flat 
dose of ociperlimab will be administered intravenously as a single agent on Day 1 followed by a 
dose of 200 mg tislelizumab administered intravenously on Day 8.  To be DLT evaluable, 
patients must receive ociperlimab alone on Day 1 of Cycle 1, followed by tislelizumab alone on 
Cycle 1 Day 8 (+ 2 days).  Refer to Section 5.4.1 and Section 5.4.2 regarding continued 
treatment of patients who are unable to receive tislelizumab on Cycle 1 Day 8 (+2 days).  If no 
DLT(s) are observed thereafter and through the completion of the initial 28-day cycle, patients 
will receive ociperlimab and tislelizumab on Day 29 and every 21 days (ie, Q3W) thereafter, as 
outlined in Section 5.1.3 and Appendix 1, until patients meet a treatment discontinuation 
criterion.   
Once the criteria outlined below (Section 3.2.1.2, Section 3.2.1.3, and Section 3.2.1.4) have been 
satisfied for a dose level of ociperlimab, the next dose level will be eligible for patient 
enrollment.   
The starting ociperlimab dose level (50 mg) will initially be evaluated in 1 patient (sentinel 
patient), whereas the second ociperlimab dose level (150 mg) will be evaluated in 3 or more 
patients.  Escalation from the first ociperlimab dose level will proceed if no DLT is observed in 
the DLT evaluable patient.  If a DLT is observed in this sentinel patient, the dose will be further 
explored following the 3+3 rules.  Starting with the 150 mg ociperlimab dose level, escalation of 
the BGB A1217 dose level will proceed if no DLT is observed during the DLT period in a 
minimum of 3 evaluable patients.  However, if a DLT occurs within the DLT observation period 
for a given dose level, enrollment for that dose level and dose finding decisions will proceed per 
the 3+3 design rules as follows: 
a. Ociperlimab dose escalation will advance if the first cycle DLT rate < 33%; 
b. Ociperlimab dose escalation will stop if the first cycle DLT rate is ≥ 33%.  A minimum 
of 6 patients will be enrolled to the current dose level of ociperlimab if DLT rate is 33% 
(eg, 1/3) or the next lower dose level if DLT rate is >33% (eg, 2/3 or 3/3); 
c. The MTD dose level is defined as the highest dose level at which < 33% of the patients 
experience a DLT. 
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For dose escalation decisions, only DLTs occurring within 28 days of Cycle 1 Day 1 for the 
corresponding dose level will be evaluated.  However, as noted below and in Section 3.2.1.4, 
additional considerations may be taken into account if clinically significant toxicity(ies) is 
observed, regardless of when it occurred. 
Based upon emerging clinical data, lower, intermediate and/or higher dose levels and/or 
alternative dosing intervals of ociperlimab may also be evaluated.  However, the dosing regimen 
of tislelizumab will remain fixed for each different ociperlimab dose level evaluated. 
The combination RP2D will be determined primarily from the Phase 1 safety, tolerability and PK 
data analyzed in its entirety, but may also consider any available efficacy and/or exploratory 
data, from a minimum of 6 patients.  Once the combination RP2D is determined, it will then be 
evaluated in the Phase 1b dose expansion. 
3.2.1.2. 
Rules for Dose Escalation  
Dose escalation will occur in accordance with the following modified 3 + 3 dose escalation rules. 
For the initial dose escalation cohort (ociperlimab 50 mg Q3W), a single patient will be enrolled. 
• If the first evaluable patient enrolled in this cohort does not experience a DLT, dose 
escalation may proceed. 
• If the first evaluable patient enrolled in this cohort experiences a DLT, additional patients 
(for a minimum of 6 evaluable patients) will be enrolled in that cohort. 
− If less than one-third of evaluable patients in a given cohort experience a DLT (eg, DLTs 
in fewer than 2 of 6 patients), escalation will proceed to the next higher dose level. 
For the remaining dose escalation cohorts, a minimum of 3 patients will be initially enrolled per 
cohort. 
• If none of the first 3 evaluable patients enrolled in a given cohort experience a DLT, dose 
escalation may proceed. 
• If 1 of the first 3 evaluable patients enrolled in a given cohort experiences a DLT, additional 
patients (for a minimum of 6 evaluable patients) will be enrolled in that cohort.   
− If less than one-third of evaluable patients in a given cohort experiences a DLT 
(eg, DLTs in fewer than 2 of 6 patients), escalation will proceed to the next higher dose 
level. 
If a DLT is observed in at least one-third or more of patients (eg, 2 or more of up to 6 patients), 
the MTD will have been exceeded and dose escalation will be stopped. 
• Additional patients (for a minimum of 6 evaluable patients) will be assessed for DLTs at the 
preceding dose level (if a minimum of 6 evaluable patients had not already been assessed at 
that dose level). 
• If the MTD is exceeded at a given dose level, a lower or intermediate dose level may be 
assessed for toxicity in the same manner as described above. 
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If the MTD is exceeded at a given dose level, the next highest dose level at which less than 
one-third of evaluable patients in a given cohort experiences a DLT (eg, DLTs in fewer than 2 of 
6 patients) will be declared the MTD. 
If less than one-third of evaluable patients (eg, DLTs in fewer than 2 of 6 patients) at the highest 
dose level experience a DLT, this dose level will be declared the MAD. 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), 
will be reviewed by the medical monitor and study team members from Pharmacovigilance/Drug 
Safety, Clinical Pharmacology, and Biostatistics with input from other members as appropriate. 
On the basis of a review of real-time safety data and available preliminary PK data and in 
consultation with the investigators, dose escalation may be halted or modified as deemed 
appropriate. 
3.2.1.3. 
Assessment of Dose-Limiting Toxicity  
For initial dose-finding recommendations, AEs will be assessed per the DLT criteria below 
(Section 3.2.1.4) during the 28-day DLT assessment window, which starts with the first day of 
study drug administration. 
Patients will be considered evaluable for DLTs if they 1) received ≥ 80% of each scheduled 
study drug administration during the DLT assessment window and/or 2) experienced a DLT. 
Patients will be considered not evaluable for DLTs, if they 1) withdraw from the study, 2) did 
not receive ≥ 80% of each scheduled study drug administration during the DLT assessment 
window and/or 3) received supportive care during the DLT assessment window that confounds 
the evaluation of DLTs (not including supportive care described as part of the DLT definition).  
Patients who are not DLT-evaluable must be replaced, if needed. 
Clinically important or persistent AEs that are not part of the DLT criteria (Section 3.2.1.4) may 
also be considered a DLT following review by the sponsor in consultation with the investigators.  
All adverse events should be considered potentially related to the study drug regardless of 
investigator/sponsor causality assessment, excluding toxicities clearly related to disease 
progression or intercurrent illness.  Additionally, any clinically significant AEs that occur after 
the DLT assessment window (eg, late imAE) for a given dose level, may be considered regarding 
subsequent dose escalation decisions.  In such cases where patients have been safely dosed at the 
next dose level, additional dose-escalation criteria (eg, increased minimum number of patients or 
expanded DLT assessment window) for subsequent dose levels will be considered by the sponsor 
in consultation with participating investigators.  Every DLT will be discussed in SMC to help the 
determination of RP2D. 
Any patient who experiences a DLT may be withdrawn from treatment or may continue to 
receive either tislelizumab alone or the combination with a lower dose level for ociperlimab 
following discussion with and approval by the medical monitor. 
3.2.1.4. 
Dose-Limiting Toxicity Definition  
All toxicities or AEs will be graded according to the NCI-CTCAE v5.0.  A DLT is defined as 
1 of the following toxicities occurring during the DLT assessment window (first 28 study days) 
and considered by the investigator to be related to ociperlimab and/or tislelizumab.   
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Hematologic: 
1. Grade 4 neutropenia lasting > 7 days 
2. ≥ Grade 3 febrile neutropenia 
3. Grade 3 thrombocytopenia with clinically significant bleeding 
4. Grade 4 thrombocytopenia lasting > 7 days 
5. ≥ Grade 4 anemia 
Non-hematologic: 
6. ≥ Grade 4 toxicity 
7. Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 7 days of initiating 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 nausea, vomiting, or diarrhea lasting for ≤ 72 hours with adequate antiemetic 
and/or other supportive care 
• Grade 3 fatigue lasting for ≤ 7 days 
• Grade 3 or higher electrolyte abnormality that lasts for ≤ 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions. 
Patients will be considered not evaluable for DLTs, if they 1) withdraw from the study during the 
DLT assessment window, 2) did not receive ≥ 80% of each scheduled study drug administration 
during the DLT assessment window and/or 3) received supportive care during the DLT 
assessment window that confounds the evaluation of DLTs (not including supportive care 
described as part of the DLT definition).  Patients who are not DLT-evaluable must be replaced, 
if needed. 
Clinically important or persistent AEs that are not part of the DLT criteria may also be 
considered a DLT following review by the sponsor in consultation with the investigators.  All 
adverse events should be considered potentially related to the study drug regardless of 
investigator or sponsor causality assessment, excluding toxicities clearly related to disease 
progression or intercurrent illness.  Additionally, any clinically significant AEs that occur after 
the DLT assessment window (eg, late imAE) for a given dose level, may be considered regarding 
subsequent dose escalation decisions.  In such cases where patients have been safely dosed at the 
next dose level, additional dose escalation criteria (eg, increased minimum number of patients or 
expanded DLT assessment window) for subsequent dose levels will be considered by the sponsor 
in consultation with participating investigators.  Every DLT will be discussed in SMC to help the 
determination of RP2D. 
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3.2.1.5. 
RP2D Determination  
The ociperlimab dose of 900 mg Q3W combined with tislelizumab 200 mg Q3W was selected as 
the RP2D for further investigations based on clinical safety, tolerability, PK, and 
pharmacodynamic data from the ongoing Phase 1/1b Study AdvanTIG-105.  Refer to the 
Ociperlimab Investigator’s Brochure for further details. 
3.2.2. 
RP2D Confirmation in Chinese Patients Phase 1 (Dose Verification in China)  
Based on the safety results of the dose-escalation trial on ociperlimab conducted in Australia, 
this study will assess the safety and pharmacokinetic characteristics of flat-dose 900 mg 
monotherapy and combination with tislelizumab 200 mg Q3W in Chinese patients with advanced 
malignant solid tumors.  Other doses may be further explored based on the safety result and 
necessity. 
Dose verification study in China will occur in cohorts with ociperlimab as monotherapy and 
cohorts with ociperlimab in combination with tislelizumab (Figure 4).  A 21-day treatment cycle 
will be used for both monotherapy part and combination part.  DLT will be assessed among 
evaluable patients within Cycle 1 (1 to 21 days).  
Three to six patients will be enrolled first to assess DLT in Cohort 1A (ociperlimab monotherapy 
900 mg Q3W) and Cohort 1B (ociperlimab 900 mg in combined with tislelizumab 200 mg 
Q3W): 
• If none of the 3-6 patients experience a DLT at 900 mg dose level, Cohort 1A will 
continue to enroll up to 10 patients in total.  
• If none of the 3-6 patients experience a DLT at 900 mg dose level combined with 
tislelizumab, Cohort 1B will continue to enroll up to 10 patients in total. 
The following DLT rules apply to both monotherapy and combination part: 
• Three additional patients will be enrolled if a DLT is observed in 1 of 3 patients; 
2 additional patients will be enrolled if a DLT is observed in 1 of 4 patients; and 
1 additional patient will be enrolled if a DLT is observed in 1 of 5 patients.  
• If ≤ 1 DLT is observed in 6 patients, the cohort will continue to enroll up to 10 patients in 
total 
• If 2 or more patients develop DLT among 3-6 patients in the cohort, the dose level will be 
considered as exceeding the MTD.  All investigators will be informed of such dose level.  
A lower dose of 450 mg Q3W in both monotherapy (Cohort 2A) and combination part 
(Cohort 2B) will be evaluated. 
DLT will be assessed among evaluable patients within Cycle 1 (1-21 days) (refer to 
Section 3.2.1.3 for detailed assessment standard).  An evaluable patient is defined as the 
individual who has received ≥ 80% of the dose and completed all safety assessments required in 
Cycle 1, or any patient who has experienced DLT in Cycle 1.  
For dose verification decisions, only DLTs occurring within 21 days of Cycle 1 Day 1 for the 
corresponding dose level will be evaluated.  However, as noted below and in Section 3.2.1.4, 
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additional considerations may be taken into account if clinically significant toxicity(ies) is 
observed, regardless of when it occurred. 
The SMC will define the RP2D for Chinese patients based on the safety data from ociperlimab, 
combined with tislelizumab 200 mg, before Chinese patients join the Phase 1b study. 
Patients in monotherapy part (Cohort 1A/2A) who experience disease progression will be given 
the option to be treated with ociperlimab at the same dose level combined with tislelizumab. 
Any patient who experiences a DLT may be withdrawn from treatment or may continue to 
receive tislelizumab alone following discussion with and approval by the medical monitor. 
3.2.2.1. 
Dose-Limiting Toxicity Definition  
The definition of DLT can be found in Section 3.2.1.4. 
3.3. Details of Phase 1b  
Depending on the allocated cohort, Phase 1b will include different stages. 
For Cohort 1 (squamous NSCLC), Cohort 2 (non-squamous NSCLC), Cohort 4 (extensive-stage 
SCLC), Cohort 6 (ESCC), Cohort 7 (EAC), and Cohort 9 (G/GEJ adenocarcinoma), patients will 
receive tislelizumab (200 mg) in combination with ociperlimab (RP2D) and chemotherapy 
(Section 5).  Phase 1b includes a safety run-in stage and a dose-expansion stage.  In safety run-in 
stage, 6 evaluable patients will be enrolled in each cohort and followed up for ≥ 21 days.  A 
SMC will be established by the sponsor and investigators to evaluate the safety and tolerability 
of the combination therapy when the 6 patients of each cohort have completed the first 21 days 
treatment.  Safety information, including but not limited to all of AEs and laboratory 
abnormalities, will be reviewed by the SMC.  If there is no new unexpected safety signal 
detected by the SMC, the enrollment will continue until a total of 20 to 40 evaluable patients for 
Cohorts 1 to 8, 30 to 60 evaluable patients for Cohort 9 and 20 to 40 evaluable patients for each 
of the 3 arms in Cohort 10 are reached in the dose-expansion stage.  
For Cohort 3 and Cohort 10 (NSCLC with PD-L1 positive, TC ≥ 1%), Cohort 5 
(CPI-experienced NSCLC), and Cohort 8 (HNSCC with PD-L1 positive, vCPS ≥ 1%), patients 
will receive tislelizumab (200 mg) in combination with ociperlimab (RP2D or specified doses) 
(Section 5).  Phase 1b includes only dose-expansion stage which will start once the RP2D of 
ociperlimab is confirmed.  
During the maintenance treatment period, prophylactic cranial irradiation is permitted in Cohort 
4 (extensive-stage SCLC) as per local standard of care. 
For Cohort 10, patients with NSCLC with PD-L1 positive (TC ≥ 1%) will be randomized to 
receive ociperlimab 450 mg, 900 mg, or 1800 mg in combination with tislelizumab 200 mg in an 
open-label setting.  The randomization will be stratified based on PD-L1 status (TC 1% to 49%, 
TC ≥ 50%) and histology. 
The recommended dose level of tislelizumab (200 mg intravenously Q3W) with ociperlimab will 
be based upon the available clinical data derived from Phase 1 and any other data as applicable.  
For all 10 cohorts, ociperlimab and tislelizumab will be continually used Q3W until the patients 
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would not benefit from therapy under investigator’s discretion, intolerable toxicity or withdrawal 
of consent. 
If the frequency of ≥ Grade 3 toxicities or other unacceptable chronic toxicities in the 
dose-expansion phase suggests that the MTD has been exceeded at that dose level, any 
remaining accrual of patients at that dose level will be halted.  Consideration will then be given 
to enrolling additional patients into the dose-expansion cohorts and Cohort 10 at a lower dose 
level. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers. 
4.1. Inclusion Criteria  
4.1.1. 
Inclusion Criteria for Phase 1  
Each patient must meet all of the following inclusion criteria to be considered eligible for 
participation in this study: 
1. Signed informed consent form (ICF) and able to comply with study requirements. 
2. Age ≥ 18 years (or the legal age of consent) at the time the ICF is signed. 
3. Histologically or cytologically confirmed unresectable locally advanced or metastatic solid 
tumors previously treated with standard systemic therapy or for which treatment is not 
available or not tolerated, and who have not received prior therapy targeting TIGIT.   
• Patients with HCC require Child-Pugh A classification before the first dose of study 
drugs (Appendix 10) 
4. ≥ 1 evaluable lesion per RECIST v1.1.  
5. If available, archived, formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (block 
or approximately 15 freshly cut unstained FFPE slides).  
• If archival tissue is unavailable, optional fresh baseline tumor biopsy is strongly 
recommended 
6. ECOG Performance Status ≤ 1. 
7. Adequate organ function as indicated by the following laboratory values during screening: 
a. Absolute neutrophil count ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L 
c. Hemoglobin ≥ 90 g/L, without blood transfusion or growth factor support ≥ 14 days 
before sample collection 
d. Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate 
(GFR) ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Appendix 7) 
e. Serum total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert syndrome) 
f. AST and ALT ≤ 3 x ULN 
8. Females of childbearing potential must be willing to use a highly effective method of birth 
control for the duration of the study, and ≥ 120 days after the last dose of study drugs, and 
have a negative urine or serum pregnancy test ≤ 7 days of the first dose of study drugs 
(Appendix 5). 
9. Nonsterile males must be willing to use highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of study drugs (Appendix 5). 
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4.1.2. 
Inclusion Criteria for Phase 1b  
Each patient must meet all of the following inclusion criteria to be considered eligible for 
participation in this study: 
1. Signed ICF and able to comply with study requirements. 
2. Age ≥ 18 years (or the legal age of consent) at the time the ICF is signed. 
3. Following determination of RP2D, the combination will be evaluated in histologically or 
cytologically confirmed tumor types with staging per AJCC 8th edition (Amin et al 2017) in 
the following disease cohorts: 
a. Cohort 1: Have histologically or cytologically confirmed stage IV squamous NSCLC  
b. Cohort 2: Have histologically or cytologically confirmed stage IV non-squamous 
NSCLC 
c. Cohort 3: Have histologically or cytologically confirmed stage IV squamous or 
non-squamous NSCLC with PD-L1 positive (TC ≥ 1%) 
− Patients must have PD-L1 IHC testing with results positive (TC ≥ 1%) performed by 
a central laboratory during the screening period 
− Patients with tumors of mixed (squamous and non-squamous) or unspecified 
non-small cell histology are eligible 
d. Cohort 4: Have histologically or cytologically confirmed extensive-stage SCLC  
e. Cohort 5: Have histologically or cytologically confirmed stage IIIB, IIIC, or IV NSCLC 
with all of the following: 
− Patients who previously treated with one or two lines of prior standard systemic 
therapy for locally advanced or metastatic disease (Disease progression within 6 
months following completion of local therapy with curative intention including 
adjuvant chemotherapy after surgical procedure or concurrent chemoradiotherapy 
with/without consolidation could be considered as treated with 1 line standard 
systemic therapy) 
− The anti-PD-(L)1 treatment must be the most recent line 
− The best response with anti-PD-(L)1 treatment of the most recent line, should be CR, 
PR, or SD 
f. Cohort 6: Have histologically or cytologically confirmed stage IV ESCC 
g. Cohort 7: Have histologically or cytologically confirmed stage IV EAC 
h. Cohort 8: Have histologically or cytologically confirmed recurrent or metastatic HNSCC 
that is considered incurable by local therapies 
− The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and 
larynx. 
− Patients must not have a primary tumor site of nasopharynx (any histology) 
− Patients must have positive PD-L1 IHC testing results (vCPS ≥ 1%) performed by a 
central laboratory during the screening period 
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− Known p16 expression for oropharyngeal cancers by local testing.  If local p16 
testing results are not available, a tumor tissue sample may be submitted for p16 
testing at the designated central laboratory.  Oral cavity, hypopharynx, and larynx 
cancer are not required to undergo HPV testing by p16 IHC 
i. Cohort 9: Have histologically or cytologically confirmed stage IV G/GEJ 
adenocarcinoma 
j. Cohort 10: Have histologically- or cytologically-confirmed stage IV squamous or non-
squamous NSCLC with PD-L1 positive (TC ≥ 1%) 
− Patients must have PD-L1 IHC testing with results positive (TC ≥ 1%) performed by 
a central laboratory during the screening period 
− Patients with unspecified non-small cell histology are not eligible 
4. ≥ 1 measurable lesion per RECIST v1.1. 
a. No prior local therapy of selected target lesion(s) OR, if prior local therapy, subsequent 
progression of each selected target lesion as per RECIST v1.1 
5. Archived tumor tissue or fresh biopsy (FFPE block [preferred] or approximately 15 freshly 
cut unstained FFPE slides, ≥ 8 slides are mandatory) are required to be collected.  For 
Cohorts 3 and 10 (NSCLC with PD-L1 positive, TC ≥ 1%) and Cohort 8 (HNSCC with 
PD-L1 positive [vCPS ≥ 1%]), prospective PD-L1 IHC testing at the designated central 
laboratory is mandatory.  
6. ECOG Performance Status ≤ 1. 
7. Adequate organ function as indicated by the following laboratory values during screening: 
a. Absolute neutrophil count ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L for patients receiving ociperlimab plus tislelizumab plus 
chemotherapy or ≥ 75 x 109/L for patients receiving ociperlimab plus tislelizumab 
c. Hemoglobin ≥ 90 g/L, without blood transfusion or growth factor support ≥ 14 days 
before sample collection 
d. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 60 mL/min 
(Cockcroft-Gault formula) (Appendix 13) 
e. Serum total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert syndrome) 
f. AST and ALT ≤ 2.5 x ULN or < 5 x ULN if hepatic metastases present. 
8. Females of childbearing potential must be willing to use a highly effective method of birth 
control for the course of the study through 180 days after the last dose of chemotherapeutic 
agents (14 months after the last dose of cisplatin; 9 months after the last dose for oxaliplatin) 
or through 120 days after the last dose of study drugs, and have a negative urine or serum 
pregnancy test ≤ 7 days of the first dose of study drugs (Appendix 5). 
9. Nonsterile males must be willing to use highly effective method of birth control for the 
course of the study through 180 days after the last dose of chemotherapeutic agents 
(11 months after the last dose of cisplatin; 6 months after the last dose for oxaliplatin) or 
through 120 days after the last dose of study drugs.
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4.2. Exclusion Criteria  
4.2.1. 
Exclusion Criteria for Phase 1  
Patients who meet any of the following criteria will be excluded from this study: 
1. Active leptomeningeal disease or uncontrolled brain metastasis 
• Patients with equivocal findings or with confirmed brain metastases are eligible if they 
are asymptomatic and radiologically stable without need for corticosteroids for ≥ 4 weeks 
before the first dose of study drugs. 
2. Active autoimmune diseases or history of autoimmune diseases that may relapse, with the 
following exceptions: 
• Controlled type 1 diabetes 
• Hypothyroidism (provided it is managed with hormone-replacement therapy only) 
• Controlled celiac disease 
• Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 
• Any other disease that is not expected to recur in the absence of external triggering 
factors 
3. Any active malignancy ≤ 2 years before the first dose of study drugs, except for the specific 
cancer under investigation and any locally recurring cancer that has been treated with 
curative intent (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast). 
4. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first 
dose of study drugs, with the following exceptions: 
• Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
• Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal 
systemic absorption 
• Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye 
allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) 
5. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases, 
including but not limited to pulmonary fibrosis, acute lung diseases, etc. 
6. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia 
≤ 14 days before the first dose of study drugs 
7. Severe chronic or active infections (including but not limited to tuberculosis infection) 
requiring systemic treatment ≤ 14 days before the first dose of study drugs  
8. Known history of human immunodeficiency virus (HIV) infection 
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9. Known history of or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
except for the following: 
• Patients with untreated chronic HBV or chronic HBV carriers whose HBV 
deoxyribonucleic acid (DNA) is ≥ 500 IU/mL or patients with positive HCV ribonucleic 
acid should be excluded.  Inactive hepatitis B surface antigen (HBsAg) carriers, treated 
and stable hepatitis B patients (HBV DNA < 500 IU/mL), and cured hepatitis C patients 
(as defined by a positive HCV antibody test and negative HCV ribonucleic acid test) may 
be enrolled. 
10. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks before the 
first dose of study drugs or anticipation of need for major surgical procedure during the 
course of the study 
11. Prior immunodeficiency, allogeneic stem cell transplantation, or organ transplantation 
12. Any of the following cardiovascular criteria: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily 
living, ≤ 28 days before the first dose of study drugs 
b. Symptomatic pulmonary embolism or other clinically significant episode of 
thromboembolic disease ≤ 28 days before the first dose of study drugs 
c. History of acute myocardial infarction ≤ 6 months before the first dose of study drugs 
d. History of heart failure meeting New York Heart Association Classification III or IV 
(Appendix 6) ≤ 6 months before the first dose of study drugs 
e. Ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study 
drugs 
f. Cerebrovascular accident ≤ 6 months before the first dose of study drugs 
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before the first dose of 
study drugs 
13. History of severe hypersensitivity reactions to other monoclonal antibodies 
14. Chemotherapy, immunotherapy (eg, interleukin, interferon, or thymosin), or investigational 
therapy ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drugs 
• Received any herbal medicine or Chinese patent medicines used to control cancer 
≤ 14 days before the first dose of study drugs 
15. Toxicities from prior therapy that have not recovered to baseline, ≤ Grade 1, or stabilized, 
except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific 
laboratory abnormalities) 
16. Live vaccine ≤ 4 weeks before the first dose of study drugs 
• Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
17. Medical condition or alcohol or drug abuse or dependence that, in the investigator’s opinion, 
will be unfavorable for the administration of study drugs or will affect the explanation of 
drug toxicity or AEs or are likely to result in insufficient compliance with study procedures. 
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18. Concurrent participation in another therapeutic clinical study 
19. Any condition that requires treatment with prohibited or restricted concomitant medication or 
therapy as described in Section 6. 
4.2.2. 
Exclusion Criteria for Phase 1b  
Patients who meet any of the following criteria will be excluded from this study: 
1. For Cohorts 1, 2, 3, 4, 9, and 10, patients with any prior therapy for metastatic disease, 
including systemic chemotherapy or local radiotherapy are excluded.  If there is prior 
neoadjuvant/adjuvant chemotherapy, the treatment-free interval from end of 
neoadjuvant/adjuvant chemotherapy to recurrence should be ≥ 6 months before ICF signing. 
2. For Cohorts 6, 7, and 8, patients with any prior systemic therapy for recurrent/metastatic 
disease are excluded.  Patients with prior systemic chemotherapy administered as a part of 
chemoradiotherapy for locally advanced disease are eligible.  If there is prior curatively 
intended systemic treatment, the treatment-free interval from end of neoadjuvant/adjuvant 
chemotherapy to recurrence should be ≥ 6 months before ICF signing. 
3. Certain types of patients are excluded: 
a. For Cohorts 1, 2, 3, and 5, tumors of mixed non-small cell histology will be categorized 
by the predominant cell type; if small cell elements are present, the patient is ineligible.  
For Cohort 10, tumors of mixed non-small cell histology are excluded. 
b. For Cohorts 2, 3, 5, and 10, non-squamous NSCLC patients with sensitizing epidermal 
growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, and 
c-ros oncogene 1 (ROS1) fusion are excluded.  All patients with non-squamous histology 
must have been tested locally for EGFR, ALK, and ROS1 status.  Use of an 
FDA-approved or local Health Authority approved test is strongly encouraged, or a 
central laboratory test can be used if a local laboratory test is not available.  
c. For Cohort 9, patients with squamous cell or undifferentiated or other histological type 
GC or diagnosed with G/GEJ adenocarcinoma with positive HER2 expression.  All 
G/GEJ adenocarcinoma patients must have been tested locally for HER2 status.  If local 
HER2 testing results are not available, a tumor tissue sample may be submitted to the 
designated central laboratory for HER2 testing. 
4. Prior therapy with an anti-PD-1, anti-PD-L1, anti-TIGIT or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways (anti-PD(L)1 exception 
for Cohort 5).  
5. Active leptomeningeal disease or uncontrolled brain metastasis. 
• Patients with equivocal findings or with confirmed brain metastases are eligible if they 
are asymptomatic and radiologically stable without need for corticosteroids for ≥ 4 weeks 
before the first dose of study drugs. 
6. Palliative radiation treatment within 4 weeks of first dose. 
Note: If palliative radiation treatment is ≥ 4 weeks before first dose but all target lesions were 
treated with radiotherapy and there was no progression afterwards, the patient is not eligible. 
7. For Cohort 6 and 7, patients with any of the following:  
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• Unintentional weight loss ≥ 5% within 1 month before the first dose 
• CTCAE ≥ Grade 2 anorexia within 7 days before the first dose  
• Nutritional Risk Index (NRI) < 83.5 (Appendix 12) per investigator’s choice.  
For Cohort 9, patients with any of the following:  
• Unintentional weight loss ≥ 20% within 2 months before randomization  
• CTCAE ≥ Grade 2 anorexia within 7 days before randomization. 
8. Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta). 
9. Evidence of complete esophageal obstruction not amenable to treatment. 
10. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or 
medical intervention (clinically significant recurrence requiring an additional intervention 
within 2 weeks of intervention). 
11. Active autoimmune diseases or history of autoimmune diseases that may relapse, with the 
following exceptions: 
• Controlled type 1 diabetes 
• Hypothyroidism (provided it is managed with hormone-replacement therapy only) 
• Controlled celiac disease 
• Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 
• Any other disease that is not expected to recur in the absence of external triggering 
factors 
12. Any active malignancy ≤ 2 years before the first dose of study drugs, except for the specific 
cancer under investigation and any locally recurring cancer that has been treated with 
curative intent (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the cervix or breast). 
13. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first 
dose of study drugs, with the following exceptions: 
• Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
• Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal 
systemic absorption 
• Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye 
allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) 
14. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases, 
including but not limited to pulmonary fibrosis, acute lung diseases, etc. 
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15. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia 
≤ 14 days before the first dose of study drugs. 
16. Severe chronic or active infections (including but not limited to tuberculosis infection) 
requiring systemic treatment ≤ 14 days before the first dose of study drugs.  
17. Known history of HIV infection. 
18. Known history of or active HBV or HCV infection except for the following: 
• Patients with untreated chronic HBV or chronic HBV carriers whose HBV DNA is 
≥ 500 IU/mL or patients with positive HCV ribonucleic acid should be excluded.  
Inactive HBsAg carriers, treated and stable hepatitis B patients (HBV DNA 
< 500 IU/mL), and cured hepatitis C patients (as defined by a positive HCV antibody test 
and negative HCV ribonucleic acid test) may be enrolled. 
19. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks before the 
first dose of study drugs or anticipation of need for major surgical procedure during the 
course of the study. 
20. Prior immunodeficiency, allogeneic stem cell transplantation, or organ transplantation. 
21. Known dihydropyrimidine dehydrogenase (DPD) deficiency for patients receiving 
5-fluorouracil (5-FU) or capecitabine. 
22. Any of the following cardiovascular criteria: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily 
living, ≤ 28 days before the first dose of study drugs 
b. Symptomatic pulmonary embolism or other clinically significant episode of 
thromboembolic disease ≤ 28 days before the first dose of study drugs 
c. History of acute myocardial infarction ≤ 6 months before the first dose of study drugs 
d. History of heart failure meeting New York Heart Association Classification III or IV 
(Appendix 6) ≤ 6 months before the first dose of study drugs 
e. Ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study 
drugs 
f. Cerebrovascular accident ≤ 6 months before the first dose of study drugs 
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before the first dose of 
study drugs 
23. History of severe hypersensitivity reactions to other monoclonal antibodies. 
24. Chemotherapy, immunotherapy (eg, interleukin, interferon, or thymosin), or investigational 
therapy ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drugs. 
• Received any herbal medicine or Chinese patent medicines used to control cancer 
≤ 14 days before the first dose of study drugs 
25. Toxicities from prior therapy that have not recovered to baseline, ≤ Grade 1, or stabilized, 
except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific 
laboratory abnormalities). 
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26. Live vaccine ≤ 4 weeks before the first dose of study drugs. 
• Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
• A non-live COVID-19 vaccine may be administered if recommended per local practice.  
The vaccine administered cannot be a live or live-attenuated vaccine.  For patients to 
accept COVID-19 vaccine during the course of the study, it is necessary to consult 
medical monitor.  
27. Medical condition or alcohol or drug abuse or dependence that, in the investigator’s opinion, 
will be unfavorable for the administration of study drugs or will affect the explanation of 
drug toxicity or AEs or are likely to result in insufficient compliance with study procedures.  
28. Concurrent participation in another therapeutic clinical study. 
29. Any condition that requires treatment with prohibited or restricted concomitant medication or 
therapy as described in Section 6. 
30. Patients not suitable for chemotherapy or immunotherapy, eg, serious imAEs in previous 
immunotherapy if any, per investigator’s discretion for cohorts in Phase 1b.  
31. Patients receiving paclitaxel must not have peripheral neuropathy ≥ Grade 2 at baseline.   
 
