A Phase 2, Multicenter, Open-Label Study of Tislelizumab (BGB-A317) in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma
Phase: PHASE2
Conditions: Classical Hodgkin Lymphoma
Sponsor: BeiGene

BGB-A317-210 
BeiGene 
Protocol Amendment Version 6.0 
23 August 2023 
 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
A Phase 2, Multicenter, Open-Label Study of 
Tislelizumab (BGB-A317) in Patients with Relapsed or 
Refractory Classical Hodgkin Lymphoma 
Protocol Identifier: 
BGB-A317-210 (TIRHOL: Tislelizumab in Patients with 
Relapsed or Refractory Classical Hodgkin Lymphoma) 
Phase: 
2 
Investigational Product: 
Tislelizumab (BGB-A317) 
Indication: 
Classical Hodgkin Lymphoma 
Sponsor for France and Belgium: 
LYSARC (The Lymphoma Academic Research 
Organisation) 
 
Centre Hospitalier Lyon Sud 
 
Bâtiment 2D 
 
69495 Pierre-Bénite Cedex - France 
Sponsor for Sites in all other 
 
Participating Countries: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
 
1840 Gateway Drive, Third Floor 
 
San Mateo, California 94404, USA 
Reference Number: 
EudraCT 2019-002105-22 
BeiGene Medical Monitor: 
 
 
 
LYSA Biology Coordinator: 
 
LYSA Pathology Coordinators: 
 
LYSA Imaging Coordinators: 
 
 
Original Protocol 0.0: 
10 July 2019 
Protocol Amendment 1.0: 
23 October 2019 
Protocol Amendment 2.0: 
26 November 2019 
Protocol Amendment 3.0: 
03 December 2020 
Protocol Amendment 4.0: 
05 August 2021 
Protocol Amendment 5.0: 
27 September 2022 
Protocol Amendment 6.0: 
23 August 2023 
 
 
 
Approved Date
8/23/2023

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Protocol Amendment Version 6.0 
23 August 2023 
 
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Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., its 
subsidiaries, and LYSARC. This document is for use by individuals and their designated representatives 
for their confidential review, consideration, and/or participation in investigational trial(s). This document 
may not be copied or distributed for review by any unauthorized individuals without the prior written 
authorization of BeiGene, Ltd., one of its subsidiaries, or LYSARC. Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without the 
prior written authorization from BeiGene, Ltd., one of its subsidiaries, or LYSARC. 
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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A Phase 2, Multicenter, Open-Label Study of Tislelizumab (BGB-A317) 
in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma 
 
Protocol Identifier: BGB-A317-210 (TIRHOL: Tislelizumab in Patients with Relapsed or 
Refractory Classical Hodgkin Lymphoma) 
 
This protocol is a confidential communication of BeiGene, Ltd., its subsidiaries, and LYSARC. 
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., one of its subsidiaries, 
or LYSARC. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to implementation of 
this sponsor-approved protocol. PRINT your name, title, and the name 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
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Protocol Amendment Version 6.0 
23 August 2023 
 
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AMENDMENT SUMMARY  
This BGB-A317-210 Protocol Amendment 6.0 (23 August 2023) replaces BGB-A317-210 
Protocol Amendment 5.0 (27 September 2022). 
The primary purpose of Amendment 6.0 is to extend the end of the study. The main changes 
made in this amendment are described in the table below. Minor, editorial, and formatting 
changes have also been made but are not included in this summary. 
 
Section Number 
Summary of Change 
Rationale for 
Change 
Potential Impact on 
Safety of Patients or 
Study Conduct 
Sponsor signature page 
Electronic signature adopted 
To align with health 
authority guidance on 
electronic signature 
use 
None 
Synopsis, Section 3.1, and 
Section 7.14  
Extended the end of the study 
to up to approximately 2 years 
after enrollment of the last 
patient 
To follow outcomes 
for patients who 
remain on the study 
treatment  
Change to conduct of 
study 
Synopsis, Section 3.1, and 
Section 7.14 
Included post-trial supply 
program  
To provide additional 
option for patients to 
receive tislelizumab 
at the end of the 
study 
None 
Approved Date
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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................3 
INVESTIGATOR SIGNATURE PAGE .........................................................................................4 
AMENDMENT SUMMARY ..........................................................................................................5 
SYNOPSIS ....................................................................................................................................13 
LIST OF ABBREVIATIONS AND TERMS ................................................................................18 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Hodgkin Lymphoma ...................................................................................................20 
1.2. 
Immune Checkpoint Inhibitors ...................................................................................21 
1.2.1. 
Pembrolizumab ...........................................................................................................21 
1.2.2. 
Nivolumab ..................................................................................................................22 
1.2.3. 
Checkpoint Inhibitors and Immune-Related Adverse Events ....................................22 
1.3. 
Tislelizumab ...............................................................................................................23 
1.3.1. 
Nonclinical Data of Tislelizumab ...............................................................................23 
1.3.2. 
Clinical Pharmacology ................................................................................................24 
1.3.3. 
Prior Clinical Experience With Tislelizumab .............................................................24 
1.3.3.1. 
STUDY BGB-A317_STUDY_001 ............................................................................25 
1.3.3.2. 
STUDY BGB-A317-102 ............................................................................................25 
1.3.3.3. 
STUDY BGB-A317-203 ............................................................................................26 
1.3.3.4. 
IMMUNE-RELATED REACTIONS .........................................................................26 
1.3.4. 
Rationale for Using Tislelizumab in the Treatment of cHL .......................................26 
1.3.5. 
Rationale for Selection of Tislelizumab Dose ............................................................27 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
2.1. 
Study Objectives .........................................................................................................29 
2.1.1. 
Primary Objective .......................................................................................................29 
2.1.2. 
Secondary Objectives .................................................................................................29 
2.1.3. 
Exploratory Objectives ...............................................................................................29 
2.2. 
Study Endpoints ..........................................................................................................30 
2.2.1. 
Primary Endpoint ........................................................................................................30 
2.2.2. 
Secondary Endpoints ..................................................................................................30 
2.2.3. 
Exploratory Endpoints ................................................................................................30 
3. 
STUDY DESIGN .......................................................................................................32 
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3.1. 
Summary of Study Design ..........................................................................................32 
3.2. 
Study Schema .............................................................................................................34 
4. 
STUDY POPULATION .............................................................................................35 
4.1. 
Inclusion Criteria ........................................................................................................35 
4.2. 
Exclusion Criteria .......................................................................................................36 
5. 
STUDY TREATMENT ..............................................................................................39 
5.1. 
Formulation, Packaging, and Handling ......................................................................39 
5.1.1. 
Tislelizumab ...............................................................................................................39 
5.2. 
Dosage, Administration, and Compliance ..................................................................39 
5.2.1. 
Tislelizumab ...............................................................................................................39 
5.3. 
Overdose .....................................................................................................................40 
5.4. 
Dose Interruption, Modification, or Delays ................................................................40 
5.4.1. 
Dose Modification for Tislelizumab ...........................................................................40 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................42 
6.1. 
Prior Therapy ..............................................................................................................42 
6.2. 
Concomitant Therapy .................................................................................................42 
6.2.1. 
Permitted Medications ................................................................................................42 
6.2.2. 
Prohibited Medications ...............................................................................................42 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................43 
7.1. 
Screening ....................................................................................................................43 
7.1.1. 
Informed Consent .......................................................................................................43 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................44 
7.1.3. 
Medical and Cancer History .......................................................................................44 
7.2. 
Enrollment ..................................................................................................................44 
7.2.1. 
Confirmation of Eligibility .........................................................................................44 
7.2.2. 
Patient Numbering ......................................................................................................45 
7.3. 
Study Drug Dispensation ............................................................................................45 
7.4. 
Safety Assessments .....................................................................................................45 
7.4.1. 
Physical Examinations ................................................................................................45 
7.4.2. 
Vital Signs Assessment...............................................................................................46 
7.4.3. 
ECOG Performance Status .........................................................................................46 
7.4.4. 
Pulmonary Function Tests ..........................................................................................46 
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7.4.5. 
Electrocardiogram and Cardiac Function Tests ..........................................................46 
7.4.6. 
Adverse Events ...........................................................................................................46 
7.4.7. 
Concomitant Medications Review ..............................................................................46 
7.5. 
Tumor Assessments ....................................................................................................46 
7.5.1. 
Imaging Studies ..........................................................................................................46 
7.5.1.1. 
PET-CT .......................................................................................................................47 
7.5.1.2. 
CT WITH CONTRAST ..............................................................................................47 
7.5.2. 
Disease Progression With Immune Checkpoint Inhibitors .........................................47 
7.6. 
Laboratory Assessments .............................................................................................48 
7.6.1. 
Hematology .................................................................................................................48 
7.6.2. 
Clinical Chemistry ......................................................................................................48 
7.6.3. 
Hepatitis B and Hepatitis C Testing ...........................................................................48 
7.6.4. 
Thyroid Function Test ................................................................................................50 
7.6.5. 
Liver Function Tests ...................................................................................................50 