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5. 
STUDY TREATMENT  
5.1. Formulation, Packaging, and Handling  
5.1.1. 
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 200 mg antibody in 10 mL or 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 condition as 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. 
5.1.2. 
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 condition as 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. 
5.1.3. 
Chemotherapy Agents  
Management (ie, handling, storage, administration, and disposal) of pemetrexed, paclitaxel, 
nab-paclitaxel, carboplatin, cisplatin, etoposide, 5-FU, oxaliplatin, and capecitabine will be in 
accordance with relevant local guidelines, prescribing information/summary of product 
characteristics.  The administered dose could be adjusted within ± 5% of the calculated dose at 
the investigator’s discretion.  The starting dose of cisplatin can be modified according to local 
practice with the expectation that the dose remains within the range of 60 to 80 mg/m2 per cycle.  
After the starting dose of cisplatin is chosen, all the cycles should follow the same dose level 
unless necessary modification is needed as specified in Section 5.4.3. 
5.2. Dosage, Administration, and Compliance  
Treatment with study drugs on Day 1 of Cycle 1 must begin within 3 business days after the 
patient is enrolled (Section 7.2).  Treatment modifications (eg, dose delay/holds) will be based 
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on specific laboratory and AE criteria, as described in Section 5.4.  Guidelines for study 
treatment modification, delay, or discontinuation as well as management of imAEs or 
infusion-related reactions are provided in Section 9.7 and Appendix 8. 
Accurate records of all study drugs received, dispensed, returned, and disposed should be 
maintained in the site’s Drug Inventory Log.  Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration. 
5.2.1. 
Ociperlimab and Tislelizumab Combination Dose Escalation  
Planned dose level(s) and dosing frequency during dose escalation for ociperlimab and 
tislelizumab are presented in Table 3. 
Table 3: 
Planned Dose Levels for Ociperlimab and Tislelizumab for Dose Escalation 
Study drugs 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration of treatment 
Ociperlimab 
50 mg 
150 mg 
450 mg 
900 mg 
(Lower, 
intermediate, 
and/or higher 
dose levels may 
be explored.) 
Cycle 1 Day 1, Cycle 2 
Day 1, then once every 
21 days 
Intravenous 
Refer to Section 7.5.1  
Tislelizumab 
200 mg 
Cycle 1 Day 8, Cycle 2 
Day 1, then once every 
21 days 
Intravenous 
Until disease 
progression, 
unacceptable toxicity, 
or voluntary 
withdrawal of consent 
per patient decision 
Cycle 1 only will be 28 days in length.  Thereafter starting with Cycle 2, each cycle will be 
21 days in length (ie, Q3W).  In the first cycle, ociperlimab will be administered on Day 1, and 
tislelizumab will be administered on Day 8 (+2 days).  Following completion of Cycle 1, patients 
will then receive tislelizumab on Day 1 of each subsequent 21-day cycle (ie, Q3W) followed by 
the administration of ociperlimab.  Other dosing regimens of ociperlimab may be explored based 
on safety, PK, and antitumor activities observed in dose levels that are completed.  However, the 
dosing regimen of tislelizumab will remain fixed as shown in Table 3.  Ociperlimab and 
tislelizumab must be administered by intravenous infusion through an intravenous line 
containing a sterile, non-pyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter. 
Table 4 outlines the infusion as well as post-infusion monitoring times for ociperlimab and 
tislelizumab.  Monitoring must occur in an area where emergency medical equipment and 
appropriately trained staff are available.  Duration of infusion and post-infusion monitoring can 
be decreased if ociperlimab and tislelizumab infusion is well tolerated, as outlined in Table 4.  
Ociperlimab and tislelizumab must not be concurrently infused with any other drug. 
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Table 4: 
Administration of Ociperlimab and Tislelizumab and Monitoring Time for 
Dose Escalation 
Cycle 
Ociperlimab and Tislelizumab combination 
C1D1  
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
C1D8  
Tislelizumab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
C2D1 
Tislelizumab infusion over 60 (± 5) minutes followed by 
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
C3D1 
Tislelizumab infusion over 30 (± 5) minutes followed by 
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
C4D1 onwards 
Tislelizumab infusion over 30 (± 5) minutes followed by 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Abbreviations: C, cycle; D, day. 
Note: The infusion rate may be decreased, or the infusion may be stopped in the event of an infusion-related 
reaction.  See Section 9.7.1 for details. 
5.2.2. 
Dose Verification in China  
Planned dose level(s) and dosing frequency during dose verification in China for ociperlimab 
and tislelizumab are presented in Table 5: 
Table 5: 
Planned Dose Levels and Dosing Frequency for Ociperlimab as 
Monotherapy and in Combination With Tislelizumab for Dose Verification 
Study drugs 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration of treatment 
Ociperlimab 
900 mg 
450 mg (if 
appropriate) 
 
D1 of each cycle, every 
21 days 
Intravenous 
Refer to Section 7.5.1 
Tislelizumab 
200 mg 
D1 of each cycle, every 
21 days 
Intravenous 
Until disease 
progression, 
unacceptable toxicity, 
or voluntary 
withdrawal of consent 
per patient decision 
Abbreviations: C, cycle; D, day. 
A 21-day treatment cycle will be used for ociperlimab alone and in combination with 
tislelizumab.  The administration of ociperlimab will occur in ociperlimab 900 mg monotherapy 
(Cohort 1A) and ociperlimab 900 mg in combined with tislelizumab (Cohort 1B).  
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Ociperlimab dose of 450 mg may be explored in both monotherapy and combination cohort 
(cohort 2A and 2B) if excessive DLT observed in 900 mg dose level.  For the combination 
cohorts (Cohort 1B and 2B), the patients will receive tislelizumab followed by the administration 
of ociperlimab on Day 1 of each 21-day cycle (ie, Q3W).  Ociperlimab and tislelizumab must be 
administered by intravenous infusion through an intravenous line containing a sterile, 
non-pyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on filter. 
Table 6 outlines the infusion as well as post-infusion monitoring times for ociperlimab as 
monotherapy and in combination with tislelizumab.  Monitoring must occur in an area where 
emergency medical equipment and appropriately trained staff are available.  Duration of infusion 
and post-infusion monitoring can be decreased if ociperlimab and tislelizumab infusion is well 
tolerated, as outlined in Table 6.  Ociperlimab and tislelizumab must not be concurrently infused 
with any other drug. 
Table 6: 
Administration of Ociperlimab as Monotherapy or in Combination With 
Tislelizumab 
Cycle 
Ociperlimab and Tislelizumab combination 
Ociperlimab 
C1D1 
Tislelizumab infusion over 60 (± 5) minutes  
Patient monitoring for ≥ 60 minutes  
followed by ociperlimab infusion over 60 
(± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
C2D1 
Tislelizumab infusion over 30 (± 5) minutes  
Patient monitoring for ≥ 60 minutes  
followed by ociperlimab infusion over 30 
(± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
C3D1 
onwards 
Tislelizumab infusion over 30 (± 5) minutes  
Patient monitoring for ≥30 minutes  
followed by ociperlimab infusion over 30 
(± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Abbreviations: C, cycle; D, day.  
5.2.3. 
Ociperlimab and Tislelizumab Combination With or Without Chemotherapy for 
Phase 1b  
The treatment regimen for Phase 1b is listed as follow: 
• Cohort 1 (squamous NSCLC): ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) + 
carboplatin AUC 5 or 6 (D1) + paclitaxel 200 or 175 mg/m2 (D1) or nab-paclitaxel 100 
mg/m2 (D1, D8, D15) Q3W for 4 to 6 cycles followed by ociperlimab 900 mg (D1) + 
tislelizumab 200 mg (D1) Q3W 
• Cohort 2 (non-squamous NSCLC): ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) 
+ cisplatin 75 mg/m2 (modification within 60 to 80 mg/m2 is permitted) or carboplatin 
AUC 5 (D1) + pemetrexed 500 mg/m2 (D1) IV Q3W for 4 to 6 cycles followed by 
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ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) + pemetrexed 500 mg/m2 (D1) 
Q3W 
• Cohort 3 (NSCLC with PD-L1 positive, TC ≥ 1%): ociperlimab 900 mg (D1) + 
tislelizumab 200 mg (D1) Q3W 
• Cohort 4 (extensive-stage SCLC): ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) 
+ cisplatin 75 mg/m2 (modification within 60 to 80 mg/m2 is permitted) or carboplatin 
AUC 5 (D1) + etoposide 100 mg/m2 (D1, D2, D3) Q3W for 4 cycles followed by 
ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) Q3W 
• Cohort 5 (CPI-experienced NSCLC): ociperlimab 900 mg (D1) + tislelizumab 200 mg 
(D1) Q3W  
• Cohort 6 (ESCC): ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) + cisplatin 75 
mg/m2 (D1, modification within 60 to 80 mg/m2 is permitted) + 5-FU 750 to 800 mg/m2 
(D1 to D5) or paclitaxel 200 or 175 mg/m2 (D1) Q3W for 6 cycles followed by 
ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) Q3W 
• Cohort 7 (EAC): ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) + cisplatin 
75 mg/m2 (D1, modification within 60 to 80 mg/m2 is permitted) + 5-FU 750 to 
800 mg/m2 (D1 to D5) or paclitaxel 200 or 175 mg/m2 (D1) Q3W for 6 cycles followed 
by ociperlimab 900 mg (D1) + tislelizumab 200 mg (D1) Q3W 
• Cohort 8 (HNSCC with PD-L1 positive, vCPS ≥ 1%): ociperlimab 900 mg (D1) + 
tislelizumab 200 mg (D1) Q3W  
• Cohort 9 (G/GEJ adenocarcinoma): ociperlimab 900 mg (D1) + tislelizumab 200 mg 
(D1) + [oxaliplatin 130 mg/m2 (D1) + capecitabine 1000 mg/m2 twice daily (D1 to D14)] 
or [cisplatin 75 mg/m2 (D1, modification within 60 to 80 mg/m2 is permitted) + 5-FU 750 
to 800 mg/m2 (D1 to D5)] Q3W for 6 cycles followed by ociperlimab 900 mg (D1) + 
tislelizumab 200 mg (D1) + capecitabine 1000 mg/m2 twice daily (D1 to D14) Q3W 
• Cohort 10 (NSCLC with PD-L1 positive, TC ≥ 1%): ociperlimab 450 mg (D1) or 900 mg 
(D1) or 1800 mg (D1) + tislelizumab 200 mg (D1) Q3W 
For Cohorts 1, 2, 4, 6, 7 and 9, the patients will receive cycles of chemotherapy (4 to 6 cycles for 
squamous and non-squamous NSCLC; 4 cycles for SCLC; up to 6 cycles for ESCC, EAC, 
G/GEJ adenocarcinoma) and treatment of ociperlimab plus tislelizumab until disease 
progression, intolerable toxicity, or withdrawal of consent.  For Cohort 9, capecitabine as an 
optional maintenance therapy is for the oxaliplatin + capecitabine regimen only.  For Cohorts 3, 
5, 8, and 10, the patients will receive treatment of ociperlimab plus tislelizumab until disease 
progression, intolerable toxicity, or withdrawal of consent.  Dosing schedules of study drugs are 
provided in Table 7.  
For Cohorts 2 and 4, either cisplatin or carboplatin could be selected as initial chemotherapy per 
investigator’s discretion in consideration of individual patient tolerability.  For patients who are 
given cisplatin as an initial treatment and experience any intolerable toxicity assessed as related 
to cisplatin, the investigator can consider replacing cisplatin with carboplatin as subsequent 
treatment per investigator’s discretion. 
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For each cycle of drug administration, ociperlimab and tislelizumab will be intravenously 
infused before chemo drugs.  The sequence of chemo drug administration will be conducted in 
accordance with the relevant local guidance and /or clinical practice. 
When the administration is delayed due to management of AEs (eg, infusion-related reaction), 
the administration of subsequent study drugs might be delayed to the second day of each cycle. 
Chemotherapy drug administration should be monitored during infusion.  If the site cannot 
monitor the whole drug administration within 1 day, the administration of chemotherapy drug 
may be delayed to the second day. 
Table 7: 
Dose, Frequency of Administration, and Route of Administration for Each 
Study Drug 
Study drug  
Dose  
Frequency of 
administration  
Route of 
administration  
tislelizumab  
200 mg  
D1 of each cycle  
Intravenous  
ociperlimab 
900 mg (Cohorts 1 to 9) 
450 mg (Arm A in 
Cohort 10) 
900 mg (Arm B in 
Cohort 10) 
1800 mg (Arm C in 
Cohort 10) 
D1 of each cycle 
Intravenous  
paclitaxel  
175 or 200 mg/m2  
D1 of each cycle  
Intravenous  
nab-paclitaxel  
100 mg/m2  
D1, D8, and D15 of 
each cycle  
Intravenous  
carboplatin  
AUC 5 or 6 
D1 of each cycle  
Intravenous  
Cisplatin 
75 mg/m2 (modification 
within 60 to 80 mg/m2 
is permitted) 
D1 of each cycle  
Intravenous  
Etoposide 
100 mg/m2 
D1, D2, and D3 of each 
cycle 
Intravenous 
pemetrexed 
500 mg/m2 
D1 of each cycle 
Intravenous 
5-FU 
750 or 800 mg/m2  
D1, D2, D3, D4, and 
D5 of each cycle 
Intravenous 
Oxaliplatin 
130 mg/m2 
D1 of each cycle 
Intravenous 
capecitabine 
1000 mg/m2 
D1 to D14 of each 
cycle 
Oral 
Abbreviations: AUC, area under the plasma or serum concentration-time curve; D, Day.  
Note: Treatment of paclitaxel or nab-paclitaxel, the choice of paclitaxel 200 or 175 mg/m2 and 
carboplatin AUC 5 or 6 will be determined per prescribing information and per local practice 
according to the treating physician’s clinical judgement.  
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Table 8 outlines the infusion as well as post-infusion monitoring times for ociperlimab, 
tislelizumab and chemotherapy.  Monitoring must occur in an area where emergency medical 
equipment and appropriately trained staff are available.  Duration of infusion and post-infusion 
monitoring can be decreased if ociperlimab and tislelizumab infusion is well tolerated, as 
outlined in Table 8. 
Table 8: 
Administration of Ociperlimab, Tislelizumab With or Without 
Chemotherapy and Monitoring Time for Dose Expansion 
Cycle 
Ociperlimab and Tislelizumab combination 
Ociperlimab, Tislelizumab and 
chemotherapy combination 
C1D1 
Tislelizumab infusion over 60 (± 5) minutes  
Patient monitoring for ≥ 60 minutes  
followed by 
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Tislelizumab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 60 minutes  
followed by 
Ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Chemotherapy (refer to labeling and local 
practice) 
C2D1 
Tislelizumab infusion over 30 (± 5) minutes  
Patient monitoring for ≥ 60 minutes  
followed by 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Tislelizumab infusion over 30 (± 5) minutes  
Patient monitoring for ≥ 60 minutes  
followed by 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
Chemotherapy (refer to labeling and local 
practice) 
C3D1 
onwards 
Tislelizumab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes  
followed by 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Tislelizumab infusion over 30 (± 5) minutes  
Patient monitoring for ≥ 30 minutes  
followed by 
Ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Chemotherapy (refer to labeling and local 
practice) 
Abbreviations: C, cycle; D, day. 
Note: The infusion rate may be decreased, or the infusion may be stopped in the event of an infusion-related 
reaction.  See Section 9.7.1 for details. 
5.2.3.1. 
Tislelizumab Plus Ociperlimab  
Patients will receive tislelizumab 200 mg on Day 1 of each subsequent 21-day cycle (ie, Q3W) 
followed by the administration of ociperlimab RP2D in Cohort 3 (NSCLC with PD-L1 positive, 
TC ≥ 1%), Cohort 5 (CPI-experienced NSCLC), Cohort 8 (HNSCC with PD-L1 positive, 
vCPS ≥ 1%).  Patients in Arm A, B, and C in Cohort 10 (NSCLC with PD-L1 positive, 
TC ≥ 1%) will receive tislelizumab 200 mg Q3W followed by the administration of ociperlimab 
450 mg, 900 mg, or 180 mg, respectively.  Ociperlimab and tislelizumab 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. 
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As a routine precaution, after infusion of ociperlimab and tislelizumab on Day 1 of Cycle 1 and 
Cycle 2, patients must be monitored for ≥ 1 hour afterward in an area with resuscitation 
equipment and emergency agents.  From Cycle 3 onward, at least a 30‑minute monitoring period 
is required in an area with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes for each drug of 
ociperlimab and tislelizumab; if this is well tolerated, then the subsequent infusions may be 
administered over 30 minutes of each drug, which is the shortest period permissible for infusion.  
Ociperlimab and tislelizumab must not be concurrently administered with any other drug. 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAE and infusion-related reactions are provided in detail in Section 9.7 and 
Appendix 8. 
5.2.3.2. 
Ociperlimab plus Tislelizumab Plus Chemotherapy  
Patients will receive tislelizumab 200 mg on Day 1 of each subsequent 21-day cycle (Q3W) 
followed by the administration of ociperlimab RP2D and chemotherapy in Cohort 1 (squamous 
NSCLC), Cohort 2 (non-squamous NSCLC), Cohort 4 (extensive-stage SCLC).  The 
administration and compliance of ociperlimab and tislelizumab refers to Section 5.2.3.1.  The 
treatment regimen of each cohort is based on the disease cohort in Section 5.2.3.  For the 
administration and compliance of chemotherapy, please refer to Section 5.2.3.2.1-5.2.3.2.9.  
None of the chemotherapy drugs should be concurrently administered with any other drug (ie, 
intravenous chemotherapy).  Each intravenous drug should be administered sequentially  
(Section 5.2.3).  Tislelizumab will be the first drug administered followed by ociperlimab and 
chemotherapy.  All chemotherapy agents’ preparation, premedication, administration, infusion 
time, monitoring, and management of complications are to follow local prescription guideline 
and regulation.   
Pre-infusion pretreatment: (1) Intravenous pretreatment for chemotherapy (eg, antiemetic) should 
be given in at least 30 minutes later after the completion of ociperlimab infusion (at least 2 hours 
later after the completion of first time ociperlimab infusion).  (2) Oral pretreatment for 
chemotherapy could be given following local practice, without limitation of intravenous 
pretreatment.   
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.4. 
5.2.3.2.1. Cisplatin  
Cisplatin 75 mg/m2 will be administered as an intravenous infusion over ≥ 2 hours on Day 1 of 
every 3 weeks for 6 cycles (4 to 6 cycles for patients with non-squamous NSCLC, 4 cycles for 
patients with extensive-stage SCLC).  Cisplatin dose can be modified according to local practice 
with the expectation that the dose remains within the range of 60 to 80 mg/m2 per cycle.  All 
patients should receive adequate hydration (including pretreatment hydration) and diuretics.  
Additional premedications should be administered as per standard practice.  
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5.2.3.2.2. Carboplatin  
Carboplatin AUC 5 or 6 will be administrated as an intravenous infusion on Day 1 of every 
3 weeks for 4 cycles (4 to 6 cycles for patients with squamous and non-squamous NSCLC).  
Additional premedications should be administered as per standard practice. 
The carboplatin dose will be calculated using the Calvert formula as follows: 
Carboplatin dose (mg) = target AUC x ([CrCl (mL/min) + 25] 
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight.  
NOTE: If calculation of the CrCl by the Cockcroft-Gault formula yields a result 
of > 125 mL/min, then a CrCl should be calculated by an alternative formula per institutional 
standards or capped at 125 mL/min.  The dose of carboplatin may be capped per local standards. 
5.2.3.2.3. Pemetrexed  
Pemetrexed 500 mg/m2 will be administered as an intravenous infusion over ≥ 10 minutes on 
Day 1 of every 3 weeks for 4 to 6 cycles in the induction stage and for continuous cycles in 
maintenance stage for patients with non-squamous NSCLC.  All patients should receive the 
appropriate supplementation of vitamin B12 and folic acid according to the manufacturer’s 
prescribing information and/or local standard practice.  In addition, all patients should receive 
the appropriate corticosteroid pre-medications as per the local standard practice. 
5.2.3.2.4. Paclitaxel  
Paclitaxel 175 or 200 mg/m2 will be administered as an intravenous fusion over ≥ 3 hours on 
Day 1 of every 3 weeks for 4 to 6 cycles for patients with squamous NSCLC per local practice.  
All patients should be pre-medicated with oral or injectable steroids according to the 
manufacturer’s prescribing information and/or standard practice.  Additional pre-medications 
(eg, diphenhydramine, and H2 antagonists) should be administered as per local standard practice. 
5.2.3.2.5. Nab-Paclitaxel  
Nab-paclitaxel 100 mg/m2 will be administered as an intravenous infusion over ≥ 30 minutes on 
Day 1, Day 8, and Day 15 of each cycle for 4 to 6 cycles for patients with squamous NSCLC.  In 
addition, all patients should receive the appropriate pre-medications as per the local approved 
label.  Additional pre-medications should be administered as per standard practice. 
5.2.3.2.6. Etoposide  
Etoposide 100 mg/m2 will be administered as intravenous infusion over ≥ 30 minutes on Day 1 
to Day 3 of every 3 weeks for 4 cycles for patients with extensive-stage SCLC.  Extravasation of 
infusion should be avoided. Additional pre-medications should be administered as per standard 
practice. 
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5.2.3.2.7. 5-fluorouracil  
5-FU 750 to 800 mg/m2 will be administered as continuous intravenous infusion over ≥ 24 hours 
on Day 1 to Day 5 of every 3 weeks.  The actual infusion time of 5-FU should be recorded, and a 
total infusion time of 120+/- 3 hours is acceptable. 
5.2.3.2.8. Oxaliplatin  
Oxaliplatin 130 mg/m2 will be administered as intravenous infusion over ≥ 2 hours on Day 1 of 
every 3 weeks.  It may be substituted in place of cisplatin, according to site or investigator 
preference or standard practice as determined before enrollment (except in China, Taiwan, Japan, 
and countries where oxaliplatin substitution is not permitted). 
5.2.3.2.9. Capecitabine  
Capecitabine will be self-administered orally twice daily, from the morning of Day 1 to the 
evening of Day 14 or from the evening of Day 1 to the morning of Day 15 of each 21-day cycle 
at the recommended dose of 1000 mg/m2 twice daily.  Alternate dose and dosing schedules are 
allowed according to local and institutional guidelines.  An adequate amount of supply of 
capecitabine will be dispensed to patients on Day 1 of each new cycle (Q3W).  Capecitabine 
should be taken with water, within 30 minutes after a meal.  If a dose of capecitabine is missed, 
the patient should take the next dose as scheduled.  A double dose of capecitabine should not be 
administered to make up for missed individual doses. 
5.3. Incorrect Administration or Overdose  
Any incorrect administration of ociperlimab 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. 
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 9.6.2.  Supportive care measures should be administered as appropriate. 
5.4. Dose Delay or Modification  
Every effort should be made to administer the study drugs according to the planned dose and 
schedule.  In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided below.  Reasons for dose modifications or delays, the supportive 
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
eCRF. 
Guidelines for treatment modification or discontinuation as well as the management of 
infusion-related reactions are provided in detail in Section 9.7 and Appendix 8.   
For AEs that are assessed as related to ociperlimab and/or tislelizumab, the following general 
guidance should be followed unless otherwise specified: 
• ≤ Grade 2: Maintain dose level 
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• Grade 3: Omit dose until resolved to ≤ Grade 1 or baseline except for alopecia or AEs 
that, in the opinion of the investigator, are not considered a safety risk for patient 
• Grade 4: Permanent discontinuation from study.  Exceptions may be considered 
following consultation with the medical monitor. 
5.4.1. 
Dose Interruption or Delay for Ociperlimab and Tislelizumab  
In Cycle 1 of Phase 1 dose-escalation study, if tislelizumab is delayed beyond Cycle 1 Day 8 
(+ 2 days), tislelizumab will not be administered in Cycle 1 but treatment may resume in 
subsequent cycles as outlined in Section 5.4.2. 
Except for Cycle 1 of the dose-escalation stage of the study, if a dose delay is required, both 
study drugs are to be delayed (ie, ociperlimab and tislelizumab must both be delayed and if 
applicable re-started at the same time).  Exceptions may be considered following consultation 
between the investigator and the medical monitor. 
If treatment is delayed due to TEAEs, treatment may resume only after the AEs have returned to 
baseline or ≤ Grade 1 severity except for alopecia or AEs that, in the opinion of the investigator, 
are not considered a safety risk to the patient.  If a treatment delay is 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 is prohibited.  A dose delay of 
≤ 12 weeks is allowed under the following guidance and at the discretion of the investigator after 
consultation with the medical monitor or designee. 
If treatment-related AEs are persistent without any improvement for more than 12 weeks, 
permanent discontinuation of the study drug should be considered.  If the patient recovers from 
the treatment-related AE after 12 weeks, re-initiation of study drug is permitted only in patients 
who are deemed to be deriving clinical benefit per the opinion of the investigator following 
agreement between the investigator and the medical monitor. 
For the cohorts without combination with chemotherapy (Cohorts 3, 5, 8, and 10), if a dose is 
delayed for ociperlimab and tislelizumab for ≤ 10 days for a planned dosing cycle (eg, Cycle 3 
Day 1), ociperlimab and tislelizumab should be administered (on the same day with 
chemotherapy, if applicable).  If the delay is > 10 days, the patient should skip both ociperlimab 
and tislelizumab.  Both ociperlimab and tislelizumab will be administered on Day 1 of the next 
planned cycle (eg, Cycle 4 Day 1). 
For the cohorts with combination of chemotherapy (Cohorts 1, 2, 4, 6, 7, and 9): If chemotherapy 
and immune therapy are delayed together by an AE, both therapies will be re-initiated together 
when the AE has resolved and posed no safety risk to the patient.  The next cycle will be 21 days 
after that to keep a 21-day window.  
The tumor assessment schedule will not be altered even if the administration of study drug is 
delayed.  
Two occurrences of dose delays because of treatment-related AEs will be permitted.  In the event 
of a third occurrence of a dose delay due to toxicity, permanent discontinuation of study drug 
should be considered after consultation with the medical monitor. 
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5.4.2. 
Dose Modifications for Ociperlimab and Tislelizumab  
There will be no dose reductions allowed for tislelizumab.  
For Phase 1 only, if patients are receiving a dose level of ociperlimab that is determined to be 
beyond the MTD, the dose level of ociperlimab may be reduced following discussion and 
agreement with the medical monitor.  Further, if a patient cannot be dosed with tislelizumab on 
Cycle 1 Day 8 (+2 days), the patient will not be considered DLT evaluable and will not be 
eligible to receive ociperlimab at the currently assigned dose level of ociperlimab.  However, 
starting on Cycle 2 Day 1 and every 21 days thereafter, the patient will be eligible, assuming any 
AE that resulted in a treatment delay has resolved per Section 5.4, to receive the combination of 
tislelizumab and a lower dose level of ociperlimab that had previously been shown to be 
tolerable according to the criteria outlined in Section 3.1 and following discussion with the 
medical monitor.   
5.4.3. 
Dose Modifications of Chemotherapy  
Dose modifications for chemotherapy should be performed per prescribing information and per 
local practice according to the treating physician’s clinical judgment.  The starting dose of 
cisplatin can be modified according to local practice with the expectation that the dose remains 
within the range of 60 to 80 mg/m2 per cycle.  After the starting dose of cisplatin is chosen, all 
the cycles should follow the same dose level unless necessary modification is needed as specified 
below. 
Baseline body weight is used to calculate the required chemotherapy doses.  Dose modifications 
are required if the patient’s body weight changes by > 10% from baseline (or the new reference 
body weight).  The dose should not be modified for any body weight change of less than 10%.  
Study drug related toxicities must be resolved to baseline or Grade 0 and 1 before administering 
the next dose, except for alopecia, Grade 2 fatigue, or AEs that, in the opinion of the investigator, 
are not considered a safety risk.  A maximum of 2 dose reductions is permitted for each 
chemotherapeutic agent.  Once the dose has been decreased, it should remain reduced for all 
subsequent administrations or further reduced if necessary.  There will be no dose escalations in 
dose-expansion stage (Phase 1b) in this study.  If additional reductions are required, that 
chemotherapeutic agent must be discontinued.  Chemotherapy treatment may be delayed up to 
21 days, if the reason for the delay is toxicity/adverse event.  All subsequent chemotherapy doses 
must be rescheduled according to the last chemotherapy dose administration date. 
SELECTED PRECAUTIONS: 
• Neutropenia: Fever or other evidence of infection must be assessed promptly and treated 
aggressively following the local clinical practice and/or the guidelines. 
• Renal toxicity:  
− Carboplatin should not be administered to patients whose creatinine clearance is 
< 45 mL/min.  
− Nephrotoxicity is common with cisplatin.  Encourage oral hydration.  Avoid 
nephrotoxic drugs such as aminoglycoside antibiotics. 
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− Pemetrexed should not be administered to patients whose creatinine clearance is 
< 45 mL/min.  
• Ototoxicity and sensory neural damage should be assessed before each cycle.  
• For toxicities not listed above, dose modifications are permitted per local standards.  
Guidance regarding dose modifications for certain toxicities is presented in detail in 
Appendix 11.  These serve as guidelines and do not replace investigator judgment and applicable 
local label recommendations if more stringent. 
5.4.4. 
Criteria for Discontinuing Chemotherapy Regimens  
Except where specified above, both chemotherapy drugs in the platinum-based doublet regimen 
should be discontinued for any of the following: 
• Any Grade 4 peripheral neuropathy 
• Persistent Grade 3 paresthesia 
• Grade 3 or 4 drug-related thrombocytopenia associated with clinically significant 
bleeding 
• Any drug-related liver function test abnormality value that meets any of the following 
criteria requires discontinuation: 
− AST or ALT > 5 to 10 x ULN for > 2 weeks  
− AST or ALT > 10 x ULN or 
− Total bilirubin > 5 x ULN or 
− Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any drug-related AE that recurs after 2 prior dose reductions (or 1 prior reduction for 
carboplatin) for the same drug-related AE requires discontinuation of the drug(s). 
• Any Grade 3 or 4 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) assessed to be causing the reaction.  The drug assessed as 
not related to the hypersensitivity reaction or infusion reaction may be continued. 
• Any Grade 4 AE that the investigator considers related to study drug and inappropriate to 
be managed by dose reduction(s) requires discontinuation of drug(s).  The drug not 
assessed to be related to the event may be continued. 
• If any toxicity does not resolve within 21 days, that component will be discontinued.  
For toxicities not listed above, the investigator would determine whether chemotherapy regimen 
should be discontinued per clinical judgment, patient’s well-being, and local standards. 
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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 
with chemotherapy, immunotherapy (eg, interleukin, interferon, or thymosin), or investigational 
therapy ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drugs.  
Patients should not have received any herbal medicine or Chinese patent medicines used to 
control cancer ≤ 14 days before the first dose of study drugs. 
6.2. Permitted Concomitant Medications/Procedures  
Unless noted otherwise, most concomitant medications and therapies deemed necessary and in 
keeping with local standards of medical care at the discretion of the investigator for supportive 
care (eg, antiemetics, antidiarrheals, hematopoietic growth factors, red blood cell/platelet 
transfusions) and in a patient’s interest are allowed.   
All concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter, herbal supplements, and intravenous medications and fluids.  All concomitant 
medication received within 28 days before the first dose of study treatment and 30 days after the 
last infusion or dose of study treatment should be recorded.  If changes (dose, stop, or start) in 
concomitant medication occur during the study, documentation of drug dosage, frequency, route, 
date, and reason for use will be recorded on the eCRF. 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient within 28 days 
before the first dose of study drug(s) and 30 days after the last dose of study drug(s) will be 
recorded. 
Bisphosphonates and RANKL inhibitors are allowed for bone metastases if initiated before 
enrollment and at a stable dose.  Bisphosphonates are permitted during the study for a 
non-malignant indication.  Use of potentially hepatotoxic drugs in patients with impaired hepatic 
function is allowed but should be carefully monitored. 
6.2.1. 
 Systemic Corticosteroids   
Systemic corticosteroids administered for the control of imAEs must be tapered gradually 
(Appendix 8) and must be administered at non-immunosuppressive doses (≤ 10 mg/day of 
prednisone or equivalent) before the next tislelizumab dose.  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 
enrollment and continue treatment during the study and for 6 months after study drug 
discontinuation. 
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6.2.3. 
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 demonstrates no new sites of bone metastases 
• The lesion being considered for palliative radiation is not a target lesion for RECIST v1.1 
• The case is discussed with the medical monitor and he/she agrees that the conditions 
required to receive palliative radiation are met 
During the maintenance treatment period, prophylactic cranial irradiation (PCI) is permitted for 
ES-SCLC patients per local standard of care.  Patients who achieve CR or PR after cycle 4 may 
be offered PCI at the investigator’s discretion.  Imaging of the brain must occur before PCI.  
Patients selected to receive PCI may receive up to 25 Gy in 10 fractions (or the biologic 
equivalent), as tolerated by the patient.  If given, PCI must begin within 6 weeks (preferably 
within 2 to 4 weeks) after the last dose of study medication in Cycle 4.  Study medication may 
continue during PCI; However, if it is necessary to suspend study treatment, dosing must be 
restarted no later than 2 weeks after completion of PCI.  Steroids can be administered, as 
required, during and after PCI. 
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 progression of disease. 
6.3. 
Prohibited Concomitant Medications/Procedures  
The following medications 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 
[regardless of cancer type]) ≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is 
shorter) before the first dose of study drugs and during the study. 
• Live vaccines within 28 days before the first dose of study drugs and 60 days following 
the last dose of study drugs. 
• Immunosuppressive agents (except to treat a drug-related AE). 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic treatment.  
For treating AEs that are not related to study treatment, consultation with the medical 
monitor or designee is required before the administration of systemic 
corticosteroids > 10 mg daily. 
• Alcohol abuse and other addictive drugs throughout the study. 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions (eg, hypericin) 
≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is shorter) before the first dose of 
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study drugs and during the study.  Patients must notify the investigator of all herbal 
remedies used during the study.   
• Radiation therapy, except for palliative radiation therapy described in Section 6.1. 
• The investigator must adhere to the contraindications and precautions found in the 
prescribing information for each chemotherapy agent. 
• Non-steroidal anti-inflammatory drugs (eg, aspirin, ibuprofen, diclofenac, celecoxib, 
naproxen, indomethacin, piroxicam, etc) are prohibited ≥ 5 days before and 2 days after 
pemetrexed therapy.  
If concomitant administration of a non-steroidal anti-inflammatory drug is necessary, 
patients should be monitored closely for toxicity, especially myelosuppression, renal, and 
gastrointestinal toxicity. 
6.4. 
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 unlikely have an effect on drug-metabolizing enzymes or transporters. 
Refer to drug-drug interaction section in manufacturer’s prescribing information for the 
influence of the respective chemotherapy agents on drug metabolizing enzymes or transporters.  
For example, the metabolism of paclitaxel is catalyzed by cytochrome P-450(CYP)2C8 and 
CYP3A4.  Caution should be exercised when administering paclitaxel or nab-paclitaxel 
concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 (eg, 
inhibitors ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, 
cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir, or inducers rifampicin, 
carbamazepine, phenytoin, efavirenz, and nevirapine).  When strong CYP2C8 and CYP3A4 
inhibitors are co-administered with nab-paclitaxel, the toxicities may be exacerbated, and the 
investigator should closely monitor for them.  Please refer to a list of strong CYP2C8 and 
CYP3A4 inhibitors (Flockhart 2007; FDA Drug Development and Drug Interactions 2023) and 
the prescribing information of paclitaxel and nab-paclitaxel for more information. 
Renal function decreases would result in an increase in systemic exposure of pemetrexed.   
Pemetrexed should not be administered to patients whose creatinine clearance is < 45 mL/min. 
Caution should be exercised when administering pemetrexed concurrently with non-steroidal 
anti-inflammatory drugs to patients whose creatinine clearance is < 80 mL/min. 
The major route of elimination of carboplatin is renal excretion.  The renal effects of nephrotoxic 
compounds may be potentiated by carboplatin. 
While pharmacokinetic data are not available to assess the effect of 5-FU administration on 
warfarin pharmacokinetics, the elevation of coagulation times that occurs with the 5-FU prodrug 
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capecitabine is accompanied by an increase in warfarin concentrations.  Thus, the interaction 
may be due to inhibition of cytochrome P450 2C9 by 5-FU or its metabolites. 
Formal drug-drug interaction studies with phenytoin have not been conducted, but the 
mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by 
capecitabine and/or its metabolites.  Other than warfarin, no formal drug-drug interaction studies 
between capecitabine and other CYP2C9 substrates have been conducted.  Care should be 
exercised when capecitabine is co-administered with CYP2C9 substrates. 
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7. 
STUDY PERIODS, VISITS, OR PROCEDURES  
7.1. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before the first dose of ociperlimab for 
Phase 1 and ≤ 28 days before the first dose of tislelizumab for Phase 1b.  A patient who agrees to 
participate in this study will sign the ICF before undergoing any screening assessment.  Refer to 
Section 8.1 for instructions regarding screening assessments. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  Results of standard-of-care tests or examinations 
performed before informed consent has been obtained and ≤ 28 days before the first dose of 
study drug(s) may be used for screening assessments rather than repeating such tests unless 
otherwise indicated.  ICFs for enrolled patients and for patients who are screened but not 
enrolled will be maintained at the study site.   
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. 
For RP2D confirmation in Chinese patients and Phase 1b, after obtaining informed consent, 
study site personnel will access the Interactive Response Technology (IRT) system to assign a 
unique number to a potential study patient. 
7.2. 
Enrollment  
All screening results and relevant medical history must be available before eligibility can be 
determined.  Prior to enrollment, the investigator is responsible for assessing and confirming that 
each patient meets all inclusion eligibility criteria for this study and that none of the exclusion 
criteria apply. All results from the screening procedures and relevant medical history must be 
available and reviewed by the investigator before eligibility can be determined.  No eligibility 
waivers will be granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation E6 guideline. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
For Cohort 10, the site personnel will access the IRT system to randomize the patient and assign 
study drugs by permuted block stratified randomization.   
7.3. 
Treatment Period  
Patients enrolled will be treated as described in Section 5.2. 
Patients may continue to receive study drugs beyond the initial investigator-assessed PD, as 
defined by RECIST v1.1 provided that the patient has investigator-assessed clinical benefit and 
is tolerating study drugs.  Refer to Section 7.5 and Section 8.5 for additional considerations 
regarding treatment continuation and withdrawal. 
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7.4. 
Follow-up Periods  
7.4.1. 
End-of-Treatment/+30-day Safety Follow-up Visit  
Patients who discontinue study treatment for any reason will be asked to return to the clinic for 
the EOT Visit, which is required to be conducted within 7 days when the EOT decision is made 
unless otherwise specified or before the initiation of a new anticancer treatment, whichever 
occurs first.  An on-site Safety Follow-up Visit at 30 days (± 7 days) after the last dose of study 
drugs (including both chemotherapy and immunotherapy, whichever is late) is required.  If the 
time window of this Safety Follow-up Visit and EOT Visit is overlapped, the tests conducted at 
the EOT Visit can be used for Safety Follow-up Visit and need not be repeated.  In addition, 
2 safety follow-up by telephone with patients should be conducted to assess imAEs and 
concomitant medications (if appropriate, such as being associated with an imAE or is a new 
anticancer therapy) at 60 days (± 14 days) and 90 days (± 14 days) after the last dose of study 
drugs regardless of whether patients started a new subsequent anticancer therapy.  If patients 
report a suspected imAE at a Safety Follow-up Visit, the investigator should arrange an 
unscheduled visit if further assessment is indicated.  
All AEs, including SAEs, will be collected as described in Section 9.6. 
See Appendix 1 for assessments to be performed at the EOT and the Safety Follow-up Visit. 
7.4.2. 
Efficacy Follow-up Period  
Patients who discontinue study drugs for reasons other than PD (eg, toxicity) will continue to 
undergo tumor assessments following the original tumor assessment schedule until the patient 
experiences PD, withdraws consent, dies, or starts subsequent anticancer therapy, or for any 
other reason listed in Section 7.5.2, whichever occurs first. 
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact the patients by telephone to determine their disease status. 
7.4.3. 
Survival Follow-up (Phase 1b)  
Patients will be followed for survival and to obtain information on subsequent anticancer therapy 
information after discontinuation of study treatment via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months (± 14 days) after the 30-day Safety Follow-up 
Visit or as directed by the sponsor until death, withdrawal of consent, loss to follow-up, or end of 
study. 
7.4.4. 
Lost to Follow-up  
If attempts to contact the patient by telephone are unsuccessful, additional attempts should be 
made to obtain protocol-required follow-up information via all possible alternative methods.  It 
may be possible to obtain the information from other contacts, such as referring physicians or 
relatives.  Each attempt, date, and method of contact should be documented in the patient’s 
source documents.  If a patient cannot be contacted despite all attempts, the patient will be 
considered lost to follow-up, and death information should be obtained through a public record 
search if local agencies permit. 
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7.5. 
Discontinuation From Study Treatment or From the Study  
7.5.1. 
Patient Discontinuation From Study Treatment  
Patients have the right to discontinue study treatment at any time for any reason.  In addition, the 
investigator has the right to discontinue a patient from study treatment at any time.  Patients who 
discontinue study treatment for reasons other than PD should be followed for assessments of 
preliminary anticancer activity (Section 8.5), safety (Section 8.2), and survival (Section 7.4.3), if 
possible. 
Benefits of continuation of study treatment beyond 2 years after start of treatment should be 
evaluated and discussed with medical monitor (Herbst et al 2020; Kottschade 2019).  
The primary reason for discontinuation from study treatment should be documented on the 
appropriate eCRF.  Patients will discontinue study treatment for reasons including, but not 
limited to, the following: 
• Progressive disease 
• Adverse events 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she were to continue the study treatment 
• Use of any concurrent 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 [regardless of cancer type]) 
• Patient noncompliance 
Patients who continue treatment after disease progression will discontinue study treatment after 
2nd disease progression and/or no response to the continuing treatment after the first PD based on 
the investigator’s assessment following consultation with the medical monitor or designee. 
7.5.2. 
Patient Discontinuation From the Study (End of Study for an Individual Patient)  
Patients will discontinue from the study for reasons that include, but are not limited to, the 
following: 
• Patient withdrawal of consent 
• Death 
• Lost to follow-up 
• Completion of all study assessments 
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7.6. 
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.  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 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 reflected by unacceptable toxicity, such as treatment-related death or 
unexpected treatment-related Grade 4 toxicity, which is observed with the concurrence of 
both the SMC and sponsor. 
• 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 must be seen for an EOT/Safety Follow-up 
Visit as described in Section  7.4.1.  
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patients’ interests.  The investigator will 
be responsible for informing IRBs/IECs of the early termination of the study. 
The sponsor has the right to close a cohort at any time.  The related investigators will be notified 
of the decision in advance.  In the cohort that is going to be closed, any patient who, in the 
opinion of the investigator, continues to benefit from tislelizumab/ociperlimab, will be offered 
the option to continue the study drug(s) in a company-sponsored clinical trial (if available in the 
patient’s country) or patient supply treatment program until the study drug is commercially 
available in the country of the patient’s residence.   
The sponsor has the right to close a site at any time.  The site will be notified of the decision in 
advance.  Reasons for closing a site may include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• GCP noncompliance 
• Study activity is completed (ie, all patients have completed, and all obligations have been 
fulfilled) 
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8. 
STUDY ASSESSMENTS  
A table of scheduled study assessments is provided in Appendix 1.  Patients will be closely 
monitored for safety and tolerability throughout the study.  All assessments must be performed 
and documented in the medical record for each patient. 
Where applicable, 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. 
8.1. 
Screening Assessments  
Screening evaluations will be performed ≤ 28 days before the first dose of study drugs (refer to 
Appendix 1 for details).  Patients who agree to participate 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 ≤ 28 days before the first dose of study drugs may be used for the purposes of 
screening rather than repeating the standard-of-care tests unless otherwise indicated. 
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 Safety Assessments (Section 8.2), Tumor and Response Evaluations (Section 8.5), 
PK and ADA Assessments (Section 8.3) and Biomarkers (Section 8.4) sections. 
Rescreening under limited conditions may be allowed after consultation with the sponsor 
(eg, when a patient’s laboratory result narrowly miss laboratory criterion and it is correctable and 
not due to rapidly deteriorating condition or PD).  Rescreening is allowed only once. 
8.1.1. 
Pulmonary Function Tests  
Patients who are suspected of having or known to have serious/severe respiratory conditions, or 
exhibit significant respiratory symptoms unrelated to the underlying cancer, or with a history of 
thoracic radiotherapy will undergo pulmonary function testing 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 on the study.  For test results indicative of significantly impaired 
pulmonary function, eg, resting pulse oximetry < 90% on room air and further desaturation upon 
exercise, forced expiratory volume in one second < 60% or carbon monoxide diffusing capacity 
(if performed) < 60% of age- and sex-adjusted predicted performance levels, the medical monitor 
needs to be consulted to confirm eligibility.  Patients with low pulmonary function will not be 
advised for enrollment. 
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8.2. 
Safety Assessments  
8.2.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic).  Vital signs will be measured while the patient is in a seated position 
after resting for 10 minutes.  When ociperlimab and tislelizumab are administered, vital signs are 
required to be measured at 3 timepoints (≤ 60 minutes before the infusion, during the infusion, 
and ≤ 30 minutes after end of infusion) during all visits. 
8.2.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of 1) head, eyes, ears, nose, and throat; 2) cardiovascular; 3) dermatological; 
4) musculoskeletal; 5) respiratory; 6) gastrointestinal; and 7) neurological systems.  Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
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 9.3 regarding AE definitions and reporting and 
follow-up requirements. 
8.2.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 3) will be assessed during the study. 
8.2.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of clinical chemistry, hematology, coagulation, and 
urinalysis will be conducted as outlined in Appendix 2 per the timepoints shown in Appendix 1. 
An investigator may obtain safety laboratory results from the local laboratory as clinically 
indicated (eg, on the day of a patient’s visit before results are available from the central 
laboratory for dose modifications or AE/SAE monitoring).  Results from the central laboratory 
will serve as the official study laboratory result, where available.  If required by local 
regulations, clinical laboratory evaluations performed by a local (instead of a central) laboratory 
are acceptable. For abnormal lab results which are Grade 3 or above AEs, a confirmatory test is 
necessary. Final assessment will base on the updated result. 
If clinical chemistry, hematology, and coagulation at screening are not performed ≤ 7 days 
before study drug administration on Day 1 of Cycle 1, these tests should be repeated and 
reviewed before study drug administration.  After Day 1 of Cycle 1, results are to be reviewed 
within 72 hours before study drug administration. 
For central laboratory assessments, details regarding sample collection and shipment will be 
provided in a separate laboratory manual. 
The following tests will also be conducted in this study at timepoints shown in Appendix 1. 
• Urine or serum pregnancy test (for women of childbearing potential, including women 
who have had a tubal ligation) must be performed and documented as negative ≤ 7 days 
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before the first dose of study drugs.  Furthermore, a negative pregnancy test (by urine or 
blood) must be completed and recorded before administration of study drugs at each 
cycle.  Pregnancy tests will also be performed at the EOT Visit and each Safety 
Follow-up Visit, until 120 days after last dose of ociperlimab and/or tislelizumab or 180 
days after the last dose of chemotherapy (whichever comes later).  A serum pregnancy 
test must be performed if the urine pregnancy test is positive or equivocal. 
• Thyroid function testing (ie, thyroid stimulating hormone, free triiodothyronine [T3], and 
free thyroxine [T4]).  Total T3 can be tested as an alternative to free T3 and total T4 can 
be tested as an alternative to free T4.  
• Hepatitis serology and viral load (refer to Section 8.2.7) 
8.2.4.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatine kinase and creatine kinase-muscle/brain 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 8 for guidelines for management of suspected 
immune-mediated myocarditis, respectively).  Serum troponins may be substituted per local 
guidelines if used consistently throughout the study. 
8.2.5. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings.  
Paper or electronic copies of ECG tracings will be kept as part of the patient’s 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, etc).  The patient should rest in semi-recumbent supine position for 
≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate 
(eg, television, radio, conversation, etc) before each ECG collection. 
At each timepoint (Appendix 1), 3 consecutive 12-lead ECGs will be performed approximately 
2 minutes apart to determine the mean QTcF interval. 
8.2.6. 
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 9.6. 
8.2.7. 
Hepatitis B and C Testing  
Testing will be performed by a central laboratory and/or the local laboratory 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 ribonucleic acid).  For patients with negative HBsAg or negative HCV 
antibody, HBV DNA or HCV RNA is optional based on clinical practice. 
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Testing at screening is mandatory for patients with HCC in Phase 1.  In addition, HCC patients 
who have detectable HBV DNA or HCV ribonucleic acid at screening will perform the 
respective viral load test every 4 cycles.  In patients without HCC, samples for hepatitis serology 
and viral load will be collected at screening and may be tested if patients have hepatic AEs 
(≥ Grade 3) during the study and as clinically indicated. 
8.3. 
Pharmacokinetic Assessment and Antidrug Antibody Testing  
Ociperlimab and tislelizumab may elicit an immune response.  Patients with signs of any 
potential immune response will be closely monitored.  Validated screening and confirmatory 
assays will be employed to detect ADAs at multiple timepoints throughout the study.  In 
addition, blood samples will be collected for characterization of ociperlimab and tislelizumab 
PK.  Serum samples will be assayed for ociperlimab and tislelizumab concentrations using 
validated immunoassays. 
Blood sampling for PK and ADA sample collection for ociperlimab and tislelizumab will be 
collected at the timepoints specified in the Schedule of Assessments (Appendix 1).   
PK and ADA assays of ociperlimab and tislelizumab with or without chemotherapy (depending 
on the allocated cohort) will be managed through a central laboratory.  Refer to the laboratory 
manual for instructions regarding sample collection, handling, labeling, storage, and shipping of 
laboratory samples. 