7.6.6. 
Pancreatic Enzymes ....................................................................................................50 
7.6.7. 
Pregnancy Test ............................................................................................................50 
7.7. 
Pharmacokinetics ........................................................................................................51 
7.8. 
Antidrug Antibody Evaluation Procedures .................................................................51 
7.9. 
Biomarkers ..................................................................................................................51 
7.9.1. 
Archival Tissue Collection for Central Confirmation of Diagnosis and 
Biomarker Analysis ....................................................................................................52 
7.10. 
Patient-Reported Outcomes ........................................................................................52 
7.11. 
End of Treatment ........................................................................................................53 
7.12. 
Follow-up Period ........................................................................................................53 
7.12.1. 
Safety Follow-up ........................................................................................................53 
7.12.2. 
Efficacy Follow-up .....................................................................................................54 
7.12.3. 
Survival Follow-up .....................................................................................................54 
7.13. 
Discontinuation From Study Treatment or From the Study .......................................54 
7.13.1. 
Patient Discontinuation From Study Treatment .........................................................54 
7.13.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ........................................................................................................................54 
7.14. 
End of Study ...............................................................................................................55 
8. 
SAFETY MONITORING AND REPORTING .........................................................57 
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8.1. 
Risks Associated With Tislelizumab ..........................................................................57 
8.2. 
General Plan to Manage Safety Concerns ..................................................................57 
8.2.1. 
Eligibility Criteria .......................................................................................................57 
8.2.2. 
Safety Monitoring Plan ...............................................................................................57 
8.3. 
Adverse Events ...........................................................................................................58 
8.3.1. 
Definitions and Reporting ...........................................................................................58 
8.3.2. 
Assessment of Severity ...............................................................................................59 
8.3.3. 
Assessment of Causality .............................................................................................59 
8.3.4. 
Following Adverse Events ..........................................................................................60 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................60 
8.4. 
Definition of a Serious Adverse Event .......................................................................61 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................62 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................62 
8.6.1. 
Adverse Event Reporting Period ................................................................................62 
8.6.2. 
Reporting Serious Adverse Events .............................................................................62 
8.6.2.1. 
PROMPT REPORTING OF SERIOUS ADVERSE EVENTS .................................62 
8.6.2.2. 
COMPLETION AND TRANSMISSION OF THE SERIOUS ADVERSE 
EVENT REPORT .......................................................................................................63 
8.6.2.3. 
REGULATORY REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS..................................................................................................63 
8.6.3. 
Eliciting Adverse Events ............................................................................................63 
8.6.4. 
Disease Progression ....................................................................................................63 
8.6.5. 
Deaths .........................................................................................................................64 
8.6.6. 
Pregnancies .................................................................................................................64 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................64 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events ......................................64 
8.7. 
Management of Adverse Events of Special Interest ...................................................65 
8.7.1. 
Infusion-Related Reactions .........................................................................................65 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................66 
8.7.3. 
Immune-Related Adverse Events ...............................................................................67 
8.7.4. 
Recording Diagnosis Versus Signs and Symptoms ....................................................68 
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8.7.5. 
Recording Adverse Events Occurring Secondary to Other Events ............................69 
8.7.6. 
Recording Persistent or Recurring Adverse Events ....................................................69 
8.7.7. 
Recording Poststudy Adverse Events .........................................................................69 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................70 
9.1. 
Primary, Secondary and Exploratory Study Endpoints ..............................................70 
9.1.1. 
Primary Endpoint ........................................................................................................70 
9.1.2. 
Secondary Endpoints ..................................................................................................70 
9.1.3. 
Exploratory Endpoints ................................................................................................70 
9.2. 
Statistical Analysis ......................................................................................................71 
9.2.1. 
Analysis Sets ...............................................................................................................71 
9.2.2. 
Patient Disposition ......................................................................................................71 
9.2.3. 
Demographic and Other Baseline Characteristics ......................................................71 
9.2.4. 
Prior and Concomitant Therapy ..................................................................................71 
9.3. 
Efficacy Analyses .......................................................................................................72 
9.3.1. 
Primary Efficacy Endpoint Analysis ..........................................................................72 
9.3.2. 
Secondary Efficacy Endpoint Analysis ......................................................................72 
9.3.3. 
Exploratory Analyses ..................................................................................................73 
9.4. 
Safety Analysis ...........................................................................................................73 
9.4.1. 
Extent of Exposure .....................................................................................................73 
9.4.2. 
Adverse Events ...........................................................................................................74 
9.4.3. 
Laboratory Analyses ...................................................................................................75 
9.4.4. 
Vital Signs ..................................................................................................................75 
9.5. 
Pharmacokinetics Analysis .........................................................................................75 
9.6. 
Immunogenicity Analysis ...........................................................................................75 
9.7. 
Sample Size Consideration .........................................................................................76 
9.8. 
Interim Analysis ..........................................................................................................76 
10. 
STUDY COMMITTEES AND COMMUNICATIONS ............................................77 
10.1. 
Safety Monitoring Committee ....................................................................................77 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................78 
11.1. 
Access to Information for Monitoring ........................................................................78 
11.2. 
Access to Information for Auditing or Inspections ....................................................78 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................79 
12.1. 
Regulatory Authority Approval ..................................................................................79 
12.2. 
Quality Assurance .......................................................................................................79 
12.3. 
Study Site Inspections.................................................................................................79 
12.4. 
Drug Accountability ...................................................................................................79 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................80 
13.1. 
Ethical Standard ..........................................................................................................80 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................80 
13.2.1. 
Protocol Amendments ................................................................................................80 
13.3. 
Informed Consent .......................................................................................................81 
13.4. 
Patient and Data Confidentiality .................................................................................81 
13.5. 
Financial Disclosure ...................................................................................................82 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................83 
14.1. 
Data Collection and Management Responsibilities ....................................................83 
14.1.1. 
Data Collection ...........................................................................................................83 
14.1.2. 
Data Management/Coding ..........................................................................................83 
14.2. 
Data Integrity and In-House Blinding ........................................................................83 
14.3. 
Study Records Retention ............................................................................................84 
14.4. 
Protocol Deviations ....................................................................................................85 
14.5. 
Publication and Data Sharing Policy ..........................................................................85 
14.6. 
Study and Study Center Closure .................................................................................86 
14.7. 
Information Disclosure and Inventions ......................................................................86 
15. 
REFERENCES ...........................................................................................................88 
16. 
APPENDICES ............................................................................................................92 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................92 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ................................................97 
APPENDIX 3. INTERNATIONAL PROGNOSTIC SCORE ....................................................98 
APPENDIX 4. THE LUGANO CLASSIFICATION .................................................................99 
APPENDIX 5. COMPARISON OF LYRIC CRITERIA AND LUGANO 
CLASSIFICATION ..................................................................................................104 
APPENDIX 6. IMMUNE-RELATED ADVERSE EVENTS EVALUATION AND 
MANAGEMENT .....................................................................................................105 
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APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...................................................................................................................122 
APPENDIX 8. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................123 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................124 
APPENDIX 10. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-LEVELS 
HEALTH QUESTIONNAIRE .................................................................................126 
APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 .................................................................................128 
 
LIST OF TABLES  
Table 1: 
Active Hepatitis B Virus or Hepatitis C Virus Infection (Detected Positive 
by Polymerase Chain Reaction)..................................................................................50 
Table 2: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................62 
Table 3: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................65 
Table 4: 
Immune-Related Adverse Events ...............................................................................68 
Table 5: 
Safety Stopping Criteria .............................................................................................75 
 
LIST OF FIGURES  
Figure 1: 
Lack of Correlation Between Clearance and Body Weight (Study 
BGB-A317_Study_001, Study BGB-A317-102, and Study BGB-A317-203) ..........27 
Figure 2: 
Study Design ...............................................................................................................34 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. and LYSARC 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Phase 2, Multicenter, Open-Label Study of Tislelizumab (BGB-A317) in Patients 
with Relapsed or Refractory Classical Hodgkin Lymphoma 
Protocol Identifier: BGB-A317-210 (TIRHOL: Tislelizumab in Patients with Relapsed or Refractory 
Classical Hodgkin Lymphoma) 
Phase of Development: 2 
Number of Patients: Approximately 42 patients 
Study Centers: Approximately 20 to 25 centers internationally. LYSARC is the sponsor for sites in 
France and Belgium, and BeiGene is the sponsor for sites in all other participating countries. 
Study Objectives: 
Primary: 
• 
To evaluate the efficacy of tislelizumab in patients with relapsed/refractory classical 
Hodgkin lymphoma (cHL), as measured by overall response rate per the Lugano 
Classification (Cheson et al 2014) (Appendix 4) and determined by the investigator  
Secondary: 
• 
To evaluate the efficacy of tislelizumab as measured per the Lugano Classification and 
determined by the investigator for the following: 
− 
Complete response rate 
− 
Duration of response  
− 
Time to response 
• 
To evaluate the safety and tolerability of tislelizumab 
Exploratory: 
• 
To evaluate the efficacy of tislelizumab for the following: 
− 
Progression-free survival (PFS), as measured per the Lugano Classification 
(Cheson et al 2014) (Appendix 4) and determined by the investigator  
− 
Overall survival 
− 
Patient-reported outcomes 
• 
To evaluate clinical outcomes per the Lymphoma Response to Immunomodulatory 
Therapy Criteria (LYRIC) (Cheson et al 2016) (Appendix 5), as determined by the 
investigator, and ancillary exploratory studies by centralized imaging for a subset of 
patients (to be determined at the time of the primary analysis) 
• 
To explore tumor biomarkers of tislelizumab response, resistance, and patient prognosis 
(eg, programmed death ligand-1 [PD-L1], cluster of differentiation 64 [CD64], major 
histocompatibility complex II [MHC II], and other proteins related to disease or treatment 
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mechanism, presence of immune cells in the tumor microenvironment, PD-
L1/programmed death ligand-2 [PD-L2] gene alteration, Epstein-Barr virus [EBV] 
infection status, etc). Gene mutation profiling and/or immune-related gene-expression 
profiling and tumor-infiltrating immune cells that are related to response or clinical benefit 
of tislelizumab may also be evaluated.  
• 
To characterize the pharmacokinetics of tislelizumab 
• 
To determine host immunogenicity to tislelizumab 
Study Design: 
This is a Phase 2, multicenter, open-label study of tislelizumab in patients with relapsed/refractory 
cHL. The primary efficacy endpoint is overall response rate (ORR), defined as the proportion of 
patients who achieve a best response of complete response (CR) or partial response (PR), as 
determined by the investigator per the Lugano Classification. 
Approximately 42 patients with relapsed/refractory cHL will be enrolled into one of two cohorts based 
on prior therapies received: Cohort 1 will include patients who have failed to achieve a response or 
who have had disease progression after autologous hematopoietic stem cell transplantation (HSCT); 
Cohort 2 will include patients who have failed to achieve a response or who have had disease 
progression after at least 1 prior systemic regimen for cHL and are not candidates for autologous or 
allogeneic HSCT. The primary efficacy analysis will be performed for both cohorts combined, and 
subgroup analyses by cohorts will be performed. 
All patients will receive tislelizumab 200 mg intravenously every 3 weeks until disease progression, 
unacceptable toxicity, or study withdrawal for other reasons. The end of the study is expected to occur 
up to approximately 2 years after enrollment of the last patient. Patients who remain on study treatment 
at the end of the study may have an opportunity to receive tislelizumab in a separate rollover or 
extension study or post-trial supply program. A patient in Cohort 2 who achieves a complete remission 
and is otherwise a candidate for autologous HSCT may proceed to autologous HSCT at the discretion 
of the investigator and with approval from the sponsor. The investigator should contact the sponsor to 
discuss autologous HSCT and tislelizumab maintenance therapy post-autologous HSCT. 
Treatment with tislelizumab will be open label. Screening procedures must be performed within 
28 days prior to the first dose of study treatment, unless noted otherwise. Once all screening 
assessments have been completed and study eligibility has been confirmed, study treatment must 
commence within 14 days of confirmation, which is within the 28-day screening window prior to the 
first dose of study treatment. 
Study Assessments: 
At screening, written informed consent, eligibility based on inclusion and exclusion criteria, and 
medical history will be collected. Baseline assessments will include pulmonary function test, hepatitis 
B and C serologies (and DNA levels, if necessary), and echocardiogram or multigated acquisition scan. 
HIV results will be recorded if previously known. Throughout the study, vital signs, physical 
examination, Eastern Cooperative Oncology Group (ECOG) performance status, complete blood count 
with differential, and serum chemistry panel will be monitored. Additional assessments will include 
height and weight, 12-lead electrocardiogram (ECG), erythrocyte sedimentation rate, pregnancy test 
(if applicable), and thyroid function evaluation.  
Tumor assessments will be performed using positron emission tomography-computed tomography 
(PET-CT) at screening, at Week 12 starting from Cycle 1 Day 1, every 12 weeks for 96 weeks, then 
every 24 weeks thereafter until disease progression.  Computed tomography (CT) with contrast will be 
performed at screening and every 24 weeks starting from Cycle 1 Day 1 until disease progression. 
Total body magnetic resonance imaging (MRI) or CT without contrast of the chest plus MRI of the 
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neck, abdomen, and pelvis is allowed if CT with contrast is contraindicated. At time points in which a 
CT scan with contrast is required, PET-CT may be adequate if the CT portion of the PET-CT is of 
diagnostic quality and contrast is administered. 
Patient-reported outcomes (European Quality of Life 5-Dimensions 5-Levels health questionnaire 
[EQ-5D-5L] and European Organisation for Research and Treatment of Cancer Quality of Life cancer 
core questionnaire [EORTC QLQ-C30]) will also be assessed. 
Pharmacokinetics (PK) and immunogenicity analyses will be conducted. For biomarker analyses, 
archival and/or fresh tumor tissue samples will be collected. 
Safety assessments will include a review of adverse events (AEs), serious adverse events (SAEs), 
clinical laboratory tests, physical examinations, pulmonary and cardiac function tests, 
electrocardiograms, ECOG performance status, and vital signs. All AEs and laboratory safety 
measurements will be graded per the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0. 
A Safety Follow-up Visit will be mandatory. All AEs and SAEs, regardless of relationship to study 
drug, will be reported until 90 days after last dose of study treatment. A Safety Monitoring Committee 
will review safety data after at least 20 patients have been on treatment for at least 9 weeks. 
Key Eligibility Summary and Patient Selection:  
Adult patients (≥ 18 years of age at time of informed consent) with a histologically confirmed 
diagnosis of cHL based on the World Health Organization (WHO) 2017 classification of tumors of 
hematopoietic and lymphoid tissue, and the presence of measurable disease, will be eligible for this 
study. Archival tissue (block or approximately 15 unstained slides) or fresh tissue are acceptable to be 
sent together with a pathology report to the central laboratory for retrospective pathology confirmation 
of cHL diagnosis and biomarker analysis. 
Patients must have relapsed cHL (disease progression after PR or CR to the most recent therapy) or 
refractory cHL (failure to achieve PR or CR to most recent therapy). Patients will be allocated to 1 of 2 
cohorts based on the following criteria: 
• 
Cohort 1: Patients who have failed to achieve a response or who have had disease 
progression after autologous HSCT 
• 
Cohort 2: Patients who have received at least 1 prior systemic regimen for cHL and are not 
candidates for autologous or allogeneic HSCT 
Patients meeting either criteria defined above will be enrolled within Cohort 1 or 2. Patients will have 
adequate performance status and organ function and will not have active autoimmune disease and 
active infection with hepatitis B or C, HIV, or known history of human T-cell lymphotropic virus. 
Investigational Product, Dose, and Mode of Administration:  
Tislelizumab (200 mg) will be administered intravenously. A cycle is 3 weeks (21 days) in duration. 
Statistical Methods: 
Analysis Sets: 
The Safety Analysis Set includes all patients who receive at least 1 dose of tislelizumab. 
This will be the primary analysis set for the efficacy and safety analyses. Efficacy and safety analyses 
will be performed for both cohorts combined. 
The PK Analysis Set includes all patients for whom valid tislelizumab PK parameters can be estimated. 