Timepoints of PK and ADA sample collection for ociperlimab and tislelizumab are provided in 
Schedule of Assessments for Phase 1 and Phase 1b (Appendix 1C, Appendix 1D, and 
Appendix 1E).  
8.4. 
Biomarkers  
Shipping, storage, and handling of blood as well as archival tumor and/or fresh tumor tissues for 
the assessment of biomarkers will be handled by a central laboratory.  Refer to the laboratory 
manual for details of sample handling and the Schedule of Assessments (Appendix 1) for 
timepoints. 
Archival or fresh tumor samples will be collected for biomarker analysis.  Tissue based 
biomarkers include but not limited to protein expression of PD-L1, TIGIT, CD226, CD155 and 
CD112, tumor mutation burden (TMB), MSI and gene mutations, EBV status, immune cell 
subpopulations, and GEP before, during, and/or after treatment. (Note: For sites in mainland 
China, tissues will be obtained to test the expression of PD-L1, TIGIT, CD226, CD155, CD112, 
TMB, MSI, gene mutations, EBV status, immune cell subpopulations, and GEP before, during, 
and/or after treatment). 
• 
In Phase 1, if available, archived, FFPE tumor tissue sample (block or approximately 15 
freshly cut unstained FFPE slides).  If archival tissue is unavailable, optional fresh baseline 
tumor biopsy is strongly recommended. 
• 
In Phase 1b, patients are required to permit the collection of tumor tissue samples or to allow 
a biopsy to be performed (archival tumor tissues [FFPE blocks or approximately 15 freshly 
cut unstained slides] or fresh biopsy, ≥ 8 slides are mandatory) for biomarker analysis.  If 
archival tumor tissues are not available, fresh biopsy samples are required.  PD-L1 and 
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TIGIT expression will be required testing for secondary endpoint analysis.  For Cohorts 3 
and 10 (NSCLC with PD-L1 positive [TC ≥ 1%]) and Cohort 8 (HNSCC with PD-L1 
positive [vCPS ≥ 1%]), PD-L1 expression will be prospectively tested using the 
investigational VENTANA PD-L1 (SP263) Assay at a central laboratory.  For Cohort 5 
(CPI-experienced NSCLC), fresh tumor biopsy samples or archival tissue samples obtained 
after prior checkpoint inhibitor treatment are highly recommended.  All patients with 
non-squamous NSCLC and G/GEJ adenocarcinoma must have been tested locally for 
EGFR/ALK/ROS1 and HER2, respectively.  In case a local laboratory test is not available, 
central laboratory tests can be used and additional slides for these tests should be sent as 
required. 
For Phase 1/1b, optional samples from biopsies performed at first response (PR/CR), Cycle 3 
Day 1 or Cycle 2 Day 1, and at EOT Visit after confirmed disease progression are recommended 
for evaluation of pharmacodynamic effects and resistance mechanism.  If feasible, post-treatment 
biopsy should be taken from the same tumor lesion as the baseline biopsy/archival tissue.   
A written informed consent is required for obtaining the optional fresh tumor biopsy samples.  
Tumor tissue should be of good quality in terms of total and viable tumor content.  Fine needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. 
Blood samples will be collected at specified times as described in the Schedule of Assessments 
(Appendix 1) to be used for blood-based biomarker evaluation.  Candidate biomarkers will 
include but not limited to ociperlimab TIGIT and tislelizumab PD-1 receptor occupancy on 
peripheral blood cells as target engagement biomarker, peripheral immune cell quantity and 
phenotype change, GEP, baseline concentration, and dynamic change of cytokine and soluble 
proteins before, during, and after drug treatment as blood-based pharmacodynamic biomarker to 
monitor drug effects on patients.  Blood-based circulating tumor DNA (ctDNA) status, TMB, 
gene mutation, MSI status, and Fc gamma receptor polymorphism will be tested as potential 
predicative biomarkers (Note: For sites in mainland China, blood-based biomarkers, including 
receptor occupancy, peripheral immune phenotype, GEP, cytokine/soluble proteins, ctDNA, 
TMB, MSI, Fc gamma receptor polymorphism, and gene mutation profiles, will be explored in 
blood samples collected before, during and after treatment).  
8.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed ≤ 28 days before the first dose of study drugs.  Results of 
standard-of-care tests or examinations performed before informed consent has been obtained and 
≤ 28 days before the first dose of study drugs 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 54 weeks, then 
every 12 weeks (± 7 days) thereafter (eg, Week 6, Week 12, …, Week 48, Week 54, Week 66, 
Week 78, Week 90, etc.), based on RECIST v1.1.  If a tumor assessment is missed or conducted 
outside of the specified assessment window, all subsequent scans should be conducted according 
to the planned schedule. 
Tumor response will be assessed before the next administration of investigational product (eg, 
the first tumor assessment is performed before Cycle 3 Day 1 and no disease progression should 
be confirmed).   
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Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral/intravenous contrast, unless contraindicated) or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis.  An MRI (or CT scan if MRI is 
contraindicated or not readily available) of the head is required at screening; 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). 
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).   
• Imaging of the brain (preferably MRI or CT) at baseline is required for all screened 
patients.  Screening evaluations will be performed ≤ 28 days before the first dose of study 
drug(s). 
• 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 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 neck or extremities should be performed at screening, only if clinically 
indicated, and followed throughout the study, if there is evidence of metastatic disease in 
these regions at screening.   
• At the investigator’s discretion, other methods of assessment of target lesions and 
non-target lesions per RECIST v1.1 may be used. 
Response will be assessed by the Investigator using RECIST v1.1 (see Appendix 9).  The same 
evaluator should perform all 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. 
For immune therapies such as ociperlimab and tislelizumab, pseudoprogression may occur due to 
immune-cell infiltration and other mechanisms leading to apparent increase of existing tumor 
masses or appearance of new tumor lesions.  Thus, if radiographic PD is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment with ociperlimab and 
tislelizumab until PD is confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 6 to 
8 weeks from the date of initial documentation of PD).  If at the investigator’s discretion a 
patient could continue to benefit from ociperlimab and tislelizumab after PD per RECIST v1.1 
criteria, the patient may continue ociperlimab and tislelizumab.  The following criteria must be 
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met in order to treat patients with suspected pseudoprogression or who may continue to benefit 
from study treatment beyond radiologic PD:  
• Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
• Stable ECOG Performance Status ≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment after PD confirmation 
and inform patients that this practice is not considered standard in the treatment of 
cancer. 
The decision to continue study drugs beyond initial investigator-assessed progression must be 
agreed to with the medical monitor and documented in the study records.  
For patients who continue treatment after disease progression, baseline of tumor assessment will 
be the results of disease progression instead of the baseline at screening.  If the tumor assessment 
shows disease progression again, treatment will discontinue. 
Tumor assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression.  Tumor assessment in such patients should continue until 
study treatment discontinuation.  A patient who discontinues study drugs early for reasons other 
than PD (eg, toxicity) will continue to undergo tumor assessments following the original plan 
until the patient begins a subsequent anticancer therapy, experiences PD, withdraws consent, is 
lost to follow-up, dies, or until the study terminates, whichever occurs first. 
Tumor assessments must be performed on schedule regardless of whether study treatment has 
been administered or withheld.  That is, they should not be adjusted for delays in cycles. 
8.6. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted 
(Appendix 1).  All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified.  Assessments scheduled on the day of study treatment 
administration of each cycle should be performed before any study treatment is given unless 
otherwise noted.  Laboratory results must be reviewed before dosing. 
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. 
8.7. 
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 Performance Status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
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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 assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 
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9. 
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. 
9.1. 
Risks Associated With Study Drugs  
9.1.1. 
Risks Associated With Ociperlimab and Tislelizumab  
Ociperlimab and tislelizumab are investigational agents that are currently in clinical 
development.  The first-in-human Study AdvanTIG-105 evaluating safety, tolerability, and 
clinical benefit of ociperlimab in combination with tislelizumab in solid tumors is still ongoing.  
The following recommendation is based on results from nonclinical and clinical studies with 
ociperlimab and tislelizumab 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 9.7.3.  
Ociperlimab-mediated TIGIT inhibition may increase the risk of immune mediated AEs.  
However, no apparent immunotoxicity, or toxicity in general, have 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 affect 
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 8. 
9.1.2. 
Risks Associated With Chemotherapeutic Agents  
Please refer to the Table 9 for the reported toxicity for the respective chemotherapeutic agents.  
The investigator should refer to the package insert for a complete list of potential side effects. 
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Table 9: 
Summary of the Common and Specific Reported Toxicities of the 
Chemotherapeutic Agents 
Agents 
Common toxicity 
Specific toxicity 
Cisplatin 
Myelosuppression with leukopenia, 
thrombocytopenia and anemia; 
infectious complications; 
nausea/vomiting and other 
gastrointestinal tract toxicity; hepatic 
impairment; fatigue; anorexia; 
constipation 
Nephrotoxicity; ototoxicity; 
peripheral neuropathies 
Carboplatin 
Ototoxicity and peripheral 
neuropathies 
Pemetrexed 
Nephrotoxicity; skin rash;  
Paclitaxel 
Hypersensitivity reaction; 
neuropathies; myalgia; 
arthralgia; cardiovascular;  
Nab-paclitaxel 
Peripheral neuropathy 
Etoposide 
Hypersensitivity reactions; 
ocular; respiratory; skin; 
neurologic 
5-FU 
Neutropenia; neurotoxicity 
Oxaliplatin 
Hypersensitivity reactions; 
neuropathy; pulmonary fibrosis; 
Hepatotoxicity 
Capecitabine 
Cardiotoxicity; renal failure; 
phototoxicity 
9.2. 
General Plan to Manage Safety Concerns  
9.2.1. 
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 at risk for study-emergent active autoimmune diseases or with 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 the first 
dose of study drugs are excluded from the study.  Patients with contraindications for platinum 
containing doublet chemotherapy are also excluded from the study (Section 4.2) for the full list 
of exclusion criteria). 
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9.2.2. 
Abnormal Liver Function Tests  
The finding of an elevated ALT or AST (> 3 x baseline value) in combination with either an 
elevated total bilirubin (> 2 x ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  Therefore, 
investigators must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST > 3 x baseline value in combination with total 
bilirubin > 2 x ULN (of which 35% is direct bilirubin) 
• Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF and reported to the sponsor immediately (ie, no more 
than 24 hours after learning of the event) via SAE reporting process as described in 
Section 9.6.2.1. 
9.2.3. 
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. 
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 (Table 10), 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 and tislelizumab in 
patients for both the dose-escalation and dose-expansion phases of the study.  Investigators are 
instructed to report all AEs (includes 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 9.7. 
9.3. 
Adverse Events  
9.3.1. 
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 has an association with a significantly worse 
outcome 
• New conditions detected or diagnosed after study drugs administration even though the 
condition might have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 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) relative to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all patient identifiers will be blinded on the 
copies of the medical records before submission to the sponsor. 
9.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study.  AEs and 
SAEs should be assessed and graded based upon NCI-CTCAE v5.0. 
Toxicities that are not specified in NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• 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 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]); whereas seriousness is classified by the criteria based on the 
regulatory definitions.  Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 9.6.2. 
9.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drugs and the 
occurrence of each AE or SAE using best clinical judgement.  Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, and other risk factors, and the temporal 
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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 chemotherapy prescribing information 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 1 of the criteria used when determining 
regulatory reporting requirements.  The investigator may change his/her opinion of causality 
considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study 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 treatment/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”: 
• 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). 
9.3.4. 
Following Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent.  The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
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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 9.6.2. 
9.3.5. 
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 5 × 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 adverse event.  For example, an elevated 
serum potassium level of 7.0 mEq/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. 
9.4. 
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 was more severe. 
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• 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 
one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
9.5. 
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 Ociperlimab Investigator’s Brochure, Tislelizumab 
Investigator’s Brochure, and chemotherapy prescribing information. 
9.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
9.6.1. 
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.  Immune-mediated AEs (serious or nonserious) 
should be reported until 90 days after the last dose of study drugs, regardless of whether or not 
the patient starts a subsequent anticancer therapy.  All SAEs considered related to the study 
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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 according to the details in Table 10.  For the follow-up period 
for AEs, see Section 9.3.4.  For the definition of TEAEs, see Section 10.3.2. 
Table 10:  
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Cohorts 
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 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 9.6.4 ) 
All nonserious AEs, 
except those due to PD 
First dose of study drug 
Up to 30 days after last dose, initiation of new 
anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Immune-related 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. 
9.6.2. 
Reporting Serious Adverse Events  
9.6.2.1. 
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 11. 
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Table 11: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Time frame for 
making initial 
report 
Documentation 
method 
Time frame for 
making follow-
up report 
Documentation 
method 
Reporting 
method 
All SAEs 
Within 24 hours 
after first 
knowledge of 
the AE 
SAE report 
As expeditiously 
as possible 
SAE report or 
pregnancy form 
Email or fax 
SAE form or 
pregnancy form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
9.6.2.2. 
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 9.6.2.1.  The SAE report 
will 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 9.3.3. 
The sponsor will provide contact information for SAE receipt. 
9.6.2.3. 
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 9.6.2.1.  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 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 9.5) 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. 
9.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
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• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
9.6.4. 
Progressive Disease  
PD, which is expected in this study population and measured as an efficacy endpoint, should not 
be reported as an AE term.  Instead, the symptoms, signs, or clinical sequelae that result from PD 
should be reported as the AE term(s). 
For instance, a patient presents with pleural effusion resulting from PD of metastasis to lungs.  
The event term should be reported as “pleural effusion” instead of PD.  If a patient experienced 
fatal multiorgan failure because of PD, the term “multiorgan failure” should be reported as the 
SAE, with death as outcome, instead of reporting “fatal PD” or “death because of PD.”  All 
SAEs and deaths, regardless of relatedness to PD, should be recorded and reported. 
9.6.5. 
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”). 
9.6.6. 
Recording Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while the patient is 
receiving study drugs, or within 120 days after the last dose of ociperlimab and/or tislelizumab, 
or within 180 days after the last dose of chemotherapy, 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 following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should 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. 
9.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information documents: 
•Ociperlimab Investigator’s Brochure 
•Tislelizumab Investigator’s Brochure 
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•Paclitaxel prescribing information 
•Nab-paclitaxel prescribing information 
•Pemetrexed prescribing information 
•Etoposide prescribing information 
•Cisplatin prescribing information 
•Carboplatin prescribing information 
•5-fluorouracil prescribing information 
•Oxaliplatin prescribing information 
•Capecitabine prescribing information 
9.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 or immune checkpoint inhibitors can cause autoimmune 
disorders, AEs considered by the investigator to be immune-mediated (see Section 9.7.3) should 
be classified as imAEs and identified as such on the eCRF AE page until Day 90 after treatment 
discontinuation.  Not all ociperlimab and tislelizumab studies include a section in the eCRF AE 
page where imAEs are clearly identified. Therefore, all studies will rely on the company list of 
Potential imAEs to identify all cases in each study to be further assessed as imAEs by the 
sponsor, in addition to those imAEs reported by the investigator via the AE CRF page. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 8. 
An extensive list of potential imAEs appears in Section 9.7.3, Table 13.  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 8. 
9.6.9. 
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.  Individual signs 
and symptoms 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. 
9.7. 
Management of Adverse Events of Special Interest  
As a routine precaution, following completion of study drugs administration, patients must be 
monitored for a period afterward in a setting where emergency medical equipment and staff who 
are trained to respond to medical emergencies are available. 
The management for infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined in the following subsections. 
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9.7.1. 
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. 
Treatment modification for symptoms of infusion-related reactions due to study drugs is 
provided in Table 12. 
Table 12: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs 
NCI-CTCAE grade 
Treatment modification for ociperlimab and 
tislelizumab  
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Any worsening is 
closely monitored.  Medical management as needed.   
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 2 - moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs, narcotics, 
intravenous fluids); prophylactic medications indicated 
for ≤ 24 hours. 
Stop infusion.  Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity.  Any 
worsening is closely monitored.  Proper medical 
management should be instituted as described in the 
text following this table.   
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described in the 
text following this table. 
The patient should be withdrawn from study drug 
treatment. 
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 following this table. 
The patient should be withdrawn from study drug 
treatment. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Once the ociperlimab or tislelizumab infusion rate has been decreased by 50% or suspended due 
to an infusion-related reaction, it must remain decreased for all subsequent infusions and 
premedication must be administered.  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 ociperlimab or tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction.  This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
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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. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction.  This includes but is not limited 
to oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
9.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) 
(Soar et al 2008).  Patients should be instructed to report any delayed reactions to the investigator 
immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction, the infusion must be stopped 
immediately, and the patient discontinued from the study.  Systemic anaphylactic/anaphylactoid 
reactions typically manifest within minutes following administration of the drug/antigen and 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. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed, and then the patient should be placed on monitor 
immediately and 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 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion.  
Alternative treatments for fever (ie, paracetamol) may be administered to the patient at the 
discretion of the investigator. 
9.7.3. 
Immune-Mediated Adverse Events  
The imAEs 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 13.  All conditions similar to those listed 
should be evaluated in patients receiving ociperlimab or tislelizumab to determine whether they 
are immune-mediated. 
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Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology and American Society of Clinical Oncology guidelines 
(Haanen et al 2017; Brahmer et al 2018) and common immune-mediated toxicities are detailed in 
Appendix 8.  For any AEs not included in Appendix 8, refer to the American Society of Clinical 
Oncology Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic 
evaluation and management of immune-mediated toxicities. 
Table 13: 
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; meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 8. 
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. 
9.7.4. 
Management of Immune-Mediated AEs in Patients With Pre-Existing Renal 
Dysfunction  
Patients with mild renal dysfunction (estimated GFR ≥ 60 mL/min/1.73 m2 by CKD-EPI 
equation) may be enrolled into the study.  Therefore, the following algorithm is proposed for the 
use of steroid treatment in the management of imAEs: 
• If the serum creatinine (ie, estimated GFR) is normal at baseline, please see Section 9.7.3 
and refer to Appendix 8 for diagnosis and management of patients with imAE related 
abnormal renal laboratory values. 
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• If the serum creatinine is Grade 1 at baseline and the increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with study drugs, 
refer to Appendix 8 for diagnosis and management of patients with abnormal renal 
laboratory values.  Check the estimated GFR using Appendix 7 and the estimated GFR 
calculator link.  In the setting of a Grade 2 serum creatinine increase only, study 
treatment can continue unless the serum creatinine increases by ≥ 50% from the baseline 
value OR the estimated GFR falls below 20 mL/min/1.73 m2. 
• If the serum creatinine is Grade 2 at baseline and the increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with study drugs, 
refer to Appendix 8 for diagnosis and management of patients with abnormal renal 
laboratory values.  In the setting of a Grade 3 serum creatinine increase only, study 
treatment will be held until serum creatinine improves to baseline and treatment may 
resume only after discussion with the medical monitor. 
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10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION  
This study is designed to establish the safety and tolerability of ociperlimab and tislelizumab to 
assess preliminary anticancer activities in dose-expansion cohorts. 
In general, data from dose escalation will be summarized by dose level except that data from 
dose verification in Chinese patients will be summarized separately; while data from dose 
expansion will be summarized by tumor type for Cohorts 1 to 9, unless otherwise specified.  For 
Cohort 10, data will be summarized by treatment arm and total.  Details of the statistical analyses 
will be included in a separate statistical analysis plan. 
10.1. 
Statistical Analysis  
Efficacy and safety analyses will be performed by Phase 1 and Phases 1b.  In Phase 1, data will 
be summarized by dose level but data from dose verification in Chinese patients will be 
summarized separately.  In Phase 1b, data will be summarized by tumor type for Cohorts 1 to 9.  
For Cohort 10, data will be summarized by treatment arm and total. 
Descriptive statistics will be mainly used in describing the safety, tolerability, and the anticancer 
activities of the ociperlimab as monotherapy and in combination with tislelizumab.  Confidence 
intervals will be constructed to describe the precision of the point estimates of interest. 
10.1.1. 
Analysis Sets  
The Safety Analysis Set includes all patients who received ≥ 1 dose of study drugs.  This will be 
the analysis set for the safety analyses. 
The Efficacy Evaluable Analysis Set includes all patients who received ≥ 1 dose of study drugs, 
have evaluable disease at baseline, and ≥ 1 evaluable postbaseline tumor response assessment 
unless any clinical PD or death occurred before the first postbaseline tumor assessment. 
The DLT Evaluable Analysis Set includes patients who received at least 80% each of the 
assigned doses ociperlimab and tislelizumab according to the treatment schedule, remained on 
study during the DLT observation period, and had sufficient safety evaluation or patients who 
experienced a DLT within the DLT observation period. 
The PK Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have 
≥ 1 derivable PK parameter. 
The ADA Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have 
both baseline ADA and ≥ 1 postbaseline ADA results. 
10.1.2. 
Patient Disposition  
The number of patients treated, discontinued from study drugs and/or the study will be counted.  
The primary reason for study drugs and/or study discontinuation will be summarized according 
to the categories in the eCRF. 
Major protocol deviations will be listed. 
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10.1.3. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized using the Safety Analysis 
Set and descriptive statistics.  Continuous variables include year of birth (or age), weight, and 
time since initial cancer diagnosis.  Categorical variables include gender, ECOG Performance 
Status, race, number of prior systemic therapies received.  Other disease-specific parameters 
might be summarized in the relevant cohort for dose expansion. 
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
ethnicity data are collected in accordance with International Council for Harmonisation guidance 
(ICH E5 1998, ICH E17 2017) adopted by the EMA and US FDA, to understand whether 
race/ethnicity could influence the PK, safety, and/or efficacy of the study drug. For example, 
population PK analysis is a well-established, quantitative method that can quantify and explain 
the variability in drug concentrations among patients.  Such variability can be attributed to 
intrinsic factors (eg, body weight, age, gender, race/ethnicity), or to extrinsic factors (eg, 
concomitant medications), and can lead to clinically relevant changes in drug concentrations that 
require a change in the dose or dosing regimen. Results from race/ethnicity and other 
demographic analyses will be incorporated into drug product labeling to provide guidance on 
safety and efficacy variations (if any) linked to certain populations (eg, race or ethnic group) as 
well as any potential dose adjustment needed for those populations. Therefore, collecting 
race/ethnicity data in the study is essential to understand whether race/ethnicity could influence 
the PK, safety, and/or efficacy. 
10.1.4. 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of first dose of 
study drugs.  Concomitant medications will be defined as medications that 1) were started before 
the first dose of study drugs and were continuing at the time of the first dose of study drugs, or 
2) were started on or after the date of the first dose of study drugs up to 30 days after the 
patient’s last dose (as of the Safety Follow-up Visit).  Concomitant medications will be coded 
using the World Health Organization Drug Dictionary drug codes.  Concomitant medications 
will be further coded to the appropriate Anatomical Therapeutic Chemical code indicating 
therapeutic classification.  Prior and concomitant medications will be summarized and listed by 
drug and drug class.  A listing of prior and concomitant medications will be provided. 
10.2. 
Efficacy Analyses  
Primary and/or secondary efficacy endpoints will be based upon investigators’ tumor 
assessments per RECIST v1.1 and will be summarized as follows to evaluate the preliminary 
anticancer activities of ociperlimab as monotherapy and in combination with tislelizumab: 
• ORR is defined as the proportion of patients who had CR or PR.  
• DOR is defined as the time from the first determination of an overall response per 
RECIST v1.1 until the first documentation of progression or death, whichever comes 
first. 
• DCR is defined as the proportion of patients with BOR, as defined in Appendix 9, of a 
CR, PR, or SD.  This will be summarized similarly as ORR. 
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• PFS is defined as the time from the date of the first dose of study drugs to the date of the 
first documentation of PD assessed by the investigator using RECIST v1.1 or death, 
whichever occurs first. 
• OS is defined as time from the first dose of study drugs to the date of death due to any 
cause. 
10.2.1. 
Secondary Efficacy Analysis in Phase 1  
The primary objective in dose escalation is to assess patients’ safety and PK profile.  As a 
secondary analysis, efficacy endpoints such as ORR and DCR will be summarized by dose, 
along with their 95% confidence interval based on the Efficacy Evaluable Analysis Set; dose 
verification in Chinese patients will not be included.  For dose verification part, efficacy 
endpoints will be summarized by cohort. 
10.2.2. 
Primary Efficacy Analysis in Phase 1b  
ORR assessed by the investigator and its 95% confidence interval will be summarized for the 
dose-expansion cohorts based on the Efficacy Evaluable Analysis Set.  ORR will be summarized 
by tumor type in dose-expansion cohorts. 
10.2.3. 
Secondary Efficacy Analysis in Phase 1b  
PFS, DOR, and DCR will be summarized for the dose expansion cohorts. 
PFS and DOR will be estimated using the Kaplan-Meier method.  The median PFS and the 
cumulative probability of PFS at every 3 months will be calculated and presented with 2-sided 
95% CIs.  PFS censoring rule will follow United States Food and Drug Administration Guidance 
for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(US FDA 2018). 
DOR will be analyzed similarly as PFS.  DCR will be analyzed similarly to ORR based on the 
Efficacy Evaluable Analysis Set.  Waterfall plots of maximum tumor shrinkage per patient will 
be presented. 
Association between clinical efficacy and predictive biomarkers (such as PD-L1 and TIGIT 
expression) will be investigated.  Clinically meaningful cutoffs will be used to dichotomize the 
biomarker evaluable patients to subgroups.  Summary statistics of ORR and PFS for PD-L1 and 
TIGIT expression subgroups will be presented. 
10.2.4. 
Exploratory Efficacy Analysis  
OS will be analyzed similarly as describe for PFS (Section 10.2.3) in treated patients.  
The correlation of response and exploratory tumor-based and/or blood-based biomarkers may be 
evaluated. 
10.3. 
Safety Analyses  
Safety will be determined by the spontaneous reporting of AEs and by laboratory values 
(hematology, clinical chemistry, coagulation, and urinalysis).  Vital signs, physical examinations, 
and ECG findings will also be used in determining the safety profile.  The severity of AEs will 
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be graded according to NCI-CTCAE v5.0.  The incidence of DLT events and TEAEs will be 
reported as the number (percentage) of patients with TEAEs by MedDRA system organ class and 
preferred term.  Descriptive summary statistics (eg, n, mean, standard deviation, median, 
minimum, and maximum for continuous variables; n [%] for categorical variables) and changes 
from baseline, will be determined for laboratory parameters and vital signs. 
Safety data will be summarized using the Safety Analysis Set and by study stage with dose 
verification in China as a separate stage. 
10.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose interruption, dose delay, and drug 
discontinuation because of AEs will be summarized for each study drug.  Reasons for dose 
modifications will be summarized as well. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
10.3.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA.  AEs will be coded to MedDRA (Version 20.0 or higher) lower level term, preferred 
term, and primary system organ class.  
TEAE is defined as an AE that has an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 30 days following the last dose of 
study drugs or initiation of new anticancer therapy, whichever occurs first.  Only those AEs that 
were treatment emergent will be included in summary tables of TEAE.  Immune-mediated AEs 
will be identified from all AEs that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 90 days from the last dose of 
study drug, regardless of whether the patient starts a new anticancer therapy.  If an imAE occurs 
outside of the above mentioned TEAE window, it will not be classified as a TEAE.  All imAEs 
will be reported separately.  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 
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 drugs. 
TEAEs include those events considered by the investigator to be related to study treatment or 
with missing assessment of the causal relationship.  SAEs, deaths, ≥ Grade 3 TEAEs, imAE, 
treatment-related TEAEs, and TEAEs that led to treatment discontinuation or dose modification 
will be summarized. 
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10.3.3. 
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 clinical study report 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 visit with the 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. 
10.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
temperature, and weight) and changes from baseline will be presented by visit for all visits.  Vital 
signs will be listed by patient and visit. 
10.3.5. 
Ophthalmologic Examination  
Ophthalmologic examination results will be listed for patients who receive the assessments in 
dose escalation. 
10.4. 
Pharmacokinetic Analyses  
Non-compartmental analysis will be carried out for ociperlimab and tislelizumab serum 
concentrations.  The PK analyses will include patients with sufficient data to enable estimation 
of key parameters, and the parameters such as, Cmax, Cmin, Tmax, AUC0-21d, CL, and Vss (as 
appropriate for data collected) may be derived and summarized with descriptive statistics (mean, 
standard deviation, and coefficient of variation). 
Individual and mean serum ociperlimab and tislelizumab concentration versus time data will be 
tabulated and plotted by dose level except that data from dose verification in Chinese patients 
will be tabulated and plotted separately.   
Additional PK analyses, including population PK analyses and exposure-response (efficacy or 
safety endpoints) analyses may be conducted as appropriate and the results of such analyses may 
be reported separately from the Clinical Study Report. 
10.5. 
Immunogenicity Analyses  
Samples to assess anti-ociperlimab 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 
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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 allow. 
10.6. 
Other Exploratory Analyses  
Summary statistics will be provided for pharmacodynamic biomarkers including but not limited 
to immune cell subtypes in the blood and/or tumor tissue.  An exploratory analysis on a potential 
correlation of these pharmacodynamic biomarkers with the dose, safety, and preliminary 
anticancer activity will be performed as appropriate. 
Exploratory predictive biomarker analyses will be performed in an effort to understand the 
association of these markers with study drugs response, such as efficacy. 
10.7. 
Sample Size Consideration  
The study plans to enroll approximately 294 to 564 evaluable patients: 
• Phase 1: Approximately 44 to 64 patients 
• Phase 1b: Approximately 250 to 500 evaluable patients in 10 prespecified cohorts (20 to 
40 evaluable patients each for Cohorts 1 to 8, 30 to 60 evaluable patients for Cohort 9, 
and 20 to 40 evaluable patients for each of the 3 arms in Cohort 10) 
For dose escalation in Phase 1, 32 patients should be sufficient to evaluate the safety and 
tolerability of increasing dose levels of ociperlimab in combination with tislelizumab per the 
modified 3+3 design rules with extra patients on R2PD for further evaluation.  An extra 12 to 
32 Chinese patients will receive ociperlimab as monotherapy and in combination with 
tislelizumab as dose verification.  Overall, 44 to 64 patients will be enrolled in Phase 1.  
For dose expansion in Phase 1b, 10 prespecified cohorts are planned, with approximate 20 to 
40 evaluable patients for Cohorts 1 to 8, 30 to 60 evaluable patients for Cohort 9.  For Cohort 10, 
approximately 60 to 120 evaluable patients (20 to 40 patients for each of the 3 arms) will be 
enrolled.  A two-stage design based on Bayesian predictive probability (Lee and Liu 2008) will 
be implemented for Cohorts 1 to 10.  The predictive probability of achieving a potential target 
ORR will be calculated in the interim analysis for Cohorts 1 to 8 after approximately 
20 evaluable patients have completed ≥ 1 postbaseline tumor assessment, for Cohort 9 after 
approximately 30 evaluable patients have completed at least 1 postbaseline tumor assessment, 
and for each arm in Cohort 10 after approximately 20 evaluable patients have completed 
≥ 1 postbaseline tumor assessment.  The interim analysis will be carried out timely when data 
become available, while the enrollment beyond 20 evaluable patients for Cohorts 1 to 8, 
30 evaluable patients for Cohort 9 and 20 evaluable patients for each arm in Cohort 10 may be 
allowed before the tumor assessment is performed.  The potential target ORR can be chosen 
based on historical rate.  The target ORR may be further updated with the study conduct when 
relative emerging information becomes available.  If the predictive probability is less than 0.2 for 
the first 20 evaluable patients in Cohorts 1 to 8, for the first 30 evaluable patients for Cohort 9, 
for the first 20 evaluable patients in each arm of Cohort 10, enrollment will stop; if the predictive 
probability is larger than 0.8, enrollment may stop with high confidence of achieving a potential 
target ORR; if the predictive probability is between 0.2 and 0.8, extra 20 evaluable patients for 
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Cohorts 1 to 8, extra 30 evaluable patients for Cohort 9, and extra 20 evaluable patients for each 
arm of Cohort 10 may be enrolled to evaluate the anticancer activities. 
10.8. 
Interim Analyses  
For Cohorts 1 to 8 in Phase 1b, after approximately 20 evaluable patients have completed at least 
1 postbaseline tumor assessment, the built-in interim analysis of calculating Bayesian predictive 
probability will be performed.  For Cohort 9, the built-in interim analysis of calculating Bayesian 
predictive probability will be performed after approximately 30 evaluable patients have 
completed at least 1 postbaseline tumor assessment.  For each arm of Cohort 10, the built-in 
interim analysis of calculating Bayesian predictive probability will be performed after 
approximately 20 evaluable patients have completed ≥ 1 postbaseline tumor assessment. 
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11. 
STUDY COMMITTEES  
11.1. 
Safety Monitoring Committee  
An SMC will be established and include both the sponsor and investigators.  The SMC will 
review all available safety, efficacy, PK, and exploratory data and make recommendations on 
dose escalation, dose modification, and dose selection for Phase 1 and Phase 1b.   
Phase 1 (Dose verification in China): For the Chinese patients who receive ociperlimab as a 
monotherapy or in combination with tislelizumab in dose verification study, the SMC will 
review all the safety data (including AEs and laboratory assessments) and make RP2D 
recommendation before initiation of Phase 1b in China.   
Phase 1b (Safety run-in): In each dose-expansion cohort treated with ociperlimab plus 
tislelizumab plus chemotherapy, the SMC will review all available safety data (including AEs 
and laboratory assessments) after the first 6 patients have completed at least 1 cycle (21 days) in 
safety run-in stage and make recommendations if cohorts could be fully open to enrollment. 
The SMC may also be called upon by the sponsor on an ad hoc basis where applicable to the 
conduct of the study.  For more details on the SMC, please refer to the SMC charter. 
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12. 
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. 
12.1. 
Access to Information for Monitoring  
In accordance with International Council for Harmonisation 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. 
12.2. 
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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13. 
QUALITY ASSURANCE AND QUALITY CONTROL  
13.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
13.2. 
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. 
13.3. 
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. 
13.4. 
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 sponsor requirements specified in 
the Pharmacy Manual.  At appropriate times during the conduct of the study or at the end of the 
study following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures.  If the site cannot meet 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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14. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
14.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the International Council for Harmonisation 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 International Council for Harmonisation E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
14.2. 
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. 
14.2.1. 
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. 
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14.3. 
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. 
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 re-consented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study.  For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
14.4. 
Patient and Data Confidentiality  
The investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH GCP Guideline, as implemented locally.  Such 
laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study.  
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
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• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part of 
this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex life, 
sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives.  
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc.). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms) designated by 
sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws.  If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of FDA, the China National Medical Products Administration, and all other 
national and local health authorities; by sponsor monitors, representatives, and collaborators; and 
by the IRBs/IECs for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to Ociperlimab Investigator’s Brochure, Tislelizumab Investigator’s Brochure, this protocol, 
eCRFs, the investigational drugs, and any other study information, are confidential and remain 
the sole and exclusive property of the sponsor during the conduct of the study and thereafter.  
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor.  The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
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If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
14.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of clinical investigators and/or disclose those financial 
interests, as required, to the appropriate health authorities.  This is intended to ensure financial 
interests and arrangements of clinical investigators with 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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15. 
DATA HANDLING AND RECORD KEEPING  
15.1. 
Data Collection and Management Responsibilities  
15.1.1. 
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. 
15.1.2. 
Data Collection  
Data required by the protocol will be entered into an EDC system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee must sign the completed 
casebooks to attest to their accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor or appropriate regulatory authorities. 
15.1.3. 
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 lower level term, preferred term, and primary 
system organ class.  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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15.2. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file, and/or 
2) patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to the following): patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, 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 assure 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 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. 
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 outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage away from the site. 
Subject to patient consent, or as otherwise allowed under applicable law, biological samples at 
the conclusion of this study may be retained for ≤ 10 years or as allowed by the IRB/IEC, 
whichever is shorter. 
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15.3. 
Protocol Deviations  
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol.  Any 
major deviations that might impact patient safety and/or data integrity must be promptly reported 
by the investigator to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
15.4. 
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 International Council for 
Harmonisation Guideline for Structure and Content of Clinical Study Reports (ICH E3 1995).  
Note that an abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study.  The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential.  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 (International 
Committee of Medical Journal Editors 2018) or stricter local criteria. 
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.  The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement.  Each 
investigator agrees that, in accordance with the terms of clinical study agreement, a further delay 
of the publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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15.5. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of 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 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 IEC/IRB 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 in accordance with the clinical 
study agreement established between the investigator and/or institutions and the sponsor. 
15.6. 
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 IEC/IRB 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 15.4. 
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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16. 
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Casado J, Pawelec G, Morgado S, et al.  Expression of adhesion molecules and ligands for 
activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of 
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17. 
APPENDICES  
 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
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APPENDIX 1A. PHASE 1 (DOSE ESCALATION IN AUSTRALIA AND DOSE VERIFICATION IN 
CHINA) SCHEDULE OF ASSESSMENTS  
Phase 1 
assessment 
Screen-
ing a 
Treatment Cycles 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy 
follow-
up d 
Cycle 1 
(28 days for dose 
escalation in 
Australia; 21 days 
for dose 
verification in 
China) 
Cycle 2  
(21 days) 
≥ 
Cycle 
3 
(21 
days) 
EOT Visit b 
Visit day  
- 28 to 
- 1 
1 
8  
15  
21 
1 
8  
15  
1  
EOT decision 
+ 30 days (Visit) 
+60 
days 
(Phone 
call) 
+90 
days 
(Phone 
call) 
Visit window 
 