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Primary Efficacy Endpoint Analysis: 
The primary endpoint is ORR assessed by the investigator per the Lugano Classification 
(Cheson et al 2014) (Appendix 4). The ORR is defined as the proportion of patients achieving a best 
response of CR or PR. 
Best overall response is defined as the best response recorded from the first dose of tislelizumab until 
data cut or the start of a new anti-lymphoma therapy. Patients with no post-baseline response 
assessment (due to any reason) will be considered non-responders. ORR and its corresponding 
Clopper-Pearson 95% confidence interval (CI) will be presented. The proportion for each of the 
response categories will also be summarized. 
The primary efficacy analysis for both cohorts combined will be conducted at least 12 weeks after the 
last patient has been dosed, either having undergone the first response assessment or having withdrawn 
prior to the first response assessment. A separate end-of-study analysis will be performed, details of 
which will be provided in the Statistical Analysis Plan (SAP).  
The historical control ORR is assumed to be approximately 45% based on previous clinical trials 
(Moskowitz et al 2013). The null and alternative hypotheses are set as follows: 
H0: ORR = 0.45 for Cohort 1 and Cohort 2 combined 
Ha: ORR > 0.45 for Cohort 1 and Cohort 2 combined 
A binomial exact test will be performed to test the hypothesis. If the 1-sided p-value is less than or 
equal to 0.05 (which is equivalent to observing 25 or more responders out of 42 patients), it will be 
concluded that single agent tislelizumab statistically significantly increases ORR compared to the 
historical control. The superiority of single agent tislelizumab will be demonstrated at 1-sided level 
alpha of 0.05. A 2-sided Clopper-Pearson 95% CI of ORR will be constructed to assess the precision of 
the rate estimate; a 2-sided 90% CI will also be constructed to be consistent with the 1-sided 95% 
confidence bound. 
Secondary Efficacy Endpoint Analyses: 
The CR as determined by the investigator will be summarized and the corresponding Clopper-Pearson 
95% CIs will be calculated. Patients with no post-baseline response assessment (due to any reason) will 
be considered non-responders. 
Duration of response will be analyzed using the Kaplan-Meier method. Time to response will be 
analyzed using descriptive statistics such as mean, median, and standard deviation. Only patients who 
have achieved an overall response will be included in the analysis of duration of response and time to 
response.  
Exploratory Efficacy Analyses: 
The distribution of PFS will be estimated using the Kaplan-Meier method. PFS at selected time points 
will be estimated with its 95% CI using Greenwood’s formula. Details of the censoring rules for PFS 
will be provided in the SAP. 
Overall survival will be censored at the last known date alive. Overall survival will be analyzed 
similarly as for PFS. 
The EORTC QLQ-C30 and EQ-5D-5L and questionnaires will be summarized for each assessment 
time point. The proportion of patients with significant changes from baseline in the questionnaires may 
be summarized as applicable. 
Clinical outcomes by tumor assessment will be summarized using the LYRIC criteria  
(Cheson et al 2016) (Appendix 5). 
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Efficacy variables (eg, ORR and PFS) will be correlated to biomarker expression levels to identify a 
potential biomarker defining a subset that is more sensitive to the programmed cell death-1 (PD-1) 
treatment. 
Correlation between steady-state trough serum concentration of tislelizumab and efficacy or safety 
endpoints may be explored. 
Safety Analyses: 
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v5.0. Laboratory 
values (eg, hematology, clinical chemistry), vital signs, and physical examination will also be used in 
determining safety. Descriptive statistics will be used to analyze all safety data in the Safety Analysis 
Set. 
Safety data will be monitored throughout the study. At approximately 9 weeks after the 20th patient has 
been dosed, data from the first 20 patients in the combined cohorts will be compared against pre-
specified safety stopping criteria. The stopping criteria will be applied for deaths from causes other 
than disease progression (non-PD), treatment-emergent SAEs, and treatment-emergent Grade 3 or 
higher immune-related AEs and are based on cutoffs representing a greater than 85% Bayesian 
posterior probability of exceeding a set event rate threshold where each event rate threshold is based 
approximately in reference to the results of approved anti-PD-1 treatments, including nivolumab 
(Armand et al 2018, Opdivo® US Prescribing Information). As enrollment is being discontinued, safety 
data will be analyzed next at the time of primary efficacy analysis. 
Sample Size Considerations: 
A total of approximately 42 patients will be enrolled. 
Assuming an alternative ORR of 65% compared to the null ORR of 45% in Cohort 1 and Cohort 2 
combined, using a binomial exact test, the power to reject the null hypothesis with 42 patients at a 
1-sided alpha of 0.05 is greater than 80%. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event  
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
cHL 
classical Hodgkin lymphoma 
CD 
cluster of differentiation, such as CD4, CD8, etc. 
CR 
complete response 
CT 
computed tomography 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life 5-Demention 5-Level 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
GCP 
Good Clinical Practice 
GHS/QoL 
Global Health Status/Quality of Life 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDT 
high-dose chemotherapy 
HL 
Hodgkin lymphoma 
HSCT 
hematopoietic stem cell transplantation 
ICH 
International Council for Harmonisation 
IFN 
interferon 
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Abbreviation 
Definition 
IgG 
Immunoglobulin G 
IL 
interleukin 
irAE 
immune-related adverse event 
LYRIC 
Lymphoma Response to Immunomodulatory Therapy Criteria 
LYSA 
The Lymphoma Study Association 
LYSARC 
The Lymphoma Academic Research Organisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed death ligand-1, programmed death receptor ligand-1, 
programmed death-1 ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PRO 
patient-reported outcomes 
QLQ-C30 
European Organisation of Research and Treatment and Quality of Life 
Core 30 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
tislelizumab 
BGB-A317 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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1. 
INTRODUCTION  
1.1. 
Hodgkin Lymphoma  
Hodgkin lymphoma (HL) is a B-cell lymphoid malignancy with an increased incidence in young 
adults between 15 and 30 years of age as well as in patients 55 years and older. The World Health 
Organization (WHO) classifies HL into 2 main types: classical HL (cHL) and nodular lymphocyte-
predominant HL (NLPHL). Classical HL accounts for 95% and NLPHL accounts for 5% of all HL 
(Weber et al 2015).  
The hallmark of cHL is the presence of malignant, multinucleated Reed-Sternberg (RS) cells. 
These cells are of follicular center B-cell origin and constitute < 1% of cells in the affected lymph 
nodes, within a characteristic reactive cellular background of normal lymphocytes, eosinophils, 
and histiocytes (McDermott and Atkins 2013). Despite their B-cell origin, RS cells have a global 
loss of B-cell gene expression. They do not produce immunoglobulin or have functional B-cell 
antigen receptors (Marafioti et al 2000). Various cytokines, chemokines, growth factors and their 
receptors (including but not limited to interleukins [IL1 to IL10], interferon [IFN], tumor necrosis 
factor-alpha [TNF-α], transforming growth factor-beta [TGF-β], granulocyte-colony stimulating 
factor [G-CSF], and granulocyte-monocyte colony stimulating factor [GM-CSF]), play a role in 
creating this microenvironment (Desai et al 2016; Riley 2009). The T-cell infiltrate in cHL is 
composed predominantly of Th2 and regulatory T cells and generally lacks Th1 cells, cluster of 
differentiation 8 (CD8) cytotoxic T cells, and natural killer cells, resulting in an inhibition of 
cytotoxic anti-tumor immune responses (Ohshima et al 2003; Opdivo® US Prescribing 
Information). 
Factors in determining the initial choice of therapy for HL include the histology of the disease 
(cHL or NLPHL), the anatomical stage of disease (limited or advanced disease), the presence of 
poor prognostic features, the presence of constitutional symptoms, and the presence of bulky 
disease. In general, patients with early-stage disease are treated with combined modality strategies 
using an abbreviated course of chemotherapy followed by involved-field radiation, while those 
with advanced-stage disease receive a longer course of chemotherapy.  
Despite a high cure rate with initial therapy, approximately 5% to 10% of HL patients will have 
primary refractory disease, and 10% to 30% of patients will relapse after achieving an initial 
complete response (CR) (Ansell 2012). Treatment for relapsed/refractory disease includes 
high-dose chemotherapy (HDT) with autologous stem cell transplantation (auto-SCT), which has 
been associated with 5-year overall survival rates of 79%, 59%, and 17% for patients in complete 
remission, partial remission, or those with resistant disease at the time of HDT/auto-SCT, 
respectively 
(Stathis and Younes 2015). 
Brentuximab 
vedotin 
is 
a 
CD30-directed 
antibody-monomethyl auristatin E conjugate, which is associated with a CR rate of 34% and an 
overall response rate (ORR) of 75% (Younes et al 2012a). In 2011, brentuximab vedotin was 
approved by the US Food and Drug Administration (FDA), and later in Europe, for the treatment 
of patients with relapsed HL after failure of auto-SCT or patients who are not transplant candidates 
and failed at least 2 prior chemotherapy regimens (Adcetris® US Prescribing Information). Two 
monoclonal antibodies directed against programmed cell death-1 (PD-1), nivolumab and 
pembrolizumab, also have been approved by the US FDA. Nivolumab is a fully human 
immunoglobin G4 (IgG4) monoclonal antibody for the treatment of patients with cHL who had 
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relapse or disease progression after HDT/auto-SCT and post-transplantation brentuximab vedotin. 
Pembrolizumab is a humanized IgG4 kappa monoclonal antibody for the treatment of patients with 
relapsed or refractory cHL (Chen et al 2017). Other therapies that have been examined for the 
treatment of relapsed/refractory HL include panobinostat, a histone deacetylase inhibitor 
(Younes et al 2012b); everolimus, a rapamycin inhibitor (Johnston et al 2010); and lenalidomide, 
an immunomodulatory agent (Fehniger et al 2011). 
1.2. 
Immune Checkpoint Inhibitors  
The immune checkpoint-inhibitory receptor PD-1 is mainly expressed in activated T-cells, 
including CD8+ cytotoxic T-lymphocytes and CD4+ T-helper lymphocytes (Ohshima et al 2002). 
It is believed that PD-1 plays an important role in the immune modulation of tumor progression 
by regulating the key inhibitory signaling in T cells that are engaged by their ligands. The PD-1 
signaling cascade negatively regulates the T-cell receptor, thereby attenuating T-cell proliferation 
and functional activities and leading to T-cell exhaustion. PD-1 expression is markedly up-
regulated in tumor-infiltrating lymphocytes, while the expression of the programmed death ligand-
1 (PD-L1) is significantly increased in tumor cells and tumor-associated immune cells in the 
presence of stimulating cytokines such as IFN-γ (gamma) and IFN-α (alpha) in the tumor 
microenvironment (Sirohi et al 2008). 
1.2.1. 
Pembrolizumab  
Pembrolizumab, a humanized anti-PD-1 IgG4 kappa monoclonal antibody, has been approved by 
the US FDA for the treatment of patients with unresectable or metastatic melanoma; metastatic 
non-small cell lung carcinoma in which tumors express PD-L1 and have progressed on or after 
platinum-containing chemotherapy; recurrent or metastatic head and neck squamous cell 
carcinoma that has progressed on or after platinum-containing chemotherapy; and 
relapsed/refractory cHL (Keytruda® US Prescribing Information).  
In a study of 31 patients with cHL who received pembrolizumab after failing brentuximab vedotin 
(71% of whom had undergone prior auto-SCT), the ORR was 65%, with a CR rate of 16% and a 
partial response (PR) rate of 48%. The majority of responses (70%) lasted > 24 weeks, with a 
median follow-up of 17 months. Progression-free survival (PFS) was 69% at 24 weeks and 46% 
at 52 weeks. For a subset of patients who had undergone auto-SCT (n=22), the ORR was 73%, 
with a CR rate of 14% and a PR rate of 59% (Armand et al 2016). 
In a study of 210 patients with relapsed/refractory cHL, 3 cohorts were analyzed: (1) patients who 
had disease progression after auto-SCT and subsequent brentuximab vedotin; (2) patients who 
were ineligible for auto-SCT due to prior salvage chemotherapy and brentuximab vedotin; and 
(3) patients who had disease progression after auto-SCT but did not receive subsequent 
brentuximab vedotin. After treatment with pembrolizumab, the ORR across all cohorts was 69.0%, 
with a CR rate of 22.4%, PR rate of 46.7%, and stable disease (SD) rate of 14.8%. In patients who 
were ineligible for auto-SCT due to prior salvage chemotherapy and brentuximab vedotin, the 
ORR was 64.2%. Overall survival was 99.5% at 6 months and 97.5% at 9 months. PFS was 72.4% 
at 6 months and 63.4% at 9 months (Chen et al 2017). No difference in ORR or CR rate was 
observed based on which prior therapies patients had received. 
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In a study of 304 patients with relapsed/refractory cHL, patients who had received at least 1 prior 
multi-agent chemotherapy regimen were randomized 1:1 to receive either pembrolizumab or 
brentuximab vedotin. The median PFS was 13.2 months (95% CI, 10.9-19.4) for patients treated 
with pembrolizumab versus 8.3 months (95% CI, 5.7-8.8) for patients treated with brentuximab 
vedotin. Pembrolizumab was found to reduce the risk of disease progression or death by 35% 
(HR=0.65 [95% CI, 0.48-0.88; p=0.0027]).  The ORR was 66% (95% CI, 57-73), with a CR rate 
of 25%, for those treated with pembrolizumab versus ORR 54% (95% CI, 46-62) and CR rate 24% 
for those treated with brentuximab vedotin. The median duration of response (DOR) was 20.7 
months with pembrolizumab and 13.8 months with brentuximab vedotin (Kuruvilla et al 2021). 
1.2.2. 
Nivolumab  
Nivolumab, a fully human anti-PD-1 IgG4 monoclonal antibody, has been approved by the 
US FDA for the treatment of patients with proto-oncogene B-Raf and v-Raf murine sarcoma viral 
oncogene homolog V600 wild-type and mutation-positive unresectable or metastatic melanoma as 
a single agent and in combination with ipilimumab for unresectable metastatic melanoma; 
metastatic non-small cell lung cancer that has progressed on or after platinum-based 
chemotherapy; advanced renal cell carcinoma after prior anti-angiogenic therapy; and cHL that 
has relapsed or progressed after HDT/auto-SCT and post-transplantation brentuximab vedotin. 
In 2 studies of nivolumab monotherapy in patients with cHL whose disease had relapsed or 
progressed after auto-SCT, a total of 258 patients were evaluated, of which 195 patients had 
received prior treatment with brentuximab vedotin. The ORR was 69% (179 patients), with a CR 
rate of 14% (37 patients) and a PR rate of 55% (142 patients). The median time to response was 
2.0 months. (Opdivo® US Prescribing Information).  
1.2.3. 
Checkpoint Inhibitors and Immune-Related Adverse Events  
Immune checkpoint inhibitors have been associated with immune-related toxicities that may 
develop during immunotherapy treatment. As such, clinical practice guidelines that address the 
management of immune-related adverse events (irAEs) in patients treated with immune checkpoint 
inhibitor therapies have recently been published (Brahmer et al 2018). 
The most commonly reported irAEs have been cutaneous, gastrointestinal, and musculoskeletal. 
The incidence of cutaneous irAEs such as rash/inflammatory dermatitis, bulbous dermatoses, and 
severe cutaneous adverse reactions have ranged from 17% to 37%, while gastrointestinal toxicities 
such as diarrhea have been reported in up to 54% and colitis in 8% to 27% of patients. 
Hepatotoxicity has been seen in 2% to 10% of patients treated with nivolumab and pembrolizumab 
monotherapy. Musculoskeletal irAEs such as arthritis, polymyalgia-like syndromes, and myositis 
have been reported in up to 40% of patients (Brahmer et al 2018). 
Lung, endocrine, and hematologic toxicities are less common, with incidences ranging from 
2% to 11%. In a meta-analysis of 20 studies of patients treated with anti-PD-1 therapies, the overall 
incidence of pneumonitis was 2.7% (Nishino et al 2016). Endocrine toxicities, including primary 
hypothyroidism, hyperthyroidism, primary adrenal insufficiency, hypophysitis, and diabetes, have 
been seen in approximately 10% of patients treated with immune checkpoint inhibitors, as reported 
in a meta-analysis of 7,551 patients from 38 randomized trials (Barroso-Sousa et al 2018). 
Hematologic toxicities include autoimmune hemolytic anemia, acquired thrombotic 
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thrombocytopenic purpura, hemolytic uremic syndrome, aplastic anemia, lymphopenia, immune 
thrombocytopenia, and acquired hemophilia. Of these, anemia and thrombocytopenia were most 
frequently reported: anemia 11% (5.4% Grades 3 and 4) and thrombocytopenia 8% (4.3% Grades 
3 and 4). 
Rare toxicities, reported in 2% or fewer patients, include renal, neurologic, cardiovascular, and 
ocular toxicities. Renal toxicities are uncommon in patients treated with immune checkpoint 
inhibitors, with acute kidney insufficiency reported in 1% to 2% of patients treated with nivolumab 
and pembrolizumab. Neurologic toxicities reported in patients treated with immune checkpoint 
inhibitors include myasthenia gravis, Guillain-Barre Syndrome, peripheral neuropathy, autonomic 
neuropathy, aseptic meningitis, encephalitis, and transverse myelitis. Cardiovascular toxicities 
have been rare in patients treated with immune checkpoint inhibitors, reported in < 0.1% of 
patients, but they can be potentially life-threatening. Cardiovascular complications reported in 
these patients include myocarditis, myocardial fibrosis, cardiomyopathy, heart failure, conduction 
abnormalities, cardiac arrest, pericarditis, and pericardial effusions. While ocular toxicities such 
as uveitis/iritis, episcleritis, and blepharitis have been reported, they are uncommon 
(Brahmer et al 2018). 
1.3. 
Tislelizumab  
Tislelizumab (also known as BGB-A317) is a humanized IgG4 variant monoclonal antibody 
directed against PD-1. It is being developed for the treatment of human malignancies. Tislelizumab 
was manufactured under Good Manufacturing Practice quality control systems. The clinical trial 
drug product is formulated in an aqueous buffer with pH 6.5 and isotonic osmolality. The 
suggested administration route is intravenous infusion after the appropriate dilution in 0.9% 
sodium chloride solution. 
1.3.1. 
Nonclinical Data of Tislelizumab  
For details of the nonclinical data for tislelizumab to date, see the current Tislelizumab 
Investigator’s Brochure. 
Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and affinity 
(KD = 0.15 nM), as demonstrated by receptor binding assays based on surface plasmon resonance. 
Tislelizumab competitively blocks the binding of both PD-L1 and programmed death ligand-2 
(PD-L2), inhibiting PD-1-mediated negative signaling in T cells. In in vitro cell-based assays, the 
humanized antibody consistently and dose-dependently enhanced the functional activity of human 
T cells and pre-activated primary peripheral blood mononuclear cells. In addition, tislelizumab 
demonstrated anti-tumor activity in several human cancer allogeneic xenograft models. 
The IgG4 variant antibody has very low binding affinity to effector receptors, including gamma 
Fc receptors (FcγRs) and C1q, by in vitro assays and has low or no antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity effect in humans. Unlike natural IgG4 
antibody, tislelizumab has no observable Fab-Arm exchange activity by the in vitro assay, 
suggesting that the antibody would be stable in vivo and unlikely to form a bispecific antibody. 
Tislelizumab binds to the cynomolgus monkey and human PD-1 with similar affinity but does not 
bind to mouse PD-1 due to the significant sequence divergence from human and monkey PD-1.  