 
 
± 2 
± 2 
± 1 
± 2  ± 2 
± 3 
± 7 
± 7 
± 14 
± 14 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
medical 
history/ 
prior 
medications e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/ 
height and 
weight f 
x 
x f 
x 
x 
x 
x f 
x 
x 
x f 
x 
x 
 
 
 
Physical 
examination g 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
 
 
 
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Phase 1 
assessment 
Screen-
ing a 
Treatment Cycles 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy 
follow-
up d 
Cycle 1 
(28 days for dose 
escalation in 
Australia; 21 days 
for dose 
verification in 
China) 
Cycle 2  
(21 days) 
≥ 
Cycle 
3 
(21 
days) 
EOT Visit b 
Visit day  
- 28 to 
- 1 
1 
8  
15  
21 
1 
8  
15  
1  
EOT decision 
+ 30 days (Visit) 
+60 
days 
(Phone 
call) 
+90 
days 
(Phone 
call) 
Visit window 
 
 
 
± 2 
± 2 
± 1 
± 2  ± 2 
± 3 
± 7 
± 7 
± 14 
± 14 
ECOG 
Performance 
Status 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
 
 
 
Triplicate 12-
lead ECG h 
x 
Predose and 6 hours after study drugs infusion 
on Day 1 of Cycles 1 and 5 
x 
x 
 
 
 
Adverse 
events i 
x 
x 
x 
x i 
x i 
x 
x i 
x i 
x 
x 
x 
x 
x 
 
Concomitant 
medications 
x 
x 
x 
x j 
x j 
x 
x j 
x j 
x 
x 
x 
x 
x 
 
Hematology k 
x k 
x k 
x k 
 
 
x k 
 
 
x k 
x 
x 
 
 
 
Serum 
chemistry k 
x k 
x k 
x k 
 
 
x k 
 
 
x k 
x 
x 
 
 
 
Coagulation 
parameters k 
x k 
As clinically indicated 
x 
 x 
 
 
 
Urinalysis k 
x k 
As clinically indicated 
 
 
 
CK and 
CK-MB l 
x 
x 
 
x 
x 
x 
 
x 
x l 
x 
x 
 
 
 
Pregnancy test 
m 
x m 
x m 
 
 
 
x m 
 
 
x m 
x 
x 
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Phase 1 
assessment 
Screen-
ing a 
Treatment Cycles 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy 
follow-
up d 
Cycle 1 
(28 days for dose 
escalation in 
Australia; 21 days 
for dose 
verification in 
China) 
Cycle 2  
(21 days) 
≥ 
Cycle 
3 
(21 
days) 
EOT Visit b 
Visit day  
- 28 to 
- 1 
1 
8  
15  
21 
1 
8  
15  
1  
EOT decision 
+ 30 days (Visit) 
+60 
days 
(Phone 
call) 
+90 
days 
(Phone 
call) 
Visit window 
 
 
 
± 2 
± 2 
± 1 
± 2  ± 2 
± 3 
± 7 
± 7 
± 14 
± 14 
Thyroid 
function (every 
3 cycles) n 
x n 
 
 
 
 
 
 
 
x n 
x 
x 
 
 
 
HBV/HCV 
tests o 
x 
Every 4 cycles starting at Cycle 5 in HCC 
patients with detectable HBV DNA at 
screening or as clinically indicated in all 
patients 
x 
x 
 
 
 
Pulmonary 
function tests p 
x p 
As clinically indicated 
 
 
 
PK and ADA x 
 
Refer to Pharmacokinetic and Immunogenicity Table, Appendix 1C 
 
 
 
Blood 
biomarkers q  
 
Refer to Biomarker Table, Appendix 1F 
 
 
 
 
PD receptor 
occupancy r 
 
Refer to Biomarker Table, Appendix 1F 
 
 
 
 
Tumor 
assessment s 
x 
For the first 54 weeks, every 6 weeks.  Every 12 weeks thereafter 
 
 
x 
Archival or 
fresh tumor 
tissue t 
x 
Refer to Biomarker Table, Appendix 1F 
 
 
 
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Phase 1 
assessment 
Screen-
ing a 
Treatment Cycles 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy 
follow-
up d 
Cycle 1 
(28 days for dose 
escalation in 
Australia; 21 days 
for dose 
verification in 
China) 
Cycle 2  
(21 days) 
≥ 
Cycle 
3 
(21 
days) 
EOT Visit b 
Visit day  
- 28 to 
- 1 
1 
8  
15  
21 
1 
8  
15  
1  
EOT decision 
+ 30 days (Visit) 
+60 
days 
(Phone 
call) 
+90 
days 
(Phone 
call) 
Visit window 
 
 
 
± 2 
± 2 
± 1 
± 2  ± 2 
± 3 
± 7 
± 7 
± 14 
± 14 
Ociperlimab 
administration u 
 
x 
  
 
 
x 
 
 
x 
 
 
 
 
 
Tislelizumab 
administration 
(dose 
escalation in 
Australia) v 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Tislelizumab 
administration 
(dose 
verification in 
China) w 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
Abbreviations: ADA, antidrug antibody; AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; CT, computed tomography; 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End-of-Treatment (Visit), HBcAb, hepatitis B core antibody; HBsAb, hepatitis B 
surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; ICF, informed consent form; imAE, immune-mediated AE; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for 
Adverse Events; PD, progressive disease; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; 
T3, triiodothyronine; T4, thyroxine. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
a. 
Written informed consent is required before performing any study-specific procedure.  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drugs may be used for screening assessments rather than repeating such 
tests unless otherwise indicated.  The ICF signature alone does not define the start of the Screening Period, but the first study-related assessment date is to 
be used for the date of the Screening Visit. 
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b. 
The EOT Visit is conducted when the investigator determines that study treatment(s) will no longer be used.  Patients who discontinue treatment for any 
reason will be asked to return to the clinic for the EOT Visit within 7 days when the EOT decision is made unless otherwise specified or before the 
initiation of a new anticancer treatment, whichever occurs first.  If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the EOT Visit, these tests need not be repeated.  Tumor assessment is not required at the EOT/Safety Follow-up Visit if < 6 weeks has passed since 
the last assessment.  
c. 
Patients who permanently discontinue ociperlimab/tislelizumab will be asked to return to the clinic for the on-site Safety Follow-up Visit, which is 
required to be conducted 30 days (± 7 days) after the last dose of ociperlimab/tislelizumab or before the initiation of subsequent anticancer therapy, 
whichever occurs first.  If the time windows of this Safety Follow-up Visit and EOT Visit are overlapped, the safety follow-up can be exempted and the 
tests required at Safety Follow-up Visit will be conducted at the EOT Visit.  In addition, 2 additional Safety Follow-up Visits (by telephone contact) should 
be conducted to assess imAEs and concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 and 90 days 
(± 14 days) after the last dose of ociperlimab/tislelizumab, regardless of whether patients started a new subsequent anticancer therapy.  If patients report a 
suspected imAE at a telephone follow-up contact, the investigator should arrange an unscheduled visit if further assessment is indicated. 
d. 
Efficacy follow-up: Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor 
assessments following the original tumor assessment plan (ie, 6 weeks [± 7 days]) during Year 1 and every 12 weeks (± 7 days) starting Year 2) until the 
patient experiences disease progression, withdraws consent, dies, or until the study terminates, whichever occurs first. 
e. 
Includes year of birth (or age), gender, self-reported race, history of treatment for the primary diagnosis, including prior medication, loco-regional 
treatment(s), and surgical treatment(s).  Information on radiographic studies performed before study entry may be collected for review by the investigator. 
f. 
Height assessment is required only at screening.  Vital signs will include measurements of temperature (˚C), pulse rate, and blood pressure (systolic and 
diastolic) while the patient is in a seated position after resting for 10 minutes.  When ociperlimab and tislelizumab are administered, vital signs are required 
to be measured at 3 timepoints (≤ 60 minutes before the infusion, during the infusion, and ≤ 30 minutes after end of infusion) during all visits.  
g. 
Refer to Section 8.2.2 for details regarding physical examination assessment requirements for screening and subsequent timepoints.  In addition, 
investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during study 
treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
h. 
The triplicate ECG recordings will be performed at the timepoints specified in the table and when clinically indicated.  All ECGs are to be obtained before 
other assessments scheduled at that same time (eg, vital sign measurements, blood draws, etc).  The patient should rest in semi-recumbent supine position 
for ≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate (eg, television, radio, conversation, etc) before each 
ECG collection. 
i. 
The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0.  All AEs will also be evaluated for seriousness.  After the ICF has been 
signed, but before the administration of 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.  Immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of ociperlimab and/or 
tislelizumab, regardless of whether or not the patient starts a subsequent anticancer therapy.  If the investigator learns of any study drug-related SAE, 
including a death, at any time after a patient has been discharged from the study, he/she should notify the sponsor using the SAE reporting procedure. 
j. 
Review of AEs and concomitant medications may be conducted by telephone on Cycle 1 Days 15 and 21 and Cycle 2 Days 8 and 15 if patient is unable to 
make it to the clinic. 
k. 
Laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Appendix 2.  If clinical chemistry, 
hematology, and coagulation at screening are not performed ≤ 7 days before study drugs administration on Day 1 of Cycle 1, these tests should be repeated 
and reviewed before study drug administration.  After Day 1 of Cycle 1, results are to be reviewed within 72 hours before study drug administration.  
Hematology and clinical chemistry (data collected as specified in Appendix 2) will be performed on Day 1 and Day 8 of the first cycle, then on Day 1 on 
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each subsequent cycle as indicated in Appendix 1A).  Urinalysis and/or coagulation test will be conducted during the treatment period only if clinically 
warranted.  Refer to Section 9.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
l. 
CK and CK-MB levels will be evaluated at the timepoints specified within the table and when clinically indicated.  Except for Day 1 of Cycle 1, results are 
to be reviewed within 72 hours before study drug administration where applicable.  If the site’s laboratory does not perform CK-MB testing, serum 
troponins (troponin I and/or T) measurements should be performed instead; if only 1 of the troponins is assessed per local standards that same test should 
be evaluated throughout.  If significant abnormalities are detected, the affected patients should be evaluated for possible myocarditis/myositis per 
institutional guidelines, including additional serum CK/CK-MB, serum troponin levels, ECG, etc. 
m. 
Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented 
as negative ≤ 7 days before the first dose of study drugs.  A negative pregnancy test (by urine or blood) must be completed and recorded ≤ 72 hours before 
the administration of study drugs at each cycle.  Pregnancy tests will also be performed at the EOT Visit and each Safety Follow-up Visit, until 120 days 
after the last dose of ociperlimab and/or tislelizumab or 180 days after the last dose of chemotherapy, whichever comes later.  During the Safety Follow-up 
period, the pregnancy results (local results are acceptable) will be collected by the investigator or designee via phone call.  A serum pregnancy test must be 
performed if the urine pregnancy test is positive or equivocal.  
n. 
Analysis of free T3, free T4, and thyroid stimulating hormone will be performed by a central laboratory and/or the local study site laboratory.  Thyroid 
function tests will be performed at screening and every 3 cycles after then (eg, Cycles 4, 7, 10, etc) and at EOT/Safety Follow-up Visit.  Total T3 can be 
tested as alternative for free T3 and total T4 can be tested as an alternative to free T4.  
o. 
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 ribonucleic acid). For patients with negative HBsAg or negative HCV antibody, 
HBV DNA or HCV RNA is optional based on clinical practice.  Samples for hepatitis serology and viral load will be collected at screening and may be 
tested if patients have hepatic AEs (≥ Grade 3) during the study and as clinically indicated. 
p. 
Patients who are suspected of having or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the 
underlying cancer, or with a history of thoracic radiotherapy will undergo pulmonary function testing 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 on the study.  For test results indicative of 
significantly impaired pulmonary function, eg, resting pulse oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
in one second (FEV1) < 60% or carbon monoxide diffusing capacity (DLCO) (if performed) < 60% of age- and sex-adjusted predicted performance levels, 
the medical monitor needs to be consulted to confirm eligibility.  Patients with low pulmonary function will not be advised for enrollment. 
q. 
Blood biomarker:  Refer to Appendix 1F. 
r. 
Receptor occupancy assay: Refer to Appendix 1F. 
s. 
Tumor imaging will be performed ≤ 28 days before the first dose of study drugs.  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drugs 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) for the first 54 weeks, then every 
12 weeks (± 7 days) after 54 weeks (eg, Week 6, Week 12, …, Week 48, Week 54, Week 66, Week 78, Week 90, etc.), based on RECIST v1.1.  Tumor 
assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI of the brain, chest, abdomen, and pelvis.  All 
measurable and evaluable lesions should be assessed and documented at the Screening Visit and reassessed at each subsequent tumor evaluation.  The 
same radiographic procedure used to assess disease sites at screening must be used throughout the study (eg, the same contrast protocol for CT scans).  See 
Section 8.5 for more information. 
t. 
Archival or fresh tumor tissue: Refer to Appendix 1F. 
u. 
Ociperlimab will be given intravenously on Cycle 1 Day 1, Cycle 2 Day 1 and once every 3 weeks thereafter (Section 5.2.1).  NOTE: Ociperlimab must 
always be prepared and administered separately from any other systemic medication including tislelizumab.  When ociperlimab infusion takes place on the 
same day with tislelizumab, ociperlimab infusion must always occur after infusion of tislelizumab has been completed. 
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v. 
For dose escalation in Australia, tislelizumab will be given intravenously on Cycle 1 Day 8, Cycle 2 Day 1, and once every 3 weeks thereafter for the 
remainder of treatment (Section 5.2.1).  NOTE: Tislelizumab must always be prepared and administered separately from any other systemic medication 
including ociperlimab. When tislelizumab infusion takes place on the same day with ociperlimab, ociperlimab infusion must always occur after infusion of 
tislelizumab has completed. 
w. 
For dose verification in China, tislelizumab will be given intravenously on Cycle 1 Day 1, Cycle 2 Day 1, and once every 3 weeks thereafter for the 
remainder of treatment in Cohort 1B and Cohort 2B (Section 5.2.2).  NOTE: Tislelizumab must always be prepared and administered separately from any 
other systemic medication including ociperlimab.  Ociperlimab infusion must always occur after infusion of tislelizumab has completed. 
x. 
PK and ADA: refer to Appendix 1C. 
 
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APPENDIX 1B. PHASE 1B SCHEDULE OF ASSESSMENTS  
Phase 1b assessment 
Screening 
a 
Treatment Cycles 
EOT 
Visit b 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy follow-
up d 
Survival 
follow-
up w 
Cycles 1 to 6 
(Every 21 days) 
≥ 
Cycle 
7 
(Every 
21 
days) 
Visit day  
- 28 to - 1 
1 
8 v  
15 v  1  
EOT 
decision 
+ 30 days (Visit) 
+ 60 
days 
(Phone 
call) 
+ 90 
days 
(Phone 
call) 
Every 3 
months 
Visit window 
 
± 3 y 
± 1  ± 2  
± 3 
± 7 
± 7 
± 14 
± 14 
± 14 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/prior 
medications e 
x 
 
 
 
 
 
 
 
 
 
 
Height, weight, and 
vital signs f 
x 
x f 
 
 
x f 
x 
x 
 
 
 
 
Physical examination g 
x 
x 
 
 
x 
x 
x 
 
 
 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
x 
x 
 
 
 
 
Triplicate 12-lead 
ECG h 
x 
As clinically indicated 
x 
x 
 
 
 
 
Adverse events i 
x 
x 
x v  
x v 
x 
x 
x 
x 
x 
 
 
Concomitant 
medications 
x 
x 
x v 
x v 
x 
x 
x 
x 
x 
 
 
Hematology  j 
x j 
x 
x v 
x v 
x j 
x 
x 
 
 
 
 
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Phase 1b assessment 
Screening 
a 
Treatment Cycles 
EOT 
Visit b 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy follow-
up d 
Survival 
follow-
up w 
Cycles 1 to 6 
(Every 21 days) 
≥ 
Cycle 
7 
(Every 
21 
days) 
Visit day  
- 28 to - 1 
1 
8 v  
15 v  1  
EOT 
decision 
+ 30 days (Visit) 
+ 60 
days 
(Phone 
call) 
+ 90 
days 
(Phone 
call) 
Every 3 
months 
Visit window 
 
± 3 y 
± 1  ± 2  
± 3 
± 7 
± 7 
± 14 
± 14 
± 14 
Serum chemistry j 
x j 
x 
x v 
x v 
x j 
x 
x 
 
 
 
 
Coagulation 
parameters j 
x j 
As clinically indicated  j 
x 
x 
 
 
 
 
Urinalysis j 
x 
As clinically indicated j 
 
 
 
 
CK and CK-MB k 
x 
x 
 
 
x 
x 
x 
 
 
 
 
Pregnancy test l 
x l 
x l 
 
 
x l 
x 
x 
 
Thyroid function 
(every 3 cycles) m 
x m 
x m 
 
 
x m 
x 
x m 
 
 
 
 
HBV/HCV tests n 
x n 
As clinically indicated  
 
 
 
 
Pulmonary function 
tests o 
x o 
As clinically indicated 
 
 
 
  
 
PK and ADA x 
 
Refer to Pharmacokinetic and Immunogenicity Table, 
Appendix 1D and Appendix 1E  
 
 
 
 
Blood biomarkers p 
 
Refer to Biomarker Table, Appendix 1G 
 
 
 
 
 
Tumor assessment q 
x 
For the first 54 weeks, every 6 weeks.  Every 12 weeks 
thereafter 
 
 
x 
 
Archival or fresh 
tumor tissue r 
x 
Refer to Biomarker Table, Appendix 1G 
 
 
 
 
 
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Phase 1b assessment 
Screening 
a 
Treatment Cycles 
EOT 
Visit b 
Safety Follow-up Visit b  
Safety follow-up by telephone c 
Efficacy follow-
up d 
Survival 
follow-
up w 
Cycles 1 to 6 
(Every 21 days) 
≥ 
Cycle 
7 
(Every 
21 
days) 
Visit day  
- 28 to - 1 
1 
8 v  
15 v  1  
EOT 
decision 
+ 30 days (Visit) 
+ 60 
days 
(Phone 
call) 
+ 90 
days 
(Phone 
call) 
Every 3 
months 
Visit window 
 
± 3 y 
± 1  ± 2  
± 3 
± 7 
± 7 
± 14 
± 14 
± 14 
Ociperlimab 
administration s 
 
x 
 
 
x 
 
 
 
 
 
 
Tislelizumab 
administration t 
 
x 
 
 
x 
 
 
 
 
 
 
Chemotherapy u 
 
x 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: ADA, antidrug antibody; AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; CT, computed tomography; 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End-of-Treatment (Visit), HBcAb, hepatitis B core antibody; HBsAb, hepatitis B 
surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; imAE, immune-mediated AE; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Events; PD, progressive disease; PK, pharmacokinetic; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; 
SAE, serious adverse event; T3, triiodothyronine; T4, thyroxine. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
a. 
Written informed consent is required before performing any study-specific procedure.  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drugs may be used for screening assessments rather than repeating such 
tests unless otherwise indicated.  The ICF signature alone does not define the start of the Screening Period, but the first study-related assessment date is to 
be used for the date of the Screening Visit. 
b. 
The EOT Visit is conducted when the investigator determines that study treatment(s) will no longer be used.  Patients who discontinue treatment for any 
reason will be asked to return to the clinic for the EOT Visit within 7 days when the EOT decision is made unless otherwise specified or before the 
initiation of a new anticancer treatment, whichever occurs first.  If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the EOT Visit, these tests need not be repeated. Tumor assessment is not required at the EOT/Safety Follow-up Visit if < 6 weeks has passed since 
the last assessment.  
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c. 
Patients who permanently discontinue ociperlimab/tislelizumab will be asked to return to the clinic for the on-site Safety Follow-up Visit, which is 
required to be conducted 30 days (± 7 days) after the last dose of ociperlimab/tislelizumab or before the initiation of subsequent anticancer therapy, 
whichever occurs first.  If the time windows of this Safety Follow-up Visit and EOT Visit are overlapped, the safety follow-up can be exempted and the 
tests required at Safety Follow-up Visit will be conducted at the EOT Visit. In addition, 2 additional Safety Follow-up Visits (by telephone contact) should 
be conducted to assess imAEs and concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 and 90 days 
(± 14 days) after the last dose of ociperlimab/tislelizumab, regardless of whether patients started a new subsequent anticancer therapy.  If patients report a 
suspected imAE at a telephone follow-up contact, the investigator should arrange an unscheduled visit if further assessment is indicated.   
d. 
Efficacy follow-up period: Patients who discontinue study drugs for reasons other than PD (eg, toxicity) will continue to undergo tumor assessments 
following the tumor assessment plan until the patient experiences PD, starts subsequent anticancer therapy, or for any other reason listed in Section 7.5.2, 
whichever occurs first. 
e. 
Includes year of birth (or age), gender, self-reported race, history of treatment for the primary diagnosis, including prior medication, loco-regional 
treatment(s), and surgical treatment(s).  Information on radiographic studies performed before study entry may be collected for review by the investigator. 
f. 
Height assessment is required only at screening.  Vital signs will include measurements of temperature (˚C), pulse rate, and blood pressure (systolic and 
diastolic) while the patient is in a seated position after resting for 10 minutes.  When both ociperlimab and tislelizumab are administered, vital signs are 
required to be measured at 3 timepoints (≤ 60 minutes before the infusion, during the infusion, and ≤ 30 minutes after end of infusion) during all visits.  
g. 
Refer to Section 8.2.2 for details regarding physical examination assessment requirements for screening and subsequent timepoints.  In addition, 
investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during study 
treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
h. 
The triplicate ECG recordings will be performed at the timepoints specified in the table and when clinically indicated.  All ECGs are to be obtained before 
other assessments scheduled at that same time (eg, vital sign measurements, blood draws, etc).  The patient should rest in semi-recumbent supine position 
for ≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate (eg, television, radio, conversation, etc) before each 
ECG collection. 
i. 
The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0.  All AEs will also be evaluated for seriousness.  After the ICF has been 
signed, but before the administration of 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.  Immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of ociperlimab and/or 
tislelizumab, regardless of whether or not the patient starts a subsequent anticancer therapy.  If the investigator learns of any study drug-related SAE, 
including a death, at any time after a patient has been discharged from the study, he/she should notify the sponsor using the SAE reporting procedure. 
j. 
Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Appendix 2.  If clinical 
chemistry, hematology, and coagulation at screening are not performed ≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should 
be repeated and reviewed before study drug administration.  Hematology and clinical chemistry (data collected as specified in Appendix 2) will be 
performed within 3 days before Day 1 of each cycle (except for nab-paclitaxel administration, hematology and clinical chemistry will be performed weekly 
on Day 8 and Day 15 of each cycle for 4 to 6 cycles, see footnote v).  The required weekly hematology and serum chemistry tests may take place at an 
alternative hospital/clinic near the patient’s home at the investigator’s discretion.  The investigator’s permission and choice of hospital/clinic should be 
documented in the patient chart and the medical monitor needs to be notified.  Those tests should be taken in one approved hospital/clinic.  The test results 
from this hospital/clinic are acceptable.  Urinalysis and/or coagulation test will be conducted during the treatment period only if clinically warranted.  
Refer to Section 9.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities.   
k. 
CK and CK-MB levels will be evaluated within 3 days before the timepoints specified within the table and when clinically indicated. If the site’s 
laboratory does not perform CK-MB testing, serum troponins (troponin I and/or T) measurements should be performed instead of CK-MB, while CK test 
should be completed together; if only 1 of the troponins is assessed per local standards that same test should be evaluated throughout.  If significant 
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abnormalities are detected, the affected patients should be evaluated for possible myocarditis/myositis per institutional guidelines, including additional 
serum CK/CK-MB, serum troponin levels, ECG, etc. 
l. 
Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented 
as negative ≤ 7 days before the first dose of study drugs.  A negative pregnancy test (by urine or blood) must be completed and recorded ≤ 72 hours before 
the administration of study drugs at each cycle.  Pregnancy tests will also be performed at the EOT Visit and each Safety Follow-up Visit, until 120 days 
after the last dose of ociperlimab and/or tislelizumab or 180 days after the last dose of chemotherapy, whichever comes later.  During the Safety Follow-up 
period, the pregnancy results (local results are acceptable) will be collected by the investigator or designee via phone call.  A serum pregnancy test must be 
performed if the urine pregnancy test is positive or equivocal. 
m. 
Analysis of free T3, free T4, and thyroid stimulating hormone will be performed by a central laboratory and/or the local study site laboratory.  Thyroid 
function tests will be performed at screening and every 3 cycles after then (eg, Cycles 4, 7, 10, etc) and at EOT/Safety Follow-up Visit.  Total T3 can be 
tested as alternative for free T3 and total T4 can be tested as an alternative to free T4.  For patients who skip a dose, extra thyroid function tests will be 
performed based on the investigator’s assessment. 
n. 
Testing will be performed by local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibodies), and viral 
load assessment (HBV DNA and HCV ribonucleic acid).  For patients with negative HBsAg or negative HCV antibody, HBV DNA or HCV RNA is 
optional based on clinical practice. Samples for hepatitis serology and viral load will be collected at screening and may be tested if patients have hepatic 
AEs (≥ Grade 3) during the study and as clinically indicated. 
o. 
Patients who are suspected of having or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the 
underlying cancer, or with a history of thoracic radiotherapy will undergo pulmonary function testing 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 on the study.  For test results indicative of 
significantly impaired pulmonary function, eg, resting pulse oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
in one second (FEV1) < 60% or carbon monoxide diffusing capacity (DLCO) (if performed) < 60% of age- and sex-adjusted predicted performance levels, 
the medical monitor needs to be consulted to confirm eligibility. Patients with low pulmonary function will not be advised for enrollment. 
p. 
Blood biomarkers: Refer to Appendix 1G. 
q. 
Tumor imaging will be performed ≤ 28 days before the first dose of study drugs.  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drugs 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) for the first 54 weeks, then every 
12 weeks (± 7 days) after 54 weeks (eg, Week 6, Week 12, …, Week 48, Week 54, Week 66, Week 78, Week 90, etc.), based on RECIST v1.1.  Tumor 
assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI, with preference for CT, of the chest, abdomen, and 
pelvis.  An MRI (or CT scan if MRI is contraindicated or not readily available) of the head is required at screening; bone scan or PET is required if 
clinically indicated.  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).  See Section 8.5 for more information. 
r. 
Archival or fresh tumor tissue: Refer to Appendix 1G. 
s. 
Ociperlimab will be given intravenously on Day 1 of each 21-day cycle (Q3W) (Section 5.1.3).  Note: Ociperlimab must always be prepared and 
administered separately from any other systemic medication including tislelizumab.  When ociperlimab infusion takes place on the same day with 
tislelizumab, ociperlimab infusion must always occur after infusion of tislelizumab has completed. 
t. 
Tislelizumab will be given intravenously on Day 1 of each 21-day cycle (Q3W) (Section 5.2).  Note: Tislelizumab must not be concurrently infused with 
any other drug.  
u. 
According to pathological diagnosis of primary disease, chemotherapy will be given 6 cycles (pemetrexed plus platinum will be given for 4 to 6 cycles for 
patients with non-squamous NSCLC, paclitaxel/nab-paclitaxel plus platinum will be given for 4 to 6 cycles for patients with squamous NSCLC, and 
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etoposide plus platinum will be given for 4 cycles for ES-SCLC).  For patients with non-squamous NSCLC and whose disease has not progressed after 4 to 
6 cycles of doublet chemotherapy, maintenance treatment of pemetrexed is permitted.  For patients with G/GEJ adenocarcinoma and whose disease has not 
progressed after 6 cycles of oxaliplatin and capecitabine, optional maintenance treatment of capecitabine is permitted.  All chemotherapy agents will be 
given on Day 1 of each cycle, every 3 weeks (nab-paclitaxel will be administered on D1, D8, and D15 of each cycle for 4 to 6 cycles for patients with 
squamous NSCLC, etoposide 100 mg/m2 will be administered on Day 1 to Day 3 for 4 cycles for patient with ES-SCLC, 5-fluorouracil 750 to 800 mg/m2 
will be administered on D1 to D5 of each cycle for 6 cycles for patients with ESCC and EAC, capecitabine 1000 mg/m2 twice a day will be administered 
on D1 to D14 of each cycle for up to 6 cycles for patients with G/GEJ adenocarcinoma). Refer to Section 5.2 for drug administration in details. 
v. 
A. Procedures during on-site visits for on Day 8 and Day 15 only apply to patients in Cohort 1 with squamous NSCLC receiving nab-paclitaxel at the 
investigator’s discretion for 4 to 6 cycles: hematology and serum chemistry will be performed on D8 and D15 of each cycle. 
B. Phone calls by site are recommended on Day 8 and Day 15 for patients in other cohorts than cohort 1 with squamous NSCLC receiving nab-paclitaxel. 
It is recommended to collect data of AEs and concomitant medications by phone calls. The patient should be asked if any new symptoms have been 
observed or existing symptoms may have worsened, and if there has been any change to medications.  The investigators need to remind patients to return to 
the clinical study site for further assessment if new AEs arise or worsen. 
C. For patients who receive chemotherapy combination therapy (Cohorts 1, 2, 4, 6, 7, and 9), extra hematology and serum chemistry by site or other local 
hospitals is recommended to be conducted no later than Day 5 of each cycle.  
w. 
Patients will be followed for survival and to obtain information on subsequent anticancer therapy information after discontinuation of study treatment via 
telephone calls, patient medical records, and/or clinic visits every 3 months (± 14 days) after the 30-day Safety Follow-up Visit or as directed by the 
sponsor until death, withdrawal of consent, loss to follow-up, or end of study. 
x. 
PK and ADA: refer to Appendix 1D and Appendix 1E. 
y. 
For Cycle 2 Day 1 and the following cycles, a 3-day window is allowed. 
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APPENDIX 1C. PHASE 1 PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING SCHEDULE 
FOR OCIPERLIMAB AND TISLELIZUMAB  
For Dose Escalation in Australia 
Study 
Week 
Study Visit 
Time 
PK 
ADA 
1 
Cycle 1, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK 
Ociperlimab ADA 
30 (±10) min after end of infusion b 
Ociperlimab PK 
 