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Overall, no apparent toxicity was noted in mice and monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues and no effect on cytokine release 
was observed in a 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 systemic 
exposure.  
1.3.2. 
Clinical Pharmacology  
An interim pharmacokinetics (PK) analysis (cutoff date 28 August 2017) was conducted by 
noncompartmental methods using serum concentrations from patients who received doses of 0.5, 
2.0, 5.0, or 10 mg/kg once every 2 weeks, or 2.0 mg/kg, 5.0 mg/kg, or 200 mg once every 3 weeks 
(Phase 1a, Parts 1, 2, and 3, and Phase 1b in Study BGB-A317_Study_001) and patients who 
received doses of 200 mg once every 3 weeks (Phase 1 of Study BGB-A317-102). The maximum 
observed serum concentration (Cmax) and area under the serum concentration-time curve (AUC) 
increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both after single-dose 
administration at steady state. Preliminary PK data from 28 patients who were administered 200 
mg once every 3 weeks (Phase 1a, Part 3 and Study BGB-A317-102) showed that tislelizumab 
concentrations after the first 200-mg dose were between the range of concentrations observed after 
2-mg/kg and 5-mg/kg doses. 
A population PK analysis showed that a 3-compartment model with first-order elimination best 
described the PK data. Systemic clearance of tislelizumab was 0.164 L/day; volume of distribution 
at steady state (Vss) was 5.238 L; and terminal half-life (t1/2) was approximately 25.5 days. Race, 
gender, and body weight were not significant covariates on the systemic clearance of tislelizumab, 
which supports fixed dosing across different ethnic groups.  
In a noncompartmental analysis for Study BGB-A317_Study_001 and Study BGB-A317-102, a 
comparison of intensive PK data after a single intravenous (IV) infusion of tislelizumab indicated 
that dose-normalized exposure (AUC0-14day) was consistent between non-Chinese patients (n = 91, 
mostly Caucasian) and Chinese patients (n = 20). This shows that the PK of tislelizumab is 
comparable between Chinese and non-Chinese patients. Additionally, AUC0-14day was also 
consistent across Asian (n = 27, including 20 Chinese and 7 non-Chinese Asian) and Caucasian (n 
= 80) patients. This finding is consistent with the evidence that ethnic differences in PK are not 
expected for therapeutic monoclonal antibodies (Chiba et al 2014, Matsushima et al 2015, 
Zhou et al 2012). 
Similarly, a comparison of trough (predose) and peak (end-of-infusion) concentration data after 
multiple IV infusions of tislelizumab 200 mg administered once every 3 weeks showed that the 
levels were generally similar for Chinese and non-Chinese patients and for different tumor types 
(advanced solid tumors and cHL).  
1.3.3. 
Prior Clinical Experience With Tislelizumab  
As of 01 September 2018, there were 18 ongoing studies with tislelizumab, including 7 with 
available preliminary data. Of the ongoing monotherapy studies, clinical data from 
BGB A317_Study_001, BGB-A317-102, and BGB A317-203 are summarized below.  
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For details of the current, ongoing studies with tislelizumab, see the current Tislelizumab 
Investigator’s Brochure. 
1.3.3.1. 
Study BGB-A317_Study_001  
Study BGB-A317_Study_001 is a 2-stage study: Phase 1a (dose escalation and dose-finding) and 
Phase 1b (efficacy and safety in select tumor types). A total of 451 patients were enrolled. As of 
27 April 2018, 148 (32.8%) patients remained on study; 49 (10.9%) were still receiving 
tislelizumab treatment; and 99 (22.0%) were in follow-up.  
The maximum administered dose was 10 mg/kg administered once every 2 weeks. The maximum 
tolerated dose was not identified. Only 1 dose-limiting toxicity of Grade 3 colitis occurred at the 
5 mg/kg dose administered once every 2 weeks. Based on the results of 103 patients in the dose-
escalation and dose-expansion part of the Phase 1a study, a dose of 5 mg/kg administered once 
every 3 weeks was selected for use in exploring tislelizumab activity in multiple tumor types in 
the Phase 1b study. An additional cohort (Phase 1a, Part 3) was added to evaluate fixed dosing at 
200 mg once every 3 weeks.  
As of 27 April 2018, of the 451 patients enrolled, 255 patients (56.5%) experienced ≥ 1 treatment-
emergent adverse event (TEAE) assessed by the investigator as related to tislelizumab. The most 
commonly occurring TEAEs found to be related to tislelizumab were Fatigue (12.9%), Rash 
(8.4%), Nausea (7.1%), and Diarrhoea (6.9%). A total of 125 patients (27.7%) experienced 
≥ 1 immune-related TEAE; of these, 22 patients (4.9%) had events found to be severe (≥ Grade 
3). There were 33 patients (7.3%) who experienced a TEAE that led to treatment discontinuation. 
Of these, 23 patients (5.1%) experienced events that were assessed as related to tislelizumab. A 
total of 11 patient deaths were reported; 2 (0.4%) were considered related to study drug by the 
investigator. 
As of 27 April 2018, 116 patients and 321 patients were efficacy-evaluable in the Phase 1a and 
Phase 1b studies, respectively. In the Phase 1a study, 21 patients achieved a CR or PR, for an ORR 
of 18.1%. In the Phase 1b study, 39 patients achieved a CR or PR, for an ORR of 12.1%.  
1.3.3.2. 
Study BGB-A317-102  
Study BGB-A317-102 is a 2-phase, nonrandomized, Phase 1/2 study of tislelizumab monotherapy 
in Chinese patients with advanced solid tumors. The Phase 1 portion includes 2 substudies: (1) 
dose verification and (2) PK evaluation of the products derived from 2 manufacturing processes 
and scales. The Phase 2 portion is an indication-expansion study.  
A total of 294 patients were enrolled. As of 11 May 2018, 196 patients (66.7%) experienced ≥ 1 
TEAE assessed by the investigator as related to tislelizumab. The most commonly occurring 
TEAEs found to be related to tislelizumab were Aspartate aminotransferase (AST) increased 
(18.0%), Alanine aminotransferase (ALT) increased (15.3%), Anaemia (12.6%), and Blood 
bilirubin increased (10.2%). A total of 133 patients (45.2%) experienced ≥ 1 immune-related 
TEAE; of these, 14 patients (4.8%) had events found to be severe (≥ Grade 3). There were 
17 patients (5.8%) who experienced a TEAE that led to treatment discontinuation. Of these, 
4 patients (1.4%) had events assessed as related to tislelizumab. Fourteen patients (4.8%) died as 
a result of TEAEs. One patient death was considered possibly related to study drug treatment. 
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As of 11 May 2018, there were 204 efficacy-evaluable patients. Of these, 28 patients achieved a 
CR or PR for an ORR of 13.7%.  
1.3.3.3. 
Study BGB-A317-203  
Study BGB-A317-203 is a single-arm multicenter Phase 2 study of tislelizumab monotherapy in 
Chinese patients with relapsed or refractory cHL. A total of 70 patients were enrolled. As of 
25 May 2018, 67 patients (95.7%) remained on study; 53 (75.7%) were still receiving 
tislelizumab treatment; and 14 (20.0%) were in follow-up.  
As of 25 May 2018, the ORR was 85.7%, with a CR rate of 61.4%, as assessed by independent 
central review. Of the 43 patients with a CR, 38 achieved a CR at the first on-study response 
assessment. The estimated 6-month PFS rate was 80% (Song et al 2018). Overall, 63 patients 
(90.0%) experienced a TEAE and 62 patients (88.6%) experienced a drug-related TEAE. Nine 
patients (12.9%) experienced a severe (≥ Grade 3) drug-related TEAE. Immune-related TEAEs 
were reported in 23 patients (32.9%). Of these, 5 patients had TEAEs of ≥ Grade 3: 2 patients had 
Pneumonitis and 1 patient each had Organizing pneumonia, Nephritis (Focal segmental 
glomerulosclerosis), and Increased creatine phosphokinase. A total of 4 patients (5.7%) 
discontinued treatment due to a TEAE. One patient died due to disease progression 
(Song et al 2018). 
1.3.3.4. 
Immune-Related Reactions  
In patients treated with tislelizumab monotherapy, a number of immune-related adverse events 
(irAEs) have been reported, including hepatitis; pneumonitis; colitis and diarrhea; and 
endocrinopathies such as diabetes mellitus, thyroid disorders, adrenal disorders, and hypophysitis. 
Other reported events include myocarditis, rhabdomyolysis, myositis, autoimmune encephalitis, 
nephritis, pancreatitis, myalgia, arthritis, skin reactions, mucositis, and autoimmune eye disorders. 
Fatal immune-related adverse events have occurred. For additional details of the irAEs seen to 
date in patients treated with tislelizumab monotherapy, see the current Tislelizumab Investigator’s 
Brochure. 
1.3.4. 
Rationale for Using Tislelizumab in the Treatment of cHL  
PD-L1 overexpression in HL cells may indicate a genetically determined vulnerability of 
lymphoma cells to PD-1 blockade (Ansell et al 2015). Furthermore, clinical data from other PD-1 
inhibitors, nivolumab and pembrolizumab, in cHL, coupled with early data of tislelizumab in 
Chinese patients with cHL, support the rationale to further explore tislelizumab in a broader 
population of patients with cHL. 
The rationale for this study is further supported by in vivo tumor growth inhibition studies, which 
demonstrated that tislelizumab has significantly higher anti-tumor activities than nivolumab or 
pembrolizumab in mouse models carrying allogenic human cancer cells and peripheral blood 
mononuclear cells (BeiGene internal data).  
The efficacy of tislelizumab has also been demonstrated in 70 Chinese patients with cHL. In these 
patients treated with tislelizumab monotherapy, the ORR was 85.7%, with a CR rate of 61.4%. 
Tislelizumab was generally well tolerated. The reported ORR and CR rates are higher than those 
observed with other PD-1 inhibitors. Therefore, study of this molecule in a global setting is 
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warranted. In light of these preliminary safety and efficacy results for monotherapy tislelizumab, 
coupled with the finding that patients’ body weight is not a significant covariate in the clearance 
of tislelizumab (Figure 1), a fixed dose of tislelizumab at 200 mg once every 3 weeks will be 
explored in this study. 
Figure 1: 
Lack of Correlation Between Clearance and Body Weight (Study 
BGB-A317_Study_001, Study BGB-A317-102, and Study BGB-A317-203) 
 
Data cutoff 28 August 2017.  
1.3.5. 
Rationale for Selection of Tislelizumab Dose  
The fixed dose of 200 mg was selected based on nonclinical studies and available clinical data, as 
described below. 
In a Phase 1 study of tislelizumab (Study BGB-A317_Study_001), a range of doses was tested (0.5 
mg/kg to 10 mg/kg once every 2 weeks [n=62] and 2 mg/kg to 5 mg/kg once every 3 weeks [n = 
41]) with no maximum tolerated dose defined at the highest dose examined. Rates of treatment-
related adverse events (AEs) and serious adverse events (SAEs) observed in patients who received 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks and once every 3 weeks were comparable, 
suggesting no clear dose dependence across these regimens. Consequently, patients receiving a 
fixed dose of tislelizumab 200 mg once every 3 weeks are expected to have similar AE profiles to 
those treated with 2 mg/kg and 5 mg/kg once every 3 weeks. 
Confirmed ORR ranged from 5% to 14% in patients treated with 2 mg/kg and 5 mg/kg once every 
2 weeks, and from 17% to 37% in patients treated at the same dose levels once every 3 weeks. 
Therefore, clinical activity of tislelizumab is expected to be maintained in patients receiving 200 
mg once every 3 weeks. 
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In a Phase 1a PK study conducted in Australia, serum concentrations of tislelizumab showed linear 
relationships for doses from 0.5 mg/kg once every 2 weeks to 10 mg/kg once every 2 weeks. 
Furthermore, according to the results of a population PK analysis, there was no significant 
correlation between patient weight and the in vivo clearance rate of tislelizumab. This conclusion 
supported the hypothesis of fixed-dose administration. A 200-mg fixed dose (ie, body weight 
adjusted dose between 3 mg/kg and 4 mg/kg) administered once every 3 weeks was expected to 
result in serum exposure between those associated with doses between 2 mg/kg and 5 mg/kg. 
This prediction was corroborated by simulations conducted using population PK analysis and 
preliminary PK data from 28 patients who were administered tislelizumab 200 mg once every 
3 weeks (Study BGB-A317_Study_001, Phase 1a, Part 3 and Study BGB-A317-102). In these 
studies, tislelizumab concentrations after the first 200-mg dose were found to be within the 
concentrations observed after 2 mg/kg and 5 mg/kg doses. Additionally, the PK profile of 
tislelizumab was consistent between Chinese patients and Caucasian patients.  
No unexpected treatment-related AEs occurred in the 200-mg fixed-dose cohort (Study BGB-
A317-Study-001, Phase 1a, Part 3) when compared with body-weight-based cohorts. In study 
BGB-A317-203, patients with cHL treated with a fixed dose of 200 mg once every 3 weeks 
reported high ORR and CR rates and manageable toxicity.  
In summary, 200 mg administered once every 3 weeks was selected as the recommended dose for 
pivotal studies based on the totality of evidence available, including clinical PK, safety, and 
efficacy. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
To evaluate the efficacy of tislelizumab in patients with relapsed/refractory classical Hodgkin 
lymphoma, as measured by the overall response rate per the Lugano Classification 
(Cheson et al 2014) (Appendix 4) and determined by the investigator. 
2.1.2. 
Secondary Objectives  
• To evaluate the efficacy of tislelizumab as measured per the Lugano Classification 
and determined by the investigator for the following: 
− Complete response rate  
− Duration of response 
− Time to response 
• To evaluate the safety and tolerability of tislelizumab 
2.1.3. 
Exploratory Objectives  
• To evaluate the efficacy of tislelizumab for the following: 
− Progression-free survival, as measured per the Lugano Classification 
(Cheson et al 2014) (Appendix 4) and determined by the investigator 
− Overall survival 
− Patient-reported outcomes  
• To evaluate clinical outcomes per the Lymphoma Response to Immunomodulatory 
Therapy Criteria (LYRIC) (Cheson et al 2016) (Appendix 5), as determined by the 
investigator, and ancillary exploratory studies by centralized imaging for a subset of 
patients (to be determined at the time of the primary analysis) 
• To explore tumor biomarkers of tislelizumab response, resistance, and patient 
prognosis (eg, PD-L1, CD64, major histocompatibility complex II [MHC II], and 
other proteins related to disease or treatment mechanism, presence of immune cells in 
the tumor microenvironment, PD-L1/PD-L2 gene alteration, Epstein-Barr virus 
[EBV] infection status, etc). Gene mutation profiling and/or immune-related gene-
expression profiling and tumor-infiltrating immune cells that are related to response 
or clinical benefit of tislelizumab may also be evaluated.  
• To characterize the pharmacokinetics of tislelizumab 
• To determine host immunogenicity to tislelizumab 
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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
The overall response rate, defined as the proportion of patients who achieve a best response of 
complete response or partial response by positron emission tomography-computed tomography 
(PET-CT) per the Lugano Classification (Cheson et al 2014) (Appendix 4) and determined by the 
investigator. 
2.2.2. 
Secondary Endpoints  
• Efficacy endpoints assessed by the investigator using the Lugano Classification: 
− Complete response rate, defined as the proportion of patients who achieve a best 
response of complete response 
− Duration of response, defined as the time from the date that response criteria are 
first met to the date that disease progression is objectively documented or death, 
whichever occurs first 
− Time to response, defined as the time from the date of the first dose of 
tislelizumab to the time the response criteria are first met  
• Safety and tolerability of tislelizumab, as defined by: 
− The incidence and severity of adverse events according to National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 
− Changes in vital signs, physical findings, and clinical laboratory results 
2.2.3. 
Exploratory Endpoints  
• Progression-free survival, as assessed by the investigator using the Lugano 
Classification and defined as the time from the first dose of tislelizumab to the date of 
disease progression or death, whichever occurs first 
• Overall survival, defined as the time from the first dose of tislelizumab to the date of 
death from any cause 
• Patient-reported outcomes (PRO) as measured via the European Organisation of 
Research and Treatment and Quality of Life Core 30 (QLQ-C30) and the European 
Quality of Life 5-Dimensions 5-Levels (EQ-5D-5L). The key end points include 
Global Health Status/Quality of Life (GHS/QoL), physical function and role function 
scales, and symptoms of fatigue, dyspnea, diarrhea, and pain measured by the 
QLQ-C30 
• Clinical outcomes (eg, progression-free survival and duration of response) per the 
LYRIC criteria (Cheson et al 2016) (Appendix 5), as determined by the investigator, 
and ancillary exploratory studies by centralized imaging for a subset of patients (to be 
determined at the time of the primary analysis) 
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• Status of exploratory biomarkers in the study population and their association with 
disease status, response, and/or resistance mechanisms of tislelizumab 
• Pharmacokinetics of tislelizumab: summary of serum concentrations of tislelizumab, 
including but not limited to tislelizumab trough serum concentration (Ctrough) 
• Immunogenicity of tislelizumab: assessment of the incidence of antidrug antibodies 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a Phase 2, multicenter, open-label study of tislelizumab in patients with relapsed/refractory 
cHL. The primary efficacy endpoint is the overall response rate (ORR), defined as the proportion 
of patients who achieve a best response of complete response (CR) or partial response (PR) per 
the Lugano Classification and as determined by the investigator. 
A total of approximately 42 patients with relapsed/refractory cHL will be enrolled into one of two 
cohorts based on prior therapies received: Cohort 1 will include patients who have failed to achieve 
a response or who have had disease progression after autologous hematopoietic stem cell 
transplantation (HSCT); Cohort 2 will include patients who have failed to achieve a response or 
who have had disease progression after at least 1 prior systemic regimen for cHL and are not 
candidates for autologous or allogeneic HSCT. The primary efficacy analysis will be performed 
for both cohorts combined, and subgroup analyses by cohorts will be performed. 
All patients will receive tislelizumab 200 mg intravenously every 3 weeks until disease 
progression, unacceptable toxicity, or study withdrawal for other reasons. The end of the study is 
expected to occur up to approximately 2 years after enrollment of the last patient. Patients who 
remain on study treatment at the end of the study may have an opportunity to receive tislelizumab 
in a separate rollover or extension study or post-trial supply program. 
Treatment with tislelizumab will be open label. Screening procedures must be performed within 
28 days prior to the first dose of study treatment, unless noted otherwise. Once all screening 
assessments have been completed and study eligibility has been confirmed, study treatment must 
commence within 14 days of confirmation, which is within the 28-day screening window prior to 
the first dose of study treatment. Treatment will continue until disease progression, unacceptable 
toxicity, withdrawal of treatment consent, or study termination. Each cycle consists of 21 days. A 
schedule of efficacy and safety assessments is presented in Appendix 1. 
Study Assessments 
At screening, written informed consent and medical history will be collected, and eligibility based 
on inclusion and exclusion criteria will be determined. Baseline assessments will include 
pulmonary function test, hepatitis B and C serologies (and DNA levels, if necessary), and 
echocardiogram or multigated acquisition scan. HIV results will be recorded if previously known. 
Throughout the study, vital signs, physical examination, Eastern Cooperative Oncology Group 
(ECOG) performance status, complete blood count with differential, and serum chemistry panel 
will be monitored. Additional assessments will include height and weight, 12-lead 
electrocardiogram (ECG), erythrocyte sedimentation rate, pregnancy test (if applicable), and 
thyroid function evaluation. 
Tumor assessments will be performed using PET-CT at screening, at Week 12 from Cycle 1 Day 
1, every 12 weeks for 96 weeks, and every 24 weeks (± 14 days) thereafter until disease 
progression. Computed tomography (CT) with contrast will be performed at screening and every 
24 weeks starting from Cycle 1 Day 1 until disease progression. Patient-reported outcomes 
(European Quality of Life 5-Dimensions 5-Levels health questionnaire [EQ-5D-5L] and European 
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Organisation for Research and Treatment of Cancer Quality of Life cancer core questionnaire 
[EORTC QLQ-C30]) will also be assessed. 
All patients should continue study assessments until disease progression is confirmed by the 
investigator, unacceptable toxicity, or withdrawal of consent, whichever comes first, or until the 
end of the study, which is expected to occur up to approximately 2 years after enrollment of the 
last patient. Patients who remain on study treatment at the end of the study may have an opportunity 
to receive tislelizumab in a separate rollover or extension study or post-trial supply program. 
Patients have the right to voluntarily withdraw from the study and the investigator has the right to 
discontinue a patient from study treatment at any time, including for a medical condition that may 
jeopardize the patient’s safety. A patient in Cohort 2 who achieves complete remission and is 
otherwise a candidate for autologous HSCT may proceed to autologous HSCT at the discretion of 
the investigator and with approval from the sponsor, on condition that the reason that the patient 
was ineligible at screening to undergo HSCT is no longer applicable. The investigator should 
contact the sponsor to discuss autologous HSCT and tislelizumab maintenance therapy 
post-autologous HSCT. 
Pharmacokinetic (PK) and immunogenicity analyses will be conducted. For biomarker analyses, 
archival and/or fresh tumor tissue samples will be collected. 
Safety assessments will include a review of adverse events (AEs), serious adverse events (SAEs), 
clinical laboratory tests, physical examinations, pulmonary and cardiac function tests, 
electrocardiograms, ECOG performance status, and vital signs. All AEs and laboratory safety 
measurements will be graded per the NCI-CTCAE v5.0. 
A Safety Follow-up Visit will be mandatory. All AEs and SAEs, regardless of relationship to study 
drug, will be reported until 90 days after the last dose of study treatment. A Safety Monitoring 
Committee will review safety data after at least 20 patients have been on treatment for at least 
9 weeks in order to determine if the proposed dosing schedule of tislelizumab is safe and tolerable. 
The timing of all study procedures is provided in the Schedule of Assessments (Appendix 1). 
Figure 2 depicts the study design. 
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3.2. 
Study Schema  
Figure 2: 
Study Design 
 