Cycle 1, Day 2 
24 (± 6) hr after end of infusion on Day 1 
Ociperlimab PK 
 
Cycle 1, Day 4 
72 (± 12) hr after end of infusion on Day 1 
Ociperlimab PK 
 
2 
Cycle 1, Day 8 (± 1 
day) 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Tislelizumab ADA 
30 (±10) min after end of tislelizumab infusion 
Tislelizumab PK 
 
3 
Cycle 1, Day 15 (± 
1 day) 
At visit 
Ociperlimab PK 
 
5 
Cycle 2, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion b 
Ociperlimab PK 
 
14 
Cycle 5, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion b 
Ociperlimab PK & tislelizumab PK 
 
15 
Cycle 5, Day 8 (± 1 
day) 
At visit 
Ociperlimab PK 
 
16 
Cycle 5, Day 15 (± 
1 day) 
At visit 
Ociperlimab PK 
 
17 
Cycle 6, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion b 
Ociperlimab PK  
 
26 
Cycle 9, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA 
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Study 
Week 
Study Visit 
Time 
PK 
ADA 
38 
Cycle 13, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA 
50 
Cycle 17, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA 
74 
Cycle 25, Day 1 
Predose (-60 min to predose) a 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA 
30-day Safety Follow-up Visit  
30 (± 7) days after last dose 
Ociperlimab PK & tislelizumab PK 
Ociperlimab ADA & 
tislelizumab ADA 
Abbreviations: ADA, antidrug antibody; PK, pharmacokinetic; min, minute; hr, hour  
Note: Sample collection must be from the arm opposite the one that was used for the study drug infusion.  If drug was administered via a central venous catheter, 
sample collection for PK and ADA should be from a different site. 
a. 
Predose (- 60 min to predose): ≤ 60 minutes before the infusion of the first immunotherapy product 
b. 
30 (± 10) min after end of infusion: 30 (± 10) min after of end of the last immunotherapy product 
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For Dose Verification in China (Tislelizumab PK and ADA Samples Not Required for Monotherapy Cohorts) a 
Study 
week 
Study visit 
Time 
PK 
ADA 
1 
Cycle 1, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
30 (±10) min after end of infusion c 
Ociperlimab PK & tislelizumab 
PK 
 
Cycle 1, Day 2 
24 (±6) hr after end of infusion c on Day 1 
Ociperlimab PK 
 
Cycle 1, Day 4 
72 (±12) hr after end of infusion c on Day 1 
Ociperlimab PK 
 
2 
Cycle 1, Day 8 (± 1 day) 
At visit 
Ociperlimab PK  
 
3 
Cycle 1, Day 15 
(± 1 day) 
At visit 
Ociperlimab PK 
 
4 
Cycle 2, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion c 
Ociperlimab PK 
 
13 
Cycle 5, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion c 
Ociperlimab PK & tislelizumab 
PK 
 
14 
Cycle 5, Day 8 (± 1 day) 
At visit 
Ociperlimab PK 
 
15 
Cycle 5, Day 15 (± 1 
day) 
At visit 
Ociperlimab PK 
 
16 
Cycle 6, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA  
30 (±10) min after end of infusion c 
Ociperlimab PK  
 
25 
Cycle 9, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
37 
Cycle 13, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
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Study 
week 
Study visit 
Time 
PK 
ADA 
49 
Cycle 17, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
73 
Cycle 25, Day 1 
Predose (-60 min to predose) b 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
30-day Safety Follow-up Visit 
30 (± 7) days after last dose 
Ociperlimab PK & tislelizumab 
PK 
Ociperlimab ADA & 
tislelizumab ADA 
Abbreviations: ADA, antidrug antibody; PK, pharmacokinetic; min, minute; hr, hour  
Note: Sample collection must be from opposite arm to that used for study drug infusion.  If the drug was administered via a central venous catheter, sample 
collection for PK and ADA should be from a different site. 
a. 
Tislelizumab PK and ADA samples will be collected only for combination therapy cohort or cohorts. 
b. 
Predose (- 60 min to predose): ≤ 60 minutes before the infusion of the first immunotherapy product 
c. 
30 (± 10) min after end of infusion: 30 (± 10) min after of end of the last immunotherapy product 
 
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APPENDIX 1D. PHASE 1B PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING FOR 
OCIPERLIMAB AND TISLELIZUMAB WITH OR WITHOUT CHEMOTHERAPY FOR COHORTS 1 
TO 9  
Study Week 
Study Visit 
Time 
PK 
ADA 
1 
Cycle 1, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30 (± 10) min after end of 
infusion b 
Tislelizumab PK and ociperlimab 
PK 
 
4 
Cycle 2, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
13 
Cycle 5, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30 (± 10) min after end of 
infusion b 
Tislelizumab PK and ociperlimab 
PK 
 
16 
Cycle 6, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
25 
Cycle 9, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
37 
Cycle 13, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
49 
Cycle 17, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
73 
Cycle 25, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30-day Safety Follow-up Visit 
30 (± 7) days after last dose 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
Abbreviations: ADA, antidrug antibody; min, minutes; PK, pharmacokinetic 
Note: Sample collection must be from opposite arm to that used for study drug infusion.  If drug was administered via a central venous catheter, sample 
collection for PK & ADA should be from a different site. 
a. 
Predose (- 60 min to predose): ≤ 60 minutes before the infusion of the first immunotherapy product 
b. 
30 (± 10) min after end of infusion: 30 (± 10) min after of end of the last immunotherapy product 
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APPENDIX 1E. PHASE 1B COHORT 10 PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING 
FOR OCIPERLIMAB AND TISLELIZUMAB  
Study Week 
Study Visit 
Time 
PK 
ADA 
1 
Cycle 1, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30 (± 10) min after end of 
infusion b 
Tislelizumab PK and ociperlimab 
PK 
NA 
2 
Cycle 1, Day 8 (± 1 
day) 
At visit 
Ociperlimab PK 
NA 
3 
Cycle 1, Day 15 (± 1 
day) 
At visit 
Ociperlimab PK 
NA 
4 
Cycle 2, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
13 
Cycle 5, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30 (± 10) min after end of 
infusion b 
Tislelizumab PK and ociperlimab 
PK 
 
16 
Cycle 6, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
25 
Cycle 9, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
37 
Cycle 13, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
49 
Cycle 17, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
73 
Cycle 25, Day 1 
Predose (- 60 min to predose) a 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
30-day Safety Follow-up Visit 
30 (± 7) days after last dose 
Tislelizumab PK and ociperlimab 
PK 
Tislelizumab ADA and ociperlimab 
ADA 
Abbreviations: ADA, antidrug antibody; min, minutes; NA, not applicable; PK, pharmacokinetic 
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Note: Sample collection must be from the arm opposite to that used for study drug infusion.  If the study drug was administered via a central venous catheter, 
sample collection for PK and ADA should be from a different site. 
a. 
Predose (- 60 min to predose): ≤ 60 minutes before the infusion of the first immunotherapy product 
b. 
30 (± 10) min after end of infusion: 30 (± 10) min after of end of the last immunotherapy product 
 
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APPENDIX 1F. PHASE 1 BLOOD AND TISSUE BIOMARKER ANALYSIS  
For Dose Escalation in Australia 
Biomarker assessment 
Screening 
Treatment Period 
Cycle 1 a 
Cycle 
2 
Cycle 
3 
Cycle 
5 
Patients with first PR or 
CR 
EOT Visit 
after 
confirmed 
disease 
progression 
Visit day (days) 
- 28 to - 1 
1 
2 
8 
15 
1 
1 
1 
 
0 to 7  
Ociperlimab/TIGIT 
receptor occupancy 
 
X 
X 
(24 hours ± 2 hours 
after end of infusion) 
X 
X 
X 
 
X 
 
 
Tislelizumab/PD-1 
receptor occupancy 
 
X 
 
 
 
X 
 
X 
 
 
Blood-based PD 
biomarker 
X 
X 
 
X 
X 
X 
X 
 
 
 
Cytokine or soluble 
proteins in blood  
 
X 
X 
(24 hours ± 2 hours 
after end of 
ociperlimab infusion) 
X 
X 
X 
X 
 
X 
(first treatment after 
confirmation) 
X c 
ctDNA 
X 
 
 
 
 
 
 
 
X 
(first treatment after 
confirmation) 
X c 
Archival or fresh tumor 
tissue b 
X 
 
 
 
 
 
X 
(optio
nal) 
 
 
X (optional) 
Abbreviations: C, Cycle; CR, complete response; ctDNA, circulating tumor DNA; D, Day; EOT, End-of-Treatment; FFPE, formalin fixed paraffin embedded; 
PD, pharmacodynamic; PD-1, programmed cell death protein-1; PR, partial response; TIGIT, T-cell immunoreceptor with Ig and ITIM domains 
a. At C1D8, C1D1, C2D1, C3D1 and C5D1, the blood samples should be collected before tislelizumab infusion.  Refer to the laboratory manual for additional 
detailed information. 
b. Archival or fresh tumor tissue: archival tumor tissues (FFPE blocks or approximately 15 unstained slides) or fresh biopsy are highly recommended for 
biomarker analysis.  If feasible, post-treatment biopsies should be taken from the same tumor lesion as the baseline biopsy/archival tumor tissues.  Written 
patient informed consent is required for optional fresh tumor biopsies. 
c. Blood samples should be collected at EOT Visit after confirmed disease progression. 
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For Dose Verification in China 
Biomarker assessment 
Screening 
Treatment period 
Cycle 1a 
Cycle 
2 
Cycle 
3 
Cycle 
5 
Patients with first 
PR or CR 
EOT Visit 
after 
confirmed 
disease 
progression 
Visit day (days) 
-28 to -1 
1 
2 
8 
15 
1 
1 
1 
 
0 to 7  
Ociperlimab/TIGIT receptor 
occupancy 
 
X 
X 
(24 hours ± 2 hours after end 
of ociperlimab infusion) 
X 
X 
X 
 
X 
 
 
Tislelizumab/PD-1 receptor 
occupancy b 
 
X 
 
 
 
X 
 
X 
 
 
RNA-seq (blood) 
 
X 
 
X 
X 
X 
X 
 
X 
X e 
Cytokine/soluble proteins 
(blood)  
 
X 
X 
(24 hours ± 2 hours after end 
of ociperlimab infusion) 
X 
X 
X 
X 
 
X 
X e 
ctDNA (blood) 
X 
 
 
 
 
 
 
 
X 
X e 
Archival or fresh tumor 
tissue c 
X 
 
 
 
 
 
 
 
X (optional) 
X (optional) 
Immunophenotyping (blood) 
 
X 
 
X 
X 
X 
 
 
 
 
Abbreviations: CR, complete response; ctDNA, circulating tumor DNA; EOT, End-of-Treatment; FFPE, formalin fixed paraffin embedded; PD, 
pharmacodynamic; PD-1, programmed cell death protein-1; PR, partial response; RNA-seq, RNA sequencing; TIGIT, T-cell immunoreceptor with Ig and ITIM 
domains 
a. Per current protocol, patient may or may not receive tislelizumab on Cycle 1 Day 8 (C1D8) during first cycle.  If the patients receive tislelizumab on C1D8, 
then the blood samples should be collected before tislelizumab infusion.  Blood samples at C1D1, C2D1, C3D1 and C5D1 should be collected before dosing.  
Refer to the laboratory manual for additional detailed information. 
b. Tislelizumab/PD-1 receptor occupancy assay: For the cohorts receiving ociperlimab as monotherapy (Cohort 1A/2A), tislelizumab/PD-1 receptor occupancy 
assay will not be tested. 
c. Archival or fresh tumor tissue: archival tumor tissues (FFPE blocks or approximately 15 unstained slides) or fresh biopsy are highly recommended for 
biomarker analysis.  If feasible, post-treatment biopsies should be taken from the same tumor lesion as the baseline biopsy/archival tumor tissues.  Written 
patient informed consent is required for optional fresh tumor biopsies.   
d. If the ctDNA sample collection is missed during screening period, it’s acceptable to collect the sample before dosing on Cycle 1 Day 1. 
e. Blood samples should be collected at EOT Visit after confirmed disease progression. 
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APPENDIX 1G. PHASE 1B BLOOD AND TISSUE BIOMARKER ANALYSIS  
Biomarker assessment 
Cohort 
Screening 
Treatment Period 
Cycle 1e 
Cycle 2 e 
Cycle 3 e 
Cycle 5 e 
Patients 
with first 
PR or CR 
EOT Visit 
after 
confirmed 
disease 
progression 
Visit Day (Days) 
-28 to -1 
1 
8 
15 
1 
1 
1 
 
0 to 7  
Ociperlimab/TIGIT 
receptor occupancy a 
Cohort 10 only 
 
X 
X 
X 
X 
 
X 
 
 
Immunophenotyping 
(blood) a 
Cohorts 3 and 5 only c 
 
X 
X 
X 
X 
 
X 
 
 
RNA-seq (blood) a 
Cohorts 3 and 5 only c 
 
X 
X 
X 
X 
 
 
 
 
Cytokine/soluble 
proteins (blood) a 
Cohorts 3, 5, and 10 
only c 
 
X 
X 
X 
X 
 
 
 
 
ctDNA-based gene 
mutation profile and Fc 
gamma receptor 
polymorphism 
(blood) a,b 
All cohorts 
 
X 
 
 
 
X 
 
 
X 
Archival or fresh  
tumor tissue d 
All cohorts 
X 
 
 
 
X 
(optional) 
 
 
X (optional) 
X (optional) 
Abbreviations: CPI, checkpoint inhibitor; CR, complete response; ctDNA, circulating tumor DNA; EOT, End-of-Treatment; FFPE, formalin fixed paraffin 
embedded; HGRAC, Human Genetic Resource Administration of China; hr, hours; MSI, microsatellite instability; NSCLC, non-small cell lung cancer; PD, 
pharmacodynamic; PD-L1, programmed cell death protein-ligand 1; PR, partial response; RNA-seq, RNA sequencing; TMB, tumor mutation burden.  
a. Blood-based immunophenotyping will include peripheral immune cell quantification, and phenotype change. Blood samples will be collected at designated 
timepoints for prespecified cohorts.  Please refer to the laboratory manual for additional detailed information. 
b. Blood samples will be taken at predose on Day 1 of Cycle 1, predose on Day 1 of Cycle 3, and at EOT Visit after confirmed disease progression to evaluate 
ctDNA-based gene mutation profiles (including TMB and MSI) and Fc gamma receptor polymorphism.  Please refer to the laboratory manual for additional 
detailed information. 
c. Cohort 3, PD-L1 positive NSCLC cohorts; Cohort 5, CPI-experienced NSCLC cohort.  
d. All patients are required to provide archival or fresh tumor tissues (FFPE blocks [preferred] or approximately 15 freshly cut unstained slides [≥ 8 slides are 
mandatory]) for biomarker analysis.  Prospective PD-L1 testing at central laboratory is mandatory for patients in Cohorts 3, 8, and 10.  Retrospective collection 
of exploratory screening archival tissues for China patients is acceptable after HGRAC approval to exploratory analysis.  If feasible, post-treatment biopsies 
should be taken from the same tumor lesion as the baseline biopsy/archival tumor tissues.  Written patient informed consent is required for optional post-
treatment fresh tumor biopsies.  Please refer to Section 8.4 for detailed tissue sample collection requirements.  
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e. On Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 5 Day 1, blood samples should be collected before dosing. 
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Clinical chemistry 
Hematology 
Coagulation 
Urinalysis (screening 
and as clinically 
indicated) 
Alkaline phosphatase 
Red blood cell count 
Prothrombin time 
pH 
Alanine aminotransferase 
Hematocrit 
Partial thromboplastin 
time or activated partial 
thromboplastin time 
Specific gravity 
Aspartate aminotransferase 
Hemoglobin 
International 
normalized ratio 
Glucose 
Albumin 
Monocyte count 
 
Protein 
Total bilirubin 
Basophil count 
 
Ketones 
Blood urea nitrogen or urea 
Eosinophil count 
 
Blood 
Potassium 
Platelet counts 
 
24-hour proteina             
Sodium 
White blood cell count c 
 
 
Calcium 
Neutrophil count 
 
 
Creatinine 
Lymphocyte count 
 
 
Fast glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Lipase 
 
 
 
Amylase 
 
 
 
Testosteroneb             
 
 
 
Creatine kinase 
 
 
 
a. On routine urinalysis, if urine protein is ≥ 2+ by dipstick 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. Testosterone assay is only for patients with metastatic castration-resistant prostate cancer.  However, the 
testosterone levels do not need to be checked if the patient has undergone surgical castration for > 4 months 
before the first dose of study drug.  Patients receiving chemical castration should have their testosterone levels 
checked at baseline and confirmed to be at the castrate levels (< 0.5 ng/mL or 1.735 nM). 
c. White blood cell count measurements could be adjusted based on local practice with approval of medical monitor 
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APPENDIX 3. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light 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 
As published by (Oken et al 1982).  Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 
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APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture syndrome  
Granulomatosis with polyangiitis  
Graves disease  
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodosa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren syndrome  
Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Koyanagi-Harada disease 
Approved Date
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APPENDIX 5. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation: 
− oral 
− injectable 
− 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 patient and that the 
vasectomized partner has received medical assessment of surgical success 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment) 
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,” and 
“Nonsterile males” 
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: 
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• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL 
“Nonsterile males” are defined as male patients who are physiologically capable of impregnating 
females. 
Adapted from: Clinical Trials Facilitation Group (CTFG) 2014.  
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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity (eg, no 
shortness of breath when walking, climbing stairs, etc). 
II 
Mild symptoms (eg, mild shortness of breath and/or angina).   
Slight limitations during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
(eg, walking short distances [20-100 meters]).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound. 
Adapted from Dolgin et al 1994.   
Original source: Criteria Committee, New York Heart Association, Inc. 1964.  
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APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
(Levey et al 2009) equation and the Modification of Diet in Renal Disease Study equation.  
National Kidney Disease Education Program calculators rely on creatinine determinations which 
are isotope dilution mass spectrometry traceable.  All laboratories should be using creatinine 
methods calibrated to be isotope dilution mass spectrometry traceable. 
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL.  
This equation is recommended when estimated GFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × min (Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1, and 
max indicates the maximum of Scr/κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators 
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APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated 
adverse event (imAE) are intended as guidance.  This document should be used in conjunction 
with expert clinical judgement (by specialist physicians experienced in the treatment of cancer 
using immunological agents) and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, progressive disease 
(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; PD, progressive 
disease; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, thyroxine; TFT, thyroid function tests; 
TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine.
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Treatment of Immune-mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention, as appropriate, 
with patients is required 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drugs may be 
considered if there is evidence of a clinical response to study treatment after 
consultation with the medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
Autoimmune 
toxicity 
Grade 
Treatment guidelines (subject to 
clinical judgement) 
Study drug 
management 
Thyroid 
disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks.  Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 
0.5 μg/kg/day).  Add oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Thyrotoxic patients 
require treatment with a beta blocker 
and may require carbimazole until 
thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines (subject to 
clinical judgement) 
Study drug 
management 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  Initiate 
pulse IV methylprednisolone 1 mg/kg 
for patients with headache/visual 
disturbance due to pituitary 
inflammation.  Convert to oral 
prednisolone and taper over at least 
1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days. 
If appearance worsens, treat as 
Grade 2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
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. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines (subject to 
clinical judgement) 
Study drug 
management 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-
1 mg/kg/day.  Taper over at least 
4 weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/diarrhea 
1 
Mild symptoms: < 3 liquid 
stools per day over 
baseline and feeling well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4 to 
6 liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids over 
2-4 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.  Follow-
up at least every 5 days is 
recommended; if there is no 
improvement of symptoms, further 
treatment should be considered to 
prevent progression of rash 
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.  Judgement of 
grade 3 or above rash should base on 
on-site visit or photo instead of phone 
call monitoring alone. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment) 
Initiate IV methylprednisolone 
1-2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3X 
ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines (subject to 
clinical judgement) 
Study drug 
management 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours: 
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-
1 mg/kg/day for 3 days then taper 
over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.   
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day.  When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 
4 weeks.   
Hold study treatment 
until improved to 
baseline grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X ULN 
Initiate IV methylprednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
6 weeks.   
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
If on oral prednisolone, change to pulsed IV methylprednisolone 
If on IV, add 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. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines (subject to 
clinical judgement) 
Study drug 
management 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; ULN 
to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 160-
250 mg/dL; 8.9-
13.9 mmol/L 
Obtain a repeat blood glucose level at 
least every week.  Manage according 
to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 250-
500 mg/dL; 13.9-27.8 
mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose 
value > 500 
mg/dL; > 27.8 mmol/L 
Admit patient to hospital and institute 
local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior 
uveitis/panuveitis or 
significant symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
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 
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 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
 
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 
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 
immunosuppressant therapy. Taper 
oral steroids over at least 4 weeks. 
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 9. 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 computed tomography (CT) scan (irrespective of scanner type) and 
magnetic resonance imaging (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, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
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• Blastic bone lesions are non-measurable. 
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. 
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 
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these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple 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. 
• 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. 
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• 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 (SD) to differentiate between response (or SD) and progressive disease 
(PD). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• 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). 
• SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if 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, SD, and PD, 
the actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 
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• 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 SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
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designation of overall progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• 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. 
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: 
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• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion.   
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment considering any requirement for confirmation.  On occasion a response may not be 
documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response.  Protocols must 
specify how any new therapy introduced before progression will affect best response 
designation.  The patient’s BOR assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions.  Furthermore, 
depending on the nature of the trial and the protocol requirements, it may also require 
confirmatory measurement.  Specifically, in nonrandomized trials where response is the primary 
endpoint, confirmation of PR or CR is needed to deem either one the “best overall response.” 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all timepoints (for example, a patient who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a BOR of PR).  
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline.  If the minimum time is not met when SD is otherwise the best timepoint 
response, the patient’s best response depends on the subsequent assessments.  For example, a 
patient who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  The same patient lost to follow-up after the first SD 
assessment would be considered inevaluable. 
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 
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Target lesions 
Non-target lesions 
New lesions 
Overall response 
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-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document objective progression even after discontinuation of 
treatment.  Symptomatic deterioration is not a descriptor of an objective response: it is a reason 
for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of 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. 
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 
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permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
results.  However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or 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 
SD is measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases.  If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD. 
Note: The DOR and SD as well as the PFS are influenced by the frequency of follow-up after 
baseline evaluation.  It is not in the scope of this guideline to define a standard follow-up 
frequency.  The frequency should 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 10. CHILD-PUGH CLASSIFICATION SCORING SYSTEM   
The information presented here has been obtained from the Washington University Medical 
Center, with sources as follows: Lucey et al 1997; Pugh et al 1973; Trey et al 1996. 
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 2 d 
3e or 4 f 
Ascites (presence and severity) 
None 
Mild 
Moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prolonged prothrombin time (seconds) 
or 
INRg             
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Events. 
 a Trey et al 1996 
b Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5 CPS waves. 
 dGrade 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 2-3 CPS Delta activity. 
g Lucey et al 1997 
 
Approved Date
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APPENDIX 11. DOSE MODIFICATION OF CHEMOTHERAPY  
Recommended Dose Modifications for Hematologic Toxicity 
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration.  Dose level adjustments are relative to that of the preceding administration.  
Recommended dose modifications for hematologic toxicity are provided in the following table. 
Chemotherapy Dose Modificationa for Hematological Toxicity 
Adverse Event 
Treatment 
Febrile neutropenia; documented infection 
The first episode of febrile neutropenia or 
documented infection will result in antibiotic 
treatment and reduction by 20% of both drugs 
doses 
If there is a second episode despite dose 
reduction, the patient must receive 
prophylactic antibiotics during the subsequent 
cycles 
If there is a third episode, the chemotherapy 
will be discontinued 
Neutropenia 
Grade 3 
(0.5-0.99 x 109/L) 
chemotherapy delay until ≤ Grade 1  
(≥ 1.5 x 109/L); restart with the full dose 
Grade 4 
(< 0.5 x 109/L) 
chemotherapy delay until recovered to ≤ 
Grade 1; dose reduction of all further doses 
by 20% 
thrombocytopenia 
Grade 1 
chemotherapy delay until recovered to 
normal; restart with the full dose 
≥ Grade 2 
chemotherapy delay until recovered to 
normal; dose reduction of all further doses by 
20% 
a. If considered in the best interest of the patient and consistent with local practice, investigators may decide to use 
supportive measures / treatment and/or secondary prophylaxis instead of dose reductions for the next cycle.  The 
provided triggers for dose modifications are recommendations only. 
Approved Date
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Recommended Dose Modifications for Non-hematologic Toxicities 
The dose adjustments of chemotherapy for non-hematologic toxicity are described in the 
following table.  All dose modifications should be made based on the worst grade toxicity.  
Chemotherapy Dose Modifications for Non-Hematological Toxicity 
Toxicity 
Grade 
Treatment  
Hyper-creatinemia 
≥ Grade 1 
Delay chemotherapy until 
recovered to Grade 0 or 
baseline, change cisplatin to 
carboplatin, if possible; dose 
reduction by 20% for other drug; 
if recur, stop chemotherapy 
Ototoxicity  
Grade 2 
Dose reduction of all further 
doses of cisplatin by 20% 
 
Grade 3-4 
Delay chemotherapy until 
recovered to ≤ Grade 2, change 
cisplatin to carboplatin 
Sensory neuropathy 
Grade 2 
Dose reduction for all further 
doses of cisplatin and/or 
paclitaxel by 20% 
 
Grade 3 
Stop cisplatin, change cisplatin 
to carboplatin; stop paclitaxel 
 
Grade 4 
Stop cisplatin/carboplatin, 
and/or paclitaxel 
Other organ toxicity 
Grade 2 
Delay chemotherapy until ≤ 
Grade 1 or baseline a 
  
Grade 3-4 
Delay chemotherapy until 
recovered to ≤ Grade 1 or 
baseline a, dose reduction of all 
further dose by 20% 
a. Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting which may have resolved to Grade 2 or baseline. 
Note: If considered in the best interest of the patient and consistent with local practice, 
investigators may decide to use supportive measures / treatment, and/or secondary prophylaxis 
instead of dose reductions for the next cycle.  The provided triggers for dose modifications are 
recommendations only.
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Recommended Dose Modifications for Nab-paclitaxel 
The dose adjustment of nab-paclitaxel refers to approved product labels for dose modifications 
regarding this regimen.  Do not administer nab-paclitaxel on Day 1 of a cycle until absolute 
neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 
cells/mm3.  
• In patients who develop severe neutropenia or thrombocytopenia withhold treatment 
until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and 
platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil 
count of at least 1500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on 
Days 8 or 15 of the cycle.  If nab-paclitaxel cannot be administered on Day 15 of the 
cycle, the next dose of nab‑paclitaxel should be administered with carboplatin on Day 
1 of the following cycle provided ANC and platelets counts have recovered to 
permissible levels. 
• Withhold nab-paclitaxel for Grade 3-4 peripheral neuropathy.  Resumes 
nab-paclitaxel and carboplatin at reduced doses when peripheral neuropathy improves 
to Grade 1 or completely resolves. 
Approved Date
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10 November 2023 
 
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APPENDIX 12. NUTRITIONAL RISK INDEX   
Recent weight loss history of the patient may not always be known and the body weight loss 
does not take the albumin level into consideration, so the Nutritional Risk Index (NRI) is 
referenced as an alternative per investigator’s choice to assess the patient’s nutritional status for 
the purpose of eligibility.  The formula is provided below (Shirasu et al 2018): 
 
NRI = (1.489 × serum albumin) + (41.7 × present body weight / ideal body weight) 
 
The Ideal Body Weight (IBW) formula is based on the Peterson formula (Peterson et al 2016):  
IBW (kg) = 2.2 x Target BMI + [3.5 x Target BMI x (Height (m) - 1.5 m)].  For the purpose of 
this study, we will use a Target BMI of 22, so the formula becomes: 
IBW (kg) = 48.4 + [77 x (Height (m) - 1.5 m)] 
 
Or you can use below online calculator to calculate the IBW, and please choose the calculation 
results of the Peterson formula:  
https://www.gigacalculator.com/calculators/ideal-weight-calculator.php  
Approved Date
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10 November 2023 
 
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APPENDIX 13. COCKCROFT-GAULT FORMULA AND CALVERT 
FORMULA  
COCKCROFT-GAULT FORMULA: 
FOR SERUM CREATININE CONCENTRATION (SCr) IN MG/DL a 
Clcr for males (mL/min)        
     (140−age)(weightb)      
(72)(SCr)
 
Clcr for females (mL/min)      
(0.85)(140−age)(weightb)
(72)(SCr)
 
 
FOR SERUM CREATININE CONCENTRATION (SCr) IN µMOL/L a 
Clcr for males (mL/min)        
     (140−age)(weightb)      
(0.81)(SCr)
 
Clcr for females (mL/min)      
(0.85)(140−age)(weightb)
(0.81)(SCr)
 
a Age in years and weight in kilograms. 
b Recommend using ideal body weight if the patient is obese (>30% over ideal body weight) in calculation of 
estimated CLCr. Calculating by actual body weight is acceptable. 
 
CALVERT FORMULA: 
(GFR*+25) x AUC=dose in mg. 
*GFR calculation formula is same as ClCr formula as shown above. 
 
Approved Date
11/10/2023


Signature Page 
Approval with eSignature
Development
10-Nov-2023 08:26:43 GMT+0000
Approved Date
11/10/2023

SAP_001.pdf: 
AdvanTIG-105 (BGB-900-105) 
BeiGene 
Statistical Analysis Plan 1.0 
August 27, 2024 
CONFIDENTIAL
Page 1
STATISTICAL ANALYSIS PLAN 
Study Protocol Number: 
AdvanTIG-105 (BGB-900-105) 
Study Protocol Title: 
Phase 1/1b Study Investigating Safety, Tolerability, 
Pharmacokinetics and Preliminary Antitumor Activity of Anti-
TIGIT Monoclonal Antibody BGB-A1217 in Combination with 
Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) in 
Patients with Unresectable Locally Advanced or Metastatic Solid 
Tumors 
Date: 
August 27, 2024 
Version: 
1.0 
NCT Number
NCT04047862


 
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SIGNATURE PAGE 
 
 
Author: 
 
Senior Statistician,  
Global Statistics and Data Science 
 
Approval 
 
Senior Director,  
Global Statistics and Data Science 
 
Vice President,  
Clinical Development 
 
Senior Physician, 
Clinical Development 
 
 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. .................. INTRODUCTION ........................................................................................................8 
2. .................. STUDY OVERVIEW ...................................................................................................8 
2.1. .............. Study design..................................................................................................................8 
2.2. .............. Study assessment ........................................................................................................12 
3. .................. STUDY OBJECTIVES ..............................................................................................12 
3.1. .............. Primary Objective .......................................................................................................12 
3.2. .............. Secondary Objective ...................................................................................................13 
3.3. .............. Exploratory Objective .................................................................................................13 
4. .................. STUDY ENDPOINTS ................................................................................................13 
4.1. .............. Primary Endpoint(s) ....................................................................................................13 
4.2. .............. Secondary Endpoints ..................................................................................................14 
4.3. .............. Exploratory Endpoints ................................................................................................15 
5. .................. SAMPLE SIZE CONSIDERATIONS .......................................................................15 
6. .................. STATISTICAL METHODS .......................................................................................15 
6.1. .............. Analysis Sets ...............................................................................................................15 
6.2. .............. Data Analysis General Considerations .......................................................................16 
6.2.1. ........... Definitions and Computations ....................................................................................16 
6.2.2. ........... Conventions ................................................................................................................16 
6.2.3. ........... Handling of Missing Data ...........................................................................................17 
6.2.4. ........... Multiplicity Adjustment..............................................................................................17 
6.3. .............. Patient Characteristics ................................................................................................17 
6.3.1. ........... Patient Disposition ......................................................................................................17 
6.3.2. ........... Protocol Deviations ....................................................................................................17 
6.3.3. ........... Demographic and Other Baseline Characteristics ......................................................17 
6.3.4. ........... Disease History ...........................................................................................................18 
6.3.5. ........... Prior Anticancer Systemic Therapies .........................................................................19 
6.3.6. ........... Prior and Concomitant Medications ...........................................................................19 
6.3.7. ........... Medical History ..........................................................................................................19 
6.3.8. ........... Post Treatment Anticancer Therapy ...........................................................................19 


 
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6.4. .............. Efficacy Analysis ........................................................................................................20 
6.4.1. ........... Primary Efficacy Endpoint(s) .....................................................................................20 
6.4.2. ........... Secondary Efficacy Endpoints ....................................................................................20 
6.4.1. ........... Subgroup Analyses .....................................................................................................22 
6.4.2. ........... Exploratory Efficacy Endpoints .................................................................................22 
Phase 1 (dose escalation + dose verification): ...............................................................................22 
6.5. .............. Safety Analyses ..........................................................................................................23 
6.5.1. ........... Extent of Exposure .....................................................................................................23 
6.5.2. ........... Adverse Events ...........................................................................................................24 
6.5.3. ........... Laboratory Values ......................................................................................................25 
6.5.4. ........... Vital Signs ..................................................................................................................26 
6.5.5. ........... Physical Examination .................................................................................................26 
6.5.6. ........... Electrocardiograms (ECG) .........................................................................................26 
6.5.7. ........... Eastern Cooperative Oncology Group (ECOG) Performance Status .........................27 
6.6. .............. Pharmacokinetic Analyses ..........................................................................................27 
6.6.1. ........... Calculation of Pharmacokinetic Parameters ...............................................................27 
6.6.2. ........... Reporting of Pharmacokinetic Concentrations for Descriptive Statistics ..................27 
6.6.3. ........... Reporting of PK Parameters for Descriptive Statistics ...............................................28 
6.6.4. ........... Software ......................................................................................................................29 
6.7. .............. Immunogenicity Analyses ..........................................................................................29 
7. .................. INTERIM ANALYSES ..............................................................................................29 
8. .................. CHANGES IN THE PLANNED ANALYSIS ...........................................................30 
9. .................. REFERENCES ...........................................................................................................32 
APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES ...............33 
APPENDIX 2. MISSING TWO TUMOR ASSESSMENTS .....................................................36 
 
LIST OF TABLES 
Table 1: ...... Censoring Rules for Analysis of PFS per RECIST v1.1 ............................................21 
Table 2: ...... Serum Chemistry and Hematology Laboratory Tests ................................................26 
Table 3: ...... Statistical Analysis Plan Changes ...............................................................................30 
Table 4: ...... scheduled tumor assessments with time window .......................................................36 


 
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LIST OF FIGURES 
Figure 1: ..... Study Schema for Phase 1 (Dose Escalation in Australia) .........................................10 
Figure 2: ..... Study Schema for Phase 1 (Dose Verification in China) ...........................................10 
Figure 3: ..... Study Schema for Phase 1b ........................................................................................11 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADAs 
antidrug antibodies 
AE 
adverse event 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BOR 
best overall response 
CD 
cluster of differentiation 
Cmax 
maximum observed plasma concentration 
CPI 
Checkpoint inhibitor 
CR 
complete response 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EAC 
esophageal adenocarcinoma 
EDC 
electronic data capture (system) 
EOT 
End-of-Treatment (Visit) 
ESCC 
esophageal squamous cell carcinoma 
ES-SCLC 
extensive-stage small cell lung cancer 
G/GEJ 
Gastric or gastroesophageal junction  
HNSCC 
head and neck squamous cell carcinoma 
imAE 
immune-mediated adverse event 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein-ligand 1 


 
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Abbreviation 
Definition 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCLC 
small cell lung cancer 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
tmax 
time to maximum plasma concentration 
vCPS 
visually-estimated Combined Positive Score 
 


 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for study BGB-900-105 (AdvanTIG-105): 
Phase 1/1b study investigating safety, tolerability, pharmacokinetics (PK) and preliminary 
antitumor activity of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination 
with anti-PD-1 monoclonal antibody tislelizumab (BGB-A317) in patients with unresectable 
locally advanced or metastatic solid tumors. The focus of this SAP is for the planned analysis 
specified in the study protocol. The analysis details for Pharmacodynamics, Pharmacogenomics 
and Biomarker are not described within this SAP. Separate analysis plans will be completed if 
needed. 
2. 
STUDY OVERVIEW 
2.1. 
 Study design 
Study BGB-900-105 (AdvanTIG-105) is an open-label and multicenter study to evaluate the 
safety, tolerability, pharmacokinetics and preliminary antitumor activity of anti-TIGIT 
monoclonal antibody ociperlimab (BGB-A1217) in combination with anti-PD-1 monoclonal 
antibody tislelizumab (BGB-A317) with or without chemotherapy in patients with unresectable 
locally advanced or metastatic solid tumors.  
This study includes both Phase 1 and Phase 1b stages. Phase 1 includes two sessions, dose 
escalation in Australia and dose verification in China. Phase 1b is dose expansion on patients 
with specific tumor types. The study designs for Phase 1 and Phase 1b are presented in Error! 
Reference source not found., Figure 2 and Figure 3, respectively. 
For Phase 1 dose escalation in Australia, a modified 3+3 scheme is used for sequential cohorts of 
4 increasing dose levels (50 mg, 150 mg, 450 mg and 900 mg) of ociperlimab, evaluated in 
combination with 200 mg of tislelizumab, to determine the maximum tolerated dose (MTD) or 
maximum administered dose (MAD). Except for the dose escalation DLT period, a 21-day 
treatment cycle is planned for all cycles thereafter. A 28-day DLT observation period will be 
utilized in the first cycle. A flat dose of ociperlimab will be administered intravenously as a 
single agent on Day 1 followed by a dose of 200 mg tislelizumab administered intravenously on 
Day 8. To be DLT evaluable, patients must receive ociperlimab alone on Day 1 of Cycle 1, 
followed by tislelizumab alone on Cycle 1 Day 8 (+ 2 days). If no DLT(s) are observed thereafter 
and through the completion of the initial 28-day cycle, patients would receive tislelizumab and 
ociperlimab sequentially on Day 29 and every 21 days (i.e., once every 3 weeks) thereafter until 
they meet a treatment discontinuation criterion.  
Phase 1 dose verification in China will be conducted to evaluate the dose recommended from 
dose escalation session. Based on safety, tolerability, and PK data of dose escalation in Australia, 
as well as the consideration of any available efficacy and/or exploratory data, the recommended 
Phase 2 dose (RP2D) of ociperlimab in combination with tislelizumab is determined. At this 
RP2D level, ociperlimab as monotherapy or ociperlimab in combination with tislelizumab will 
be administered on Chinese patients once every 3 weeks to verify the safety and tolerability. The 


 
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SMC will define the RP2D for Chinese patients based on the safety data from ociperlimab, 
combined with tislelizumab 200 mg, before Chinese patients join the Phase 1b study.  
For Phase 1b dose expansion, approximately 250 to 500 evaluable patients (having measurable 
disease at baseline and postdose) will be enrolled into 10 different disease cohorts, including:  
x Cohort 1 (n = 20-40): Patients with metastatic squamous non-small cell lung cancer 
(NSCLC) will be treated with ociperlimab plus tislelizumab plus carboplatin plus 
paclitaxel or nab-paclitaxel.  
x Cohort 2 (n = 20-40): Patients with metastatic non-squamous NSCLC will be treated 
with ociperlimab plus tislelizumab plus pemetrexed plus cisplatin or carboplatin.  
x Cohort 3 (n = 20-40): Patients with metastatic NSCLC (PD-L1 positive, [TC] ≥ 1%) 
will be treated with ociperlimab plus tislelizumab. 
x Cohort 4 (n = 20-40): Patients with extensive-stage small cell lung cancer (SCLC) 
will be treated with ociperlimab plus tislelizumab plus etoposide plus cisplatin or 
carboplatin.  
x Cohort 5 (n = 20-40): Checkpoint inhibitor (CPI)-experienced NSCLC patients who 
have received prior therapies including an anti-PD-(L)1 in the most recent line of 
treatment will be treated with ociperlimab plus tislelizumab. 
x Cohort 6 (n = 20-40): Patients with metastatic esophageal squamous cell carcinoma 
(ESCC) will be treated with ociperlimab plus tislelizumab plus cisplatin plus 
5-fluorouracil or paclitaxel.  
x Cohort 7 (n = 20-40): Patients with metastatic esophageal adenocarcinoma (EAC) 
will be treated with ociperlimab plus tislelizumab plus cisplatin plus 5-fluorouracil or 
paclitaxel.  
x Cohort 8 (n = 20-40): Patients with recurrent or metastatic head and neck squamous 
cell carcinoma (HNSCC, PD-L1 positive, [vCPS] ≥ 1%) will be treated with 
ociperlimab plus tislelizumab.  
x Cohort 9 (n = 30-60): Patients with unresectable, locally advanced, recurrent or 
metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma will be 
treated with ociperlimab plus tislelizumab plus oxaliplatin plus capecitabine or 
ociperlimab plus tislelizumab plus cisplatin plus 5-fluorouracil (5-FU).  
x Cohort 10 (n=20-40 per arm, 3 dose arms): Patients with metastatic NSCLC (PD-L1 
positive, [TC] ≥1%) will be treated with ociperlimab plus tislelizumab. 
Study results will be summarized by each study session (dose escalation, dose verification and 
do expansion).  


 
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Figure 1: 
Study Schema for Phase 1 (Dose Escalation in Australia) 
 
Abbreviations: C, Cycle; D, day; DLT, dose-limiting toxicity; MAD, maxima administered dose; MTD, maximal 
tolerated dose; PK, pharmacokinetics; RP2D, recommended Phase 2 dose. 
 
Figure 2: 
Study Schema for Phase 1 (Dose Verification in China) 
 


 
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Abbreviations: DLT, dose-limiting toxicity; mono, monotherapy; pts, patients; RP2D, recommended Phase 2 dose. 
 
Figure 3: 
Study Schema for Phase 1b 
 
 
Abbreviations: 5-FU, 5-fluorouracil; Carbo, carboplatin; Cis, cisplatin; EAC, esophageal adenocarcinoma; ESCC, 
esophageal squamous cell carcinoma; G/GEJ, gastric or gastroesophageal junction; NSCLC, non-small cell lung 


 
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cancer; PD-L1, programmed cell death-1 ligand; Q3W, once every 3 weeks; ES-SCLC, extensive-stage small cell 
lung cancer; SMC, Safety Monitoring Committee. 
Note: For Cohort 9, capecitabine as optional maintenance therapy is for oxaliplatin + capecitabine regimen only. 
2.2. 
Study assessment 
Tumor imaging will be performed ≤ 28 days before the first dose of study drugs. During the 
study, tumor assessment will be performed approximately every 6 weeks (±7 days) from Day1 of 
Cycle 1 for the first 54 weeks, then every 12 weeks (±7 days) thereafter based on RECIST v1.1. 
If a tumor assessment is missed or conducted outside of the specified assessment window, all 
subsequent scans should be conducted according to the planned schedule. A patient who 
discontinues study drugs early for reasons other than progressive disease (PD) (e.g., toxicity) will 
continue to undergo tumor assessments until the patient begins a subsequent anticancer therapy, 
experiences PD, withdraws consent, is lost to follow-up, dies, or until the study terminates, 
whichever occurs first. 
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. Immune-mediated AEs should be reported until 90 
days after the last dose of study drugs, regardless of whether or not 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. 
3. 
STUDY OBJECTIVES 
Two sets of objectives are presented for Phase 1 (dose escalation and dose verification) and 
Phase 1b (dose expansion), respectively. 
3.1. 
Primary Objective 
Phase 1 (dose escalation + dose verification)  
x To assess the safety and tolerability of ociperlimab in combination with tislelizumab 
in patients with advanced solid tumors 
x To determine the maximum tolerated dose (MTD) or maximum administered dose 
(MAD) of ociperlimab in combination with tislelizumab 
x To determine the recommended Phase 2 dose (RP2D) of ociperlimab in combination 
with tislelizumab 
Phase 1b (dose expansion)      
x To assess overall response rate (ORR) determined by investigator per Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for patients in each 
dose-expansion cohort 


 
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3.2. 
Secondary Objective 
Phase 1 (dose escalation + dose verification) 
x To assess the preliminary anticancer activity of ociperlimab in combination with 
tislelizumab 
x To characterize the pharmacokinetics (PK) of ociperlimab in combination with 
tislelizumab 
x To assess host immunogenicity to ociperlimab in combination with tislelizumab 
Phase 1b (dose expansion) 
x To evaluate disease control rate (DCR), duration of response (DOR), and 
progression-free survival (PFS) determined by investigator per RECIST v1.1 for 
patients in each dose-expansion cohort 
x To further characterize the safety and tolerability of ociperlimab in combination with 
tislelizumab with or without chemotherapy 
x To further characterize the PK of ociperlimab in combination with tislelizumab with 
or without chemotherapy  
x To further assess host immunogenicity to ociperlimab in combination with 
tislelizumab with or without chemotherapy 
x To evaluate the association of PD-L1 and TIGIT expression level with clinical 
efficacy  
3.3. 
Exploratory Objective 
Phase 1b (dose expansion) 
x To assess overall survival (OS) for each dose expansion cohort 
4. 
STUDY ENDPOINTS 
Two sets of study endpoints are presented for Phase 1 (dose escalation and dose verification) and 
Phase 1b (dose expansion), respectively. 
4.1. 
Primary Endpoint(s) 
Phase 1 (dose escalation + dose verification) 
x Adverse events (AEs) and serious AEs (SAEs) as characterized by type, frequency, 
severity (as graded by National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] version 5.0), timing, seriousness, and relationship to 
study drugs; physical examinations, electrocardiograms (ECGs), and laboratory 
assessments as needed; and AEs meeting protocol-defined DLT criteria 


 
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x MTD or MAD, as defined as the highest dose at which less than one-third of patients 
experienced a DLT or the highest dose administered, respectively 
x RP2D of ociperlimab in combination with tislelizumab, determined by MTD or 
MAD, as well as long-term tolerability, PK, efficacy, and any other relevant data as 
available 
Phase 1b (dose expansion) 
x ORR, as assessed by the investigator, defined as the proportion of patients with a 
complete response (CR) or partial response (PR) by RECIST v1.1 for each dose 
expansion cohort 
4.2. 
Secondary Endpoints 
Phase 1 (dose escalation + dose verification) 
x ORR, defined as above for dose escalation cohort and dose verification cohort. 
x DOR, as assessed by the investigator, defined as the time from the first objective 
response until the first documentation of disease progression or death, whichever 
occurs first. 
x DCR, as assessed by the investigator, defined as the proportion of patients with best 
overall response (BOR) per RECIST v1.1 of a CP, PR or stable disease (SD).  
x Serum concentrations at specific timepoints and PK parameters (Cmax, Cmin, Tmax, 
AUC0-21d, t1/2, CL, and Vss, as appropriate) for ociperlimab and tislelizumab 
x Immunogenic responses to ociperlimab and tislelizumab, evaluated through the 
detection of antidrug antibodies (ADAs) 
Phase 1b (dose expansion) 
x PFS, as assessed by the investigator, defined as the time from the date of first dose of 
study drug to the date of first documentation of disease progression per RECIST v1.1 
or death, whichever occurs first. 
x DOR by the investigator as defined above for each dose expansion cohort 
x DCR by the investigator as defined above for each dose expansion cohort 
x AEs/SAEs, physical examinations, ECGs and laboratory assessments 
x Serum ociperlimab and tislelizumab concentrations at specific timepoints with or 
without chemotherapy 
x Immunogenic responses to ociperlimab and tislelizumab, evaluated through the 
detection of ADAs with or without chemotherapy 
x PD-L1 and TIGIT expression as the predictive biomarker for efficacy (including but 
not limited to ORR and PFS) 


 
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4.3. 
Exploratory Endpoints 
Phase 1 (dose escalation + dose verification) 
x Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivatives) 
samples obtained before, during and/or after treatment with ociperlimab and their 
association with clinical efficacy.  
Phase 1b (dose expansion) 
x OS defined as time from the first dose of study drugs to the date of death due to any 
cause. 
x Biomarkers from patient-derived tumor tissue(s) and/or blood (or blood derivatives) 
samples obtained before, during and/or after treatment with ociperlimab in 
combination with tislelizumab with or without chemotherapy and their association 
with clinical efficacy.  
5. 
SAMPLE SIZE CONSIDERATIONS 
The study plans to enroll approximately 294 to 564 patients: 
x Phase 1 (dose escalation and dose verification): Approximately 44 to 64 patients 
x Phase 1b (dose expansion): Approximately 250 to 500 patients in 10 prespecified 
tumor type cohorts (20 to 40 patients per cohort for Cohort 1 to 8, 30 to 60 patients 
for Cohort 9, and 20 to 40 patients for each of the 3 arms in Cohort 10) 
For dose escalation in Phase 1, 32 patients should be sufficient to evaluate the safety and 
tolerability of increasing dose levels of ociperlimab in combination with tislelizumab per the 
modified 3+3 design rules. An extra 12 to 32 Chinese patients will receive ociperlimab as 
monotherapy or in combination with tislelizumab as dose verification. Overall, 44 to 64 patients 
will be enrolled in Phase 1.  
6. 
STATISTICAL METHODS 
6.1. 
Analysis Sets 
The Safety Analysis Set includes all patients who received ≥ 1 dose of any study drug. This will 
be the analysis set for baseline characteristics, safety analyses, and efficacy analyses except for 
the response analyses.  
The Efficacy Evaluable Analysis Set includes all treated patients who had measurable disease 
at baseline and ≥ 1 evaluable postbaseline tumor response assessment unless discontinued from 
any component of study treatment due to clinical PD or death within 7 weeks after first dose. 
This will be primary analysis set for efficacy analysis.  
The DLT Evaluable Analysis Set includes patients who received at least 80% each of the 
assigned doses of ociperlimab and tislelizumab according to the treatment schedule, remained on 


 
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study during the DLT observation period and had sufficient safety evaluation or patients who 
experienced a DLT within the DLT observation period. 
The PK Analysis Set includes all patients who received ≥ 1 dose of any component of study 
drugs per the protocol, for whom any corresponding postdose PK data are available. 
The ADA Analysis Set includes all patients who received at least 1 dose of any component of 
study drugs for whom both baseline antidrug antibody result and at least 1 corresponding 
postbaseline antidrug antibody result are available. 
6.2. 
Data Analysis General Considerations 
6.2.1. 
Definitions and Computations 
Study drugs include ociperlimab (BGB-A1217), tislelizumab (BGB-A317) and multiple types of 
chemotherapy including carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed, etoposide, 
5-FU, oxaliplatin and capecitabine.  
Study Day: Study days will be calculated in reference to the date of the first dose of any study 
drug. For assessments conducted on or after the date of the first dose of any study drug, study 
day will be calculated as (assessment date – date of first dose of any study drug + 1).  For 
assessments conducted before the date of the first dose of any study drug, study day is calculated 
as (assessment date – date of first dose of any study drug). There is no study day 0. In the 
situation where the event date is partial or missing, the date will appear partial or missing in the 
listings. Study day and any corresponding durations will be presented based on the imputations 
specified in the Appendix 1. 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the first dose of any study drug.  
All calculations and analyses will be conducted using SAS® version 9.4 or higher (SAS Institute, 
Inc., Cary, North Carolina). 
6.2.2. 
Conventions 
The following conventions will be applied to all analyses: 
x 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
x 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded 
up to 1 significant digit. 
x P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as 
‘> 0.9999’.   
x Duration of imagine-based event endpoints (such as PFS) will be based on the actual 
date the radiograph was obtained rather than the associated visit date. 


 
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x For laboratory results collected as <, <=, >, or >=, a numeric value, 0.0000000001 
will be subtracted or added, respectively, to the value. 
x For by-visit observed data analyses, percentages will be calculated based on the 
number of patients with non-missing data as the denominator, unless otherwise 
specified. 
x For continuous endpoints, summary statistics will include n, mean, standard 
deviation, median, 1st quartile (Q1), 3rd quartile (Q3) and range (minimum and 
maximum). 
x For discrete endpoints, summary statistics will include frequencies and percentages. 
6.2.3. 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events, disease history, 
prior therapy, concomitant medications, and subsequent anticancer therapy.  Specific rules for 
handling of missing or partially missing dates for adverse events and prior/concomitant 
medications/procedures are provided in the Appendix 1. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included.  
6.2.4. 
Multiplicity Adjustment 
Not applicable. 
6.3. 
Patient Characteristics 
6.3.1. 
Patient Disposition 
The number (percentage) of patients treated, discontinued from the study/treatment, reasons for 
discontinued from the study/treatment, and the duration of study follow-up will be summarized 
in Safety Analysis Set. The primary reason for study drug and/or the study being discontinued 
will be summarized according to the categories from eCRF in Safety Analysis Set. 
6.3.2. 
Protocol Deviations 
Important protocol deviation criteria will be established and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be summarized 
for all patients in the Safety Analysis Set. They will also be listed by each category. Deviation 
categories are not mutually exclusive. Multiple deviations within the same category are counted 
once per patients.  
6.3.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the Safety Analysis Set, including but not limited to the following variables: 


 
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x 
Age (continuously and by categories [<65 or >=65 years]) 
x 
Height (cm) 
x 
Weight (kg) 
x 
BMI (kg/m2) 
x 
Sex 
x 
Race 
x 
Ethnicity 
x 
Geographic Region 
x 
ECOG Performance Status 
x 
PD-L1 expression (Only for Phase 1b: Cohort 3, 5, 10: PD-L1 TC <1% vs PD-L1 
TC>=1%; Cohort 8: PD-L1 TAP <1% vs PD-L1 TAP >=1%; Cohort 1,2,4,6,7,9: not 
present) 
x 
TIGIT expression (Only for Phase 1b: Cohort 10) 
6.3.4. 
Disease History 
The number (percentage) of patients reporting a history of disease and characteristics, as 
recorded on the eCRF, will be summarized in the Safety Analysis Set. 
Phase 1 (dose escalation + dose verification): 
The following disease history and baseline disease characteristics will be summarized in Safety 
Analysis Set: 
y 
Type of solid tumor 
y 
Patients with metastatic disease at study entry 
y 
Time from initial diagnosis to first dose date 
y 
Time from diagnosis metastatic disease to first dose date 
A listing of disease history will be provided. 
Phase 1b (dose expansion): 
The following disease history and baseline disease characteristics will be summarized in Safety 
Analysis Set: 
y 
Type of solid tumor 
y 
Patients with metastatic disease at study entry  
y 
Disease stage at study entry 
y 
TNM staging at study entry 
y 
Time from initial diagnosis to first dose date 


 
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y 
Time from diagnosis metastatic disease to first dose date 
y 
Histology 
y 
Histologic grade 
y 
EGFR mutation status 
y 
ALK rearrangement status 
A listing of disease history will be provided. 
6.3.5. 
Prior Anticancer Systemic Therapies 
The number (percentage) of patients with any prior anticancer systemic therapy, number of prior 
lines, time from end of last anticancer drug therapy to first dose date, time from last disease 
progression to first dose date, and treatment setting will be summarized in the Safety Analysis 
Set. 
6.3.6. 
Prior and Concomitant Medications 
Prior medications are defined as medications that stopped before the first dose of study drug. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the patient's last dose. 
Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes GLOBAL B3 September 1, 2018 or higher. They will 
be further classified to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name (PT) in the Safety Analysis 
Set. A listing of prior and concomitant medications will be provided. 
6.3.7. 
Medical History 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 or higher. The number (percentage) of patients reporting a history of any medical 
condition, as recorded on the case report form (CRF), will be summarized by system organ class 
(SOC) and PT in the Safety Analysis Set. A listing of medical history will be provided. 
6.3.8. 
Post Treatment Anticancer Therapy 
Separate flags of start date of new anticancer therapy for efficacy and safety analyses are derived 
individually. 
x 
As for efficacy analysis, start date of new anticancer therapy will be the earliest date of 
prohibited anticancer therapy taken during treatment and date of the post-treatment systemic 
anticancer therapy.  
x 
The start date of new anticancer therapy in defining TEAE for safety is always the first date 
of new systemic anticancer therapy taken after the last study treatment.  


 
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Tumor response per RECIST v1.1 or event-driven endpoints have not been commonly used for 
the efficacy evaluation of traditional Chinese medicine (TCM). ORR, PFS or OS benefit of 
Chinese herbal medicines or Chinese patent medicines has not yet been established. Therefore, 
they will not be taken into account as new anticancer therapy in the efficacy and safety analyses. 
Post treatment anticancer therapy is defined as the anticancer therapy started after the last dose 
date of study treatment. A summary of number and percentage of patients who received 
subsequent systematic anticancer therapy/immunotherapy by cohort will be provided based on 
Safety Analysis Set. 
Time from last dose date to first post-treatment systemic anticancer therapy will be summarized 
descriptively. Patient data listings of post-treatment systemic therapy will be provided. 
6.4. 
Efficacy Analysis 
Efficacy analyses will be provided based on both the Efficacy Evaluable Analysis Set and the 
Safety Analysis Set. The Efficacy Evaluable Analysis Set will be the primary analysis set for 
response analyses; and the Safety Analysis Set will be the primary analysis set for time-to-event 
analyses.  
6.4.1. 
Primary Efficacy Endpoint(s) 
Phase 1 (dose escalation + dose verification): 
No primary efficacy endpoint is planned for phase 1. 
Phase 1b (dose expansion): 
ORR by Investigators 
BOR is defined as the best response recorded from the date of first dose until PD or up to start of 
new anticancer therapy, whichever comes first. If the first tumor assessment occurs after the new 
anticancer therapy, the BOR is considered as NE.   
ORR is defined as the proportion of patients achieving BOR of CR or PR assessed by 
investigators per RECIST v1.1. Patients with no postbaseline response assessment (for any reason) 
will be considered as non-responders.  
The proportion of patients in each response category will be presented. ORR will be summarized 
with a Clopper-Pearson 95% CI constructed to assess the precision of the point estimate.  
6.4.2. 
Secondary Efficacy Endpoints 
Phase 1 (dose escalation + dose verification): 
ORR by Investigators 
ORR by investigator is the secondary efficacy endpoint for Phase 1 and will be analyzed same as 
the ORR by investigator in Phase 1b. 
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DOR is defined as the time from the first objective response until the first documentation of PD 
as assessed by the investigator per RECIST v1.1, or death, whichever occurs first. All the 
censoring rules for PFS will be applied to DOR. DOR will be analyzed in the responders only. The 
distribution of DOR, including median, Q1, Q3, and event-free rates will be estimated using the 
Kaplan-Meier method for each treatment group. The 95% CIs for median, Q1, and Q3 of DOR will 
be estimated using the method of Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). And 
95% CIs for event-free rates will be estimated using Greenwood's formula (Greenwood, 1926).  
DCR by Investigators 
DCR is defined as the proportion of patients with BOR as CR, PR, or SD assessed by 
investigator per RECIST v1.1. DCR assessed by investigators will be analyzed similarly to ORR. 
Phase 1b (dose expansion): 
DOR by Investigators  
DOR by investigator is secondary efficacy endpoint in Phase 1b and will be analyzed similarly to 
DOR by investigator in Phase 1. 
DCR by Investigators 
DCR by investigator is secondary efficacy endpoint in Phase 1b and will be analyzed similarly to 
DCR by investigator in Phase 1. 
PFS by Investigators 
PFS is defined as the time from the date of first dose of study drugs to the date of first 
documentation of disease progression assessed by investigator per RECIST v1.1 or death, 
whichever occurs first. PFS will be analyzed in the Safety Analysis Set. The censoring rules for 
the analysis of PFS are presented in Table 1. 
Kaplan-Meier methodology will be used to estimate median, Q1 and Q3 of PFS, and the 
event-free rates. The 95% CIs for median and other quantiles of PFS will be estimated using the 
method of Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). The 95% CIs for event-
free rates will be estimated using Greenwood's formula (Greenwood, 1926). Kaplan-Meier 
curves will be constructed to provide a visual description of the PFS change with time.  
Table 1: 
Censoring Rules for Analysis of PFS per RECIST v1.1 
Derivation rules 
Outcome 
No progression at the time of data 
cut-off or withdrawal from study 
or lost to follow up 
Date of last adequate radiologic 
assessment * prior to or on date of data 
cut-off or withdrawal from study or lost 
to follow up 
Censored 
New anticancer therapy started 
prior to disease progression or 
death  
Date of last adequate radiological 
assessment before the new anticancer 
therapy 
Censored 
No baseline or postbaseline tumor 
assessments without death within 
13 weeks after first dose  
Date of first dose 
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No baseline or postbaseline tumor 
assessments with death within 13 
weeks after first dose  
Date of death 
Event 
Death or progression after more 
than one missed visit ** 
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
Progression documented between 
scheduled visits 
Date of first radiologic PD assessment 
Event 
Death between adequate 
assessment visits 
Date of death 
Event 
Death before first PD assessment 
Date of death 
Event 
*Adequate tumor assessment is a radiologic assessment of CR, PR, SD or PD as determined by the reviewers.
**More than one missed visit is identified in the Appendix. 
6.4.1. 
Subgroup Analyses 
Subgroup analysis on key efficacy endpoints (ORR, PFS) 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 PD-L1 expression and TIGIT expression. 
6.4.2. 
Exploratory Efficacy Endpoints 
Phase 1 (dose escalation + dose verification): 
No exploratory efficacy endpoint is planned for phase 1. 
Phase 1b (dose expansion): 
Overall Survival 
OS is defined as the time from first dose date to the documented death date for patients who died 
prior to or on the cutoff date. For patients who are alive by the cutoff date, OS will be censored 
at the last known alive date. The last known alive date will be defined as either the data cutoff 
date for patients who are still on treatment, or last available date showing patients alive or cut-off 
date whichever comes first for other alive patients. 
Every effort should be made to ensure complete death dates. In the rare case, if day of death date 
is missing, death date is imputed as the max (last available date showing patients alive + 1, first 
day of month of death date). Death with missing month and/or year will not be imputed for OS 
analysis. The patient with imputed death date will be considered as an event for OS analysis. 
The distribution of OS, including median, Q1, Q3, and event-free rates will be estimated using 
the Kaplan-Meier method for each treatment group. 95% CIs for median, Q1, and Q3 of OS will 
be estimated using the method of Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). 


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The 95% CIs for event-free rates will be estimated using Greenwood's formula (Greenwood, 
1926). Kaplan-Meier survival probabilities over time for each treatment group will be plotted. 
6.5. 
Safety Analyses 
All safety analyses will be performed by each treatment group for dose escalation, dose 
verification and dose expansion in Safety Analysis Set. Safety and tolerability will be assessed, 
where applicable, by incidence, severity, and change from baseline values for all relevant 
parameters including adverse events (AEs), laboratory values (e.g., hematology, clinical 
chemistry), vital signs, and ECG findings, etc.  
6.5.1. 
Extent of Exposure 
The following measures of the extent of exposure will be summarized for ociperlimab and 
tislelizumab: 
x Duration of exposure (days): defined as the duration from the first dose date of study 
drug to the last dose date of the study drug. The duration of exposure will be 
calculated as (last date of exposure - date of first dose+1). 
 If patients in dose escalation phase discontinued treatment with only 1 cycle of 
ociperlimab (with non-missing EOT date), use min (cutoff date, death date, last 
dose date+27) as the ‘last date of exposure’ for ociperlimab. 
 For other patients discontinued treatment (with non-missing EOT date), use min 
(cutoff date, death date, last dose date+20) as the ‘last date of exposure’ for 
tislelizumab and ociperlimab. 
 Otherwise, if patient has treatment ongoing, using cutoff date as the ‘last date of 
exposure’ to calculate duration of exposure. 
x Number of treatment cycles received: defined as the total number of treatment cycles 
in which at least one dose of the study drug is administered. 
x Total dose received per patient (mg): defined as the cumulative dose of the study drug 
during the treatment period of the study. It will be calculated by summing all actual 
doses per administration at all visits prior to or on the cutoff date. 
x Actual dose intensity (ADI) (mg/cycle) of Tislelizumab: defined as the cumulative 
dose (mg) received by a patient divided by (last dose date – first dose date + 21)/21. 
x ADI (mg/cycle) of Ociperlimab in dose escalation phase: defined as the cumulative 
dose (mg) received by a patient divided by (second dose cycle number -1)+ (last dose 
date – second dose date + 21)/21 for patients with at least two cycles of treatment or 
divided by 1 for patients with only one cycle of treatment. 
x ADI (mg/cycle) of Ociperlimab in dose verification and dose expansion phases: 
defined as the cumulative dose (mg) received by a patient divided by (last dose date – 
first dose date + 21)/21. 


 
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x Relative dose intensity (%): defined as the ratio of the actual dose intensity and the 
planned dose intensity. Planned dose intensity is defined as the planned dose on study 
day 1 by a patient divided by the duration of exposure. The planned dose intensity for 
tislelizumab is 200 mg/cycle. The planned dose intensities for ociperlimab are 50 
mg/cycle, 150 mg/cycle, 450 mg/cycle and 900 mg/cycle respectively for each dose 
level in dose escalation phase (Phase 1), 900 mg/cycle for Cohort 1A and Cohort 1B 
in dose verification phase (Phase 1), 900 mg/cycle for dose expansion cohorts (Phase 
1b, Cohort 1 to Cohort 9), and 450 mg/cycle, 900 mg/cycle and 1800 mg/cycle for 
each treatment arm in Cohort 10 of Phase 1b. 
The number of patients with dose modifications which includes dose missed, dose delays and inf
usion interruptions and their reasons will be summarized by counts and percentages according to 
study drug. 
Patient data listings will be provided for all dosing records, and for the above calculated 
summary statistics. 
6.5.2. 
Adverse Events  
AEs will be graded by the investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology 
using MedDRA. Adverse events will be coded to the MedDRA (version 22.0 or higher) lowest 
level term closest to the verbatim term, along with the linked MedDRA preferred term (PT) and 
primary system organ class (SOC). 
6.5.2.1. Treatment-emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the first dose of study drug up to 
30 days following study drug discontinuation or initiation of the first new systemic anticancer 
therapy, whichever occurs first. AE start date should be collected. Any AE with missing start 
date will be considered as TEAE. Only those AEs that were treatment emergent will be included 
in summary tables of TEAE. All AEs (treatment emergent or otherwise) will be presented in 
patient data listings. 
DLT events will be summarized by each treatment group in phase 1 (dose escalation and dose 
verification). 
An AE overview table, including the number and percentage of patients with TEAEs, serious 
treatment-emergent adverse events, TEAEs with Grade 3 or above, TEAEs that led to death, 
TEAEs that led to treatment discontinuation, TEAEs that led to treatment modification, 
treatment-related TEAEs will be provided. Treatment-related AEs include those events 
considered by the investigator to be related to study drug(s) or with a missing assessment of the 
causal relationship.  
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 within an SOC 
and PT, even if the patient experienced more than 1 TEAE within a specific SOC and PT. The 
number (percentage) of patients with serious TEAE, treatment-related TEAEs, serious treatment-


 
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related TEAEs, TEAEs with grade 3 or above, TEAEs that led to death, TEAEs that led to 
treatment discontinuation, and TEAEs that led to treatment modification will be summarized by 
SOC and PT. 
6.5.2.2. Immune-mediated Adverse Event 
Immune-mediated adverse events (imAEs) are of special interest and summarized by category 
within a pre-defined list. The identification of immune-mediated adverse events is described in 
Immune-Mediated Adverse Event Identification Charter. Immune-mediated AEs will be 
identified from all AEs that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 90 days after the last dose of 
study drug, regardless of whether the patient starts a new anticancer therapy. If an imAE occurs 
outside of the above-mentioned TEAE window, it will not be classified as a TEAE.  
An overview table of imAE will be provided. In addition, summaries of imAEs by category and 
PT, grade 3 or higher imAEs, imAEs leading to death, imAEs leading to study drug 
discontinuation will also be presented. Patient data listings of imAEs will also be provided.  
6.5.2.3. Infusion-related Reactions 
For IRRs considered by investigator, an overview table and summary of incidence by SOC and 
PT will be provided.  
6.5.2.4. Deaths 
All deaths and causes of death will be summarized by dose for dose escalation phase, by cohort 
for dose verification phase, by cohort for tumor expansion phase from Cohort 1 to Cohort 9, by 
treatment arm for tumor expansion phase in Cohort 10, including those occurred during the study 
treatment period and those reported during the safety follow up and survival follow-up period 
after treatment completion/discontinuation. A patient listing of death will be provided. 
6.5.3. 
Laboratory Values 
Laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will 
be conducted, of which certain elements will be collected as specified in Table 2. Parameters 
selected from Table 2 will be summarized as appropriate. 
Descriptive statistics (n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables) for laboratory parameters will be summarized 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 .  
Laboratory parameters that are graded in NCI-CTCAE Version 5.0 will be summarized by shifts 
from baseline CTCAE grades to maximum postbaseline grades. In the summary of laboratory 
parameters by CTCAE grade, parameters with CTCAE grading in both high and low directions 
will be summarized separately.  
Hy’s Law for liver injury will also be summarized.  
Box-whisker plots will be generated for parameters of interest.  
Patient data listings will be provided as appropriate. 


 
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Table 2: 
Clinical Laboratory Assessment 
Clinical chemistry 
Hematology 
Coagulation 
Alkaline phosphatase 
Hemoglobin 
Activated partial thromboplastin time 
Alanine aminotransferase 
Platelet counts 
International normalized ratio 
Aspartate aminotransferase 
Neutrophil count  
 
Albumin 
Lymphocyte count 
 
Total bilirubin 
White blood cell count 
 
Blood urea nitrogen  
 
 
Potassium 
 
 
Sodium 
 
 
Calcium 
 
 
Creatinine 
 
 
Glucose 
 
 
Lactate dehydrogenase 
 
 
Lipase 
 
 
Amylase 
 
 
Creatine kinase 
 
 
6.5.4. 
Vital Signs 
The change from baseline might be summarized for all vital sign parameters except for height. 
Vital signs will be listed by patient and visit. Box-whisker plot will be generated for parameters 
of interest, as appropriate. 
6.5.5. 
Physical Examination 
Physical examination will be assessed during screening and study visits. Physical examination 
findings prior to first dose of study treatment will be collected in medical history, clinically 
significant abnormalities found in physical examination will be reported in adverse events. No 
separate physical examination data will be collected and reported in this study. 
6.5.6. 
Electrocardiograms (ECG) 
The number and percentage of patients satisfying the following QTcF conditions at any time 
post-baseline will be summarized: 
x >450, > 480, or > 500 msec  
x >30 or >60 msec maximum increase from baseline 
Patient listing of ECG will be provided for all ECG recordings. 


 
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6.5.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
A shift table from baseline to worst postbaseline in ECOG performance status will be 
summarized. 
6.6. 
Pharmacokinetic Analyses 
The following analysis plan provides the framework for the analyses of the PK data. The 
objective is to summarize available ociperlimab and tislelizumab PK concentrations following an 
IV administration. The PK analyses will include only patients received ociperlimab and/or 
tislelizumab and with enough data to enable estimation of key parameters. Additional PK 
analyses (such as modeling and simulation using nonlinear mixed effects modelling) may be 
conducted if deemed necessary and will be described in a separate analysis plan. 
6.6.1. 
Calculation of Pharmacokinetic Parameters 
Actual dose and blood draw times will be used to calculate the PK parameters. Parameters will 
be listed individually and summarized by treatment group using descriptive statistics.  
The following PK parameters will be calculated as appropriate for the data collected. Other PK 
parameters may be calculated if supported by the data. 
Parameter 
(Units) 
Definition 
Method of Determination 
AUC0-t 
(μg·d/mL) 
Area under the concentration versus 
time curve from time 0 to t hour 
Calculated using the linear up/log down variant 
of the trapezoidal rule 
AUC0-inf 
(μg·d/mL) 
AUC from zero to infinite time with 
extrapolation of the terminal phase 
Calculated using the linear up/log down variant 
of the trapezoidal rule 
Cmax (μg/mL) 
Maximum observed drug concentration 
during a dosing interval 
Reported value 
tmax (h) 
Time to reach Cmax 
Actual elapsed time for observed Cmax. 
t1/2 (days) 
half-life 
ln(2)/λz, where λz is the first-order rate constant 
of drug associated with the terminal portion of 
the curve 
CL (L/d) 
Clearance 
Calculated as Dose/AUCinf 
Vz (L) 
volume of distribution during the 
terminal phase 
Calculated as CL/λz, where λz is the first-order 
rate constant of drug associated with the 
terminal portion of the curve 
6.6.2. 
Reporting of Pharmacokinetic Concentrations for Descriptive Statistics 
The PK analyst will appropriately flag and annotate treatment of any anomalous concentrations, 
exclusions and any special treatment for descriptive statistics and plots. The concentration and 
time data will be listed individually and summarized by treatment group using descriptive 
statistics.  
The following conventions will be used for reporting descriptive statistics for concentration data. 
x PK concentrations should be reported in listings at the same level of precision as that 
in the source data.  


 
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x If a concentration at a given time point is below the assay quantification limit (BLQ), 
the concentration shall be reported as the term “BLQ” with the lower limit of 
quantitation (LLOQ) defined in the footnotes. BLQ values shall be treated as zero for 
computation of descriptive statistics. BLQ values will not be included for calculations 
of geometric mean and geometric coefficient of variation (CV%). 
x If the calculated mean concentration is BLQ, the mean value shall be reported in 
outputs (such as tables) as BLQ and SD and geometric CV% shall be reported as ND 
(not determined). Minimum, median, and maximum may be reported.  
6.6.3. 
Reporting of PK Parameters for Descriptive Statistics  
The PK analyst will appropriately flag and annotate treatment of any anomalous PK parameters, 
exclusions and any special treatment for descriptive statistics. 
x All the PK parameters should have at least the following summary statistics: sample 
size (n), mean, standard deviation (SD), coefficient of variance (CV%), median, 
minimum, maximum, geometric mean, geometric CV%.  
x For in-text tables, Geometric mean (geometric CV%) will be the default method of 
reporting PK parameters. tmax should be presented as median, range (minimum, 
maximum), when presenting the summary statistics.  t1/2 should be presented as 
arithmetic mean, range (minimum, maximum). 
x For any parameters that n ≤ 2, SD should not be presented. 
x The units for all PK parameters will be provided.  
x It is recognized that the number of decimals in reported concentrations, for example: 
“9632.94401 ng/mL” or “9.963294401 ug/mL" are highly improbable and will be 
queried (since bioanalytical assays generally do not have this level of precision). 
Usually the first-in-human dose escalation trial will provide the numerical range of 
PK parameters e.g. AUC range from 10 to 10,000 ng.hr/mL and Cmax range from 1 to 
1000 ng/mL.   
In this scenario, for reporting PK parameters such as AUC and Cmax, the following 
guidance is provided for rounding:  
 If the numerical value is below 100 then one decimal place may be used e.g. 0.1 
or 99.9 
 For values ranging from >100, whole numbers should be used e.g. 100 or 9999.  
 If > 10,000 the clinical pharmacologist may decide on changing units e.g. from 
μg/ml to mg/ml. 
 For reporting times e.g. for tmax or t1/2, if <1 hr use 2 decimals; time up to 24 hr 
should be reported to one decimal place e.g. 23.5 hr, time >24 hr should be 
rounded to nearest whole number e.g. 105 hr.  


 
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6.6.4. 
Software  
For the calculations of PK parameters Phoenix® WinNonlin® Version 8 or higher (Certara, NJ. 
USA) will be used. 
6.7. 
Immunogenicity Analyses 
The scope of anti-drug antibodies (ADA) calculations used for characterizing clinical 
immunogenicity depend on the incidence and kinetics of detected (ADA). Therefore, not all 
parameters described below may be derived. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of subjects who develop detectable ADAs.  The incidence of positive and neutralizing 
ADAs will be reported for ADA-evaluable subjects according to the following definitions: 
x ADA-evaluable subject: Subjects with reportable non-missing baseline result and at least 
one reportable sample taken after drug administration during the treatment or follow-up 
observation period with reportable result (used for computing treatment-induced ADA 
incidence). 
x Treatment-emergent ADA: The sum of both treatment-boosted and treatment-induced 
ADA positive subjects. Synonymous with “ADA Incidence”. 
x Treatment-induced ADA: ADA-evaluable subjects that were ADA-negative at baseline 
and ADA-positive following administration of biologic product. 
x Treatment-boosted ADA: Baseline-positive ADA-evaluable subject with significant 
increases (4-fold or higher) in ADA titer after biologic drug administration. Baseline-
positive ADA-evaluable subject is an ADA-evaluable subject with positive ADA result at 
baseline. 
x Persistent ADA: Treatment-induced ADA detected at two or more sampling time points 
during the treatment (including follow-up period if any), where the first and last ADA 
positive samples (irrespective of any negative samples in between) are separated by a 
period of 16 weeks or longer, or, treatment-induced ADA detected in the last sampling 
time point, or, treatment-induced ADA detected at >=1 sampling point(s) with the last 
ADA-positive sample less than 16 weeks before an ADA-negative last sample. 
x Transient ADA: Treatment-induced ADA that is not considered as persistent ADA.  
x Neutralizing ADA: patients with positive NAb. 
The individual immunogenicity results will also be listed. 
Additional ADA analyses (such as the effect of immunogenicity on PK, efficacy and safety) may 
be conducted if deemed necessary and will be described in a separate analysis plan. 
7. 
INTERIM ANALYSES 
Not applicable. 


 
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8. 
CHANGES IN THE PLANNED ANALYSIS 
Table 3 summarizes the major changes in the planned analyses from the statistical section of the 
study protocol, including the timing, rational and descriptions of the changes. The changes are all 
made before database lock and not based on any comparative data. 
Table 3: 
Statistical Analysis Plan Changes 
SAP 
version 
Approval 
date 
Change 
made 
from 
Rationale of 
the change 
Description of the change 
1.0 
This 
version 
Protocol 
V5.0 
To align with 
BeiGene’s 
current 
standard 
In the protocol, the analysis set for PFS 
and OS analyses is Efficacy Evaluable 
Analysis Set. In this SAP, the analysis set 
for PFS and OS analyses is Safety 
Analysis Set. 
1.0 
This 
version 
Protocol 
V5.0 
To align with 
actual 
enrollment 
practice 
In the protocol, “Approximately 250 to 
500 evaluable patients in 10 prespecified 
cohorts”. In this SAP, “Approximately 
250 to 500 patients in 10 prespecified 
cohorts”. All wordings of “evaluable 
patients” regarding sample size 
considerations from protocol are replaced 
by wordings of “patients” regarding 
sample size considerations in this SAP. 
1.0 
This 
version 
Protocol 
V5.0 
To align with 
actual 
enrollment 
practice and 
BeiGene’s 
current 
standard 
In the section 10.8 (interim analysis) of 
protocol, interim analysis is planned to 
guide the enrollment process. In this 
SAP, interim analysis is not applicable. 
The planned interim analysis in protocol 
has no formal readouts and has little 
effect on the enrollment process in 
practice. 
1.0 
This 
version 
Protocol 
V5.0 
To align with 
BeiGene’s 
current 
standard 
In the protocol, “The Efficacy Evaluable 
Analysis Set includes all patients who 
received ≥ 1 dose of study drugs, have 
evaluable disease at baseline, and ≥ 1 
evaluable postbaseline tumor response 
assessment unless any clinical PD or 
death occurred before the first 
postbaseline tumor assessment.” In this 
SAP, “The Efficacy Evaluable Analysis 


 
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Set includes all treated patients who had 
measurable disease at baseline and 
≥ 1 evaluable postbaseline tumor 
response assessment unless discontinued 
from any treatment due to clinical PD or 
death within 7 weeks after first dose. This 
will be primary analysis set for efficacy 
analysis. ” 
1.0 
This 
version 
Protocol 
V5.0 
To keep an 
identical 
expression 
Revised all “tumor expansion cohort” as 
“dose expansion cohort”, which 
represents cohort 1 to 10 in phase 1b.  
1.0 
This 
version 
Protocol 
V5.0 
To align with 
BeiGene’s 
current 
standard 
In protocol, the PK Analysis Set is 
defined as “all patients who received ≥ 1 
dose of study drug(s) and have ≥ 1 
derivable PK parameter”. In this SAP, 
“The PK Analysis Set includes all 
patients who received ı 1 dose of any 
component of study drugs per the 
protocol, for whom any corresponding 
postdose PK data are available”. 
1.0 
This 
version 
Protocol 
V5.0 
To align with 
BeiGene’s 
current 
standard 
In protocol, the ADA Analysis Set is 
defined as “all patients who received ≥ 1 
dose of study drug(s) and have both 
baseline ADA and ≥ 1 postbaseline ADA 
results”. In this SAP, “The ADA 
Analysis Set includes all patients who 
received at least 1 dose of any component 
of study drugs for whom both baseline 
antidrug antibody result and at least 1 
corresponding postbaseline antidrug 
antibody result are available.” 
 


 
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9. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982; 
38:29-41. 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926; 33:1-26. 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958; 53:457-81. 


 
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APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES 
Please note: all the imputed start date should be prior to/or by last known alive date.  The last 
known alive date only is based on complete dates without imputation.   
1. Impute partial dates for concomitant medication 
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
x 
If both month and day are missing, then set to December 31 
x 
If only day is missing, then set to last day of the month 
x 
If the imputed end date > death date, then set to death date 
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
x 
If both month and day are missing, then set to January 01 
x 
If only day is missing, then set to the first day of the month 
x 
If the imputed start date > min(death date, concomitant medication end date), then set to 
min(death date, concomitant medication end date). 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
2. Impute partial dates for adverse events 
If year of the start date is missing or start date is completely missing, do not impute.  Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
x 
If both month and day are missing, then set to December 31 
x 
If only day is missing, then set to last day of the month 
x 
If the imputed end date > min (death date, end of study date), then set to min (death 
date, end of study date) 
If year of the end date is missing or end date is completely missing, do not impute. 
If start date of an adverse event is partially missing, impute as follows: 
x 
If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x 
If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 


 
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x 
If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date 
x 
If day is missing and month and year ≠ month and year of treatment start date, the set to 
first of the month 
x 
If the imputed AE start date is after AE end date (maybe imputed), then update AE start 
date with AE end date as final imputed AE start date 
x 
If the imputed start date > min (death date, end of study date), then set to min (death 
date, end of study date) 
3.  Impute partial dates related to disease history and prior therapy (Drug, 
surgery/procedure, radiotherapy) 
The following rules will be applied to impute partial dates such as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. If only one 
date is collected, use the start date imputation rules.  
Impute end date first. If end date is partially missing, impute as follows: 
x 
If both month and day are missing, then set to December 31 
x 
If only day is missing, then set to the last day of the month 
x 
If imputed end date > first dose date, then set to first dose date – 1 (except the prior 
systemic therapy for cancer, if imputed end date ≥ first dose date - 14 days, then set to 
first dose date – 15 days) 
If start date is partially missing, impute as follows: 
x 
If both month and day are missing, then set to January 01 
x 
If only day is missing, then set to the first day of the month 
x 
If the imputed start date > end date, then set to the end date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute.  
4. Impute subsequent anti-cancer therapy 
If start date of subsequent anti-cancer therapy is partially missing, impute as follows: 
x 
If both month and day are missing, then set to December 31 
x 
If only day is missing, then set to last day of the month 
x 
If the imputed start date > min (death date, study discontinuation date, data cutoff date, 
start date of the subsequent anti-cancer therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy) 
If stop date of is partially missing, impute as follows:  
x 
If both month and day are missing, then set to December 31  


 
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x 
If only day is missing, then set to last day of the month  
x 
If the imputed stop date > min (death date, study discontinuation date, data cutoff date, 
start date of the next subsequent anti-cancer therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy)  
The (imputed) stop date must be after or equal to the (imputed) start date. If year of the start 
date/stop date is missing, do not impute. 
 


 
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APPENDIX 2. MISSING TWO TUMOR ASSESSMENTS 
Identifying two missing tumor assessments 
(1) Input scheduled TA visit list for the study: 6wk-12wk-18wk-24wk-30wk-36wk-
42wk-48wk-54wk-66wk-78wk-90wk…. TA as every 6 weeks for the first 54 weeks, 
then every 12 weeks thereafter. 
(2) Identify last evaluable TA before PD or death (--LPTADT) and map it to the closest 
scheduled visit (--LPTADT_WK). 
a. In the event of unscheduled TA, choose the closest scheduled visit number (e.g., 
6wk or 30wk) as LPTADT_WK. It can be achieved programmatically by 
following the classification rule (e.g., defining thresholds) depicted in Table 4 
below.   
b. Otherwise, assign the scheduled visit number (assuming it is coded correctly) to 
LPTADT_WK 
(3) Find the 2nd TA visit after LPTADT_WK according to the list in step 1 
(LPTADT_WK_2) 
a. If LPTADT_WK_2+1wk (1 week TA window) < earliest of PD/death date, then 
censor PFS at the LPTADT 
b. Otherwise, PFS event at the earliest of PD/death date 
The Threshold column is defined as the mid-point between current and next visit (except for 
baseline); it is the upper limit for LPTADT to be mapped to the prior scheduled assessment (step 
2a above).  
Table 4: 
scheduled tumor assessments with time window 
Weeks 
Scheduled week - 
1 
Scheduled 
week 
Scheduled week + 
1 
Threshold  
Baseline 
  
Baseline 
  
  
Every 6 weeks for the first 54 
weeks 
  
  
  
Week 5 
Week6 
Week 7 
Week 9 
Week 11 
Week 12 
Week 13 
Week 15 
Week 17 
Week 18 
Week 19 
Week 21 
Week 23 
Week 24 
Week 25 
Week 27 
Week 29 
Week 30 
Week 31 
Week 33 
Week 35 
Week 36 
Week 37 
Week 39 
Week 41 
Week 42 
Week 43 
Week 45 
Week 47 
Week 48 
Week 49 
Week 51 
Week 53 
Week 54 
Week 55 
Week 60 
 Every 12 weeks afterwards 
  
Week 65 
Week 66 
Week 67 
Week 72 
Week 77 
Week 78 
Week 79 
Week 84 
Week 89 
Week 90 
Week 91 
… 
 … 
 … 
 … 
 …