Abbreviations: AHSCT: autologous hematopoietic stem cell transplant; C1D1: cycle 1 day 1; cHL: classical Hodgkin 
lymphoma; CT: computed tomography; EOT Visit: End-of-Treatment Visit; IV: intravenous; PD: progressive disease; 
PET-CT: positron emission tomography-computed tomography; Q3W: once every 3 weeks. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for enrollment into Cohort 1 and Cohort 2 are provided in 
Section 4.1 and Section 4.2, respectively. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Patients may be enrolled in the study only if they meet all of the following criteria: 
1. Male or female ≥ 18 years of age at time of informed consent (or acceptable age 
according to local regulations, whichever is older) 
2. Histologically confirmed diagnosis of relapsed or refractory cHL 
3. Relapsed cHL (disease progression after PR or CR to the most recent therapy) or 
refractory cHL (failure to achieve PR or CR to most recent therapy). Patients will be 
allocated to 1 of 2 cohorts based on the following criteria: 
• Cohort 1: Relapsed or refractory to prior autologous HSCT 
− Has failed to achieve a response or has had disease progression after autologous 
HSCT. 
− Is not a candidate for additional autologous or allogeneic HSCT 
• Cohort 2: Relapsed or refractory to salvage chemotherapy, and has not received prior 
autologous or allogeneic HSCT 
− Has received at least 1 prior systemic regimen for cHL 
− Is not a candidate for autologous or allogeneic HSCT 
4. Measurable disease defined as ≥ 1 FDG-avid nodal lesion that is > 1.5 cm in the longest 
diameter, or ≥ 1 FDG-avid extra-nodal lesion (eg, hepatic nodules) that is > 1 cm in the 
longest diameter 
5. Able to provide fresh or archival tumor tissues (formalin-fixed paraffin-embedded 
[FFPE] blocks or approximately 15 freshly cut, unstained FFPE slides) from an evaluable 
core or excisional biopsy with an associated pathological report 
6. ECOG performance status of 0 or 1 
7. Life expectancy ≥ 12 weeks 
8. Adequate organ function, as indicated by the following laboratory values: 
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, independent of growth factor support 
within 7 days of first dose 
• Platelet ≥ 75 x 109/L, independent of transfusion, growth factor, or thrombopoietin 
receptor agonist support within 7 days of first dose 
• Hemoglobin (Hgb) ≥ 8 g/dL or ≥ 5 mmol/L 
• Creatinine clearance > 30 mL/min  
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• AST (SGOT) and ALT (SGPT) ≤ 2.5 x the ULN or ≤ 5 x ULN if liver lymphoma 
involvement is present 
• Serum total bilirubin ≤ 1.5 x ULN (total bilirubin level < 4 x ULN for patients with 
Gilbert syndrome) 
9. No evidence of dyspnea at rest and a pulse oximetry of > 92% while breathing room air 
10. DLCO (adjusted for alveolar volume) > 60% of predicted value; FEV1 and FVC, 
FEV1/ FVC all > 50% predicted value 
11. Female patients of childbearing potential must be willing to use a highly effective method 
of contraception for the duration of the study and for ≥ 120 days after the last dose of 
tislelizumab, and have a negative urine or serum pregnancy test within 7 days before the 
first dose of study drug. Please refer to Appendix 9 for a list of acceptable birth 
control/contraception methods and contraceptive guidelines 
12. Males are eligible to enter and participate in the study if they have been vasectomized or 
if they agree to use barrier contraception with other highly effective methods as described 
in Appendix 9 during the study treatment period and for ≥ 120 days after the last dose of 
tislelizumab 
13. Ability to provide written informed consent and can understand and comply with the 
requirements of the study 
4.2. 
Exclusion Criteria  
Patients will not be enrolled in the study if they meet any of the following criteria: 
14. Nodular lymphocyte-predominant Hodgkin lymphoma or gray zone lymphoma 
15. Prior allogeneic hematopoietic stem cell transplantation 
16. History of severe hypersensitivity reaction to monoclonal antibodies 
17. New York Heart Association (NYHA) class III or IV heart failure, unstable angina, 
severe uncontrolled ventricular arrhythmia, electrocardiographic evidence of acute 
ischemia, or myocardial infarction within 6 months of first day of screening 
18. Prior malignancy within the past 3 years except for curatively treated basal or squamous 
cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or 
other site for which in situ carcinoma has metastatic potential 
19. Prior therapy targeting PD-1, PD-L1, PD-L2, or CTLA-4 pathways 
20. Has received: 
• Systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 
4 weeks prior to Cycle 1 Day 1 
• Recent treatment with another monoclonal antibody within 4 weeks prior to Cycle 1 
Day 1 
• Investigational treatment or device within 4 weeks (or 5 half-lives, whichever is 
shorter) prior to Cycle 1 Day 1 
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• Or has not recovered from AEs (ie, ≤ Grade 1 or baseline level) due to prior therapy. 
(Note: Patients with alopecia or ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study if all other criteria are met) 
21. Active autoimmune disease or history of autoimmune disease that may relapse 
(see Appendix 8) 
• Patients with the following are not excluded and may proceed to further screening: 
Vitiligo, eczema, type I diabetes mellitus, and endocrine deficiencies including 
thyroiditis managed with replacement hormone and/or physiologic corticosteroids 
• Patients with the following should be evaluated for the presence of target organ 
involvement and the potential need for systemic treatment, but should otherwise be 
eligible: Rheumatoid arthritis and/or other arthropathies, Sjögren’s syndrome, or 
psoriasis controlled with topical medication, and patients with positive serology such 
as positive antinuclear antibody or anti-thyroid antibody 
22. Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of the 
first dose of tislelizumab 
Note: Patients with the following are not excluded and may proceed to further screening: 
• Adrenal replacement doses of ≤ 10 mg daily prednisone equivalent in the absence of 
active autoimmune disease 
• Topical, ocular, intra-articular, intranasal, and inhalational corticosteroid (with 
minimal systemic absorption) 
• A brief course of corticosteroid for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) 
23. History of interstitial lung disease or noninfectious pneumonitis or has evidence of 
interstitial lung disease or noninfectious pneumonitis 
24. Serious acute or chronic infection requiring systemic therapy 
25. Known central nervous system (CNS) lymphoma 
26. Underlying medical conditions that, in the investigator’s opinion, will render the 
administration of study drug hazardous or obscure the interpretation of toxicity or AEs 
27. Known history of infection with HIV, human T-cell lymphotropic virus-1, or human 
T-cell lymphotropic virus-2 
28. Serologic status reflecting active hepatitis B or C infection as follows: 
• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible only 
if hepatitis B virus (HBV) DNA is undetectable by an assay with sensitivity 
≤ 20 IU/mL. If so, patients may either undergo regularly scheduled monitoring of 
HBV DNA or less frequent monitoring of HBV DNA while on prophylactic antiviral 
medication as defined by regional standard of care. 
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• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV 
antibody are eligible only if HCV RNA is undetectable. 
29. Autologous hematopoietic stem cell transplantation within 100 days of first dose of 
tislelizumab 
30. CAR-T therapy within 12 months prior to the first dose of study drug 
31. Use of any live vaccine against infectious diseases (eg, influenza, varicella, etc) within 
4 weeks (28 days) of the first dose of tislelizumab, and any intended use within 60 days 
after the last dose of tislelizumab 
32. Major surgery within 4 weeks of the first dose of tislelizumab 
33. Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment 
34. Has hypersensitivity to tislelizumab or any of its excipients 
35. Concurrent participation in another therapeutic clinical trial 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
See the Pharmacy Manual for detailed information regarding product preparation, administration, 
accountability, and disposal. 
5.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use glass 
vial containing a total of 100 mg antibody in 10 mL of isotonic solution. Tislelizumab has been 
aseptically filled in single-use vials with a Flurotec-coated butyl rubber stopper and an aluminum 
cap. Each vial is packaged in a single-carton box.  
The contents of the label will be in accordance with all applicable regulatory requirements. 
Tislelizumab (investigational product) will be dispatched to a study center only after receipt of the 
required documents in accordance with applicable regulatory requirements and the sponsor’s 
procedures. 
Only patients enrolled in the study may receive investigational product, in accordance with all 
applicable regulatory requirements. Only authorized study center personnel may supply or 
administer investigational product. All investigational products must be stored in a secure area 
with access limited to the investigator and authorized study center personnel and under physical 
conditions that are consistent with investigational product-specific requirements. The 
investigational product must be kept at 2°C to 8°C (36°F to 46°F) and protected from light. 
5.2. 
Dosage, Administration, and Compliance  
See the Pharmacy Manual for detailed information regarding product preparation, administration, 
accountability, and disposal. 
5.2.1. 
Tislelizumab  
Patients will receive tislelizumab at 200 mg intravenously once every 3 weeks. One cycle is 
21 days. The minimum amount of time between doses is 10 days. Patients should not receive 
premedication to prevent an infusion reaction before the first infusion of tislelizumab in order to 
determine whether premedication is necessary. If a patient experiences an infusion reaction, he/she 
may receive premedication on subsequent dosing days. The premedication should be chosen per 
institutional standard of care, at the discretion of the treating physician. 
Tislelizumab 200 mg will be administered by intravenous infusion. It is recommended to use a 
volumetric pump through an intravenous line containing a sterile, nonpyrogenic, low-protein 
binding 0.2 or 0.22 micron in-line or add-on filter. A pump may not be required if infusion speed 
can be controlled through alternative means and consistent with approved institutional procedures. 
Specific instructions for product preparation and administration are provided in the Pharmacy 
Manual. 
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As a routine precaution, patients who receive the first and second infusion of tislelizumab must be 
observed for 2 hours after infusion. From Cycle 3 onward, a minimum of a 30-minute monitoring 
period is required in an area with resuscitation equipment and emergency agents. Resuscitation 
equipment and emergency agents need to be available. 
The initial infusion will be delivered over 60 minutes. If the 60-minute infusion is tolerated, each 
subsequent infusion may be administered over 30 minutes, which is the shortest time period 
permissible for infusion. Tislelizumab must not be concurrently administered with any other drug. 
Guidelines for treatment interruption or discontinuation and for the management of irAEs and 
infusion-related reactions are provided in detail in Appendix 6 and Section 8.7.1, respectively.  
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Overdose  
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect administration 
of study drug should be noted in the patient’s chart and on the appropriate electronic case report 
form (eCRF). AEs associated with an overdose or incorrect administration of study drug will be 
recorded on the AE eCRF. Any SAEs associated with an overdose or incorrect administration are 
required to be reported within 24 hours of awareness via the SAE reporting process as described 
in Section 8.6.2. Supportive care measures should be administered as appropriate. 
5.4. 
Dose Interruption, Modification, or Delays  
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. 
5.4.1. 
Dose Modification for Tislelizumab  
There will be no dose reduction of tislelizumab in this study. Dose delays of < 12 weeks will be 
permitted. The investigator should make every effort to maintain dose intensity in patients.  
Patients may temporarily suspend study treatment if they experience a toxicity that is considered 
related to tislelizumab and requires that a dose be withheld. Patients should resume tislelizumab 
treatment as soon as possible after the AE recovers to baseline or Grade 1 severity (whichever is 
more severe), unless the AE is a hematologic toxicity as described below, within 12 weeks after 
the last dose of tislelizumab. If the patient is unable to resume tislelizumab in that timeframe, study 
treatment should be discontinued. 
In case a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the sponsor medical 
monitor. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other event, 
the visit should be scheduled on the nearest feasible date (refer to the visit window in Appendix 1), 
with subsequent dosing rescheduled according to the planned schedule every 3 weeks. 
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Dose administration of tislelizumab will be held in the event of the following hematologic 
toxicity(s) if assessed as related to study drug and not due to underlying lymphoma: 
• Grade 4 anemia 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia associated with bleeding 
• Grade 4 neutropenia 
• Grade 3 febrile neutropenia 
If hematologic toxicity is considered to be immune-related, refer to Appendix 6 for specific 
guidance on management, dose modification and discontinuation criteria. 
In general and if not considered to be immune-related, dosing may resume upon recovery of 
cytopenia(s) to at least Grade 2 or better and within 12 weeks after the last dose of tislelizumab. If 
the patient is unable to resume tislelizumab in that timeframe, study treatment will be discontinued. 
For potential cases of Hy’s Law, defined as ALT or AST >3X ULN and total bilirubin >2X ULN 
in the absence of initial findings of cholestasis or other reason(s) (eg, concomitant disease or 
medication, liver involvement of disease, etc) for concurrent increased AST or ALT and total 
bilirubin, discontinue study treatment. Obtain hepatology consultation and manage per local 
institutional guidance. 
Dose administration of tislelizumab will be held temporarily until resolution or improvement in 
the event of the following immune-related toxicity(s) if assessed as related to study drug and not 
due to underlying lymphoma: 
• Grade 2 hepatitis 
• Grade 2 to 3 skin reaction(s), dermatitis  
Dose administration of tislelizumab will be permanently discontinued in the event of the following 
immune-related toxicity(s) if assessed as related to study drug and not due to underlying 
lymphoma: 
• Grade 3 to 4 hepatitis 
• Grade 4 skin reaction(s), dermatitis 
• Stevens-Johnson syndrome or toxic epidermal necrolysis 
• Guillain-Barré syndrome 
Management guidelines for irAEs and infusion-related reactions in patients treated with 
tislelizumab are described in Appendix 6 and Section 8.7.1, respectively. 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
Permitted and excluded prior therapies are outlined in the inclusion and exclusion criteria 
(Section 4.1 and Section 4.2). 
6.2. 
Concomitant Therapy  
6.2.1. 
Permitted Medications  
In general, concomitant medications and therapies deemed necessary for supportive care 
(eg, antiemetics, antidiarrheals) and safety of the patient are allowed. All treatments that the 
investigator considers necessary for a patient’s welfare may be administered at the discretion of 
the investigator in keeping with the community standards of medical care. All concomitant 
medications will be recorded on the eCRF, including all prescription and over-the-counter 
medications, and intravenous medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date will also be included on the eCRF. All 
concomitant medications received within 28 days before the first dose of study medication and 90 
days after the last dose of study medication should be recorded. 
Systemic corticosteroids may be used for the control of irAEs as detailed in the most current 
American Society of Clinical Oncology (ASCO) Practice Guideline for the management of irAEs 
in patients treated with immune checkpoint inhibitor therapy (Brahmer et al 2018).  
Patients may continue to receive hormone replacement if initiated prior to enrollment.  
Transfusions and growth factors can be administered to mitigate immune related neutropenia and 
thrombocytopenia while on study treatment. 
6.2.2. 
Prohibited Medications  
The following medications are prohibited during screening and treatment periods: 
• Immunosuppressive agents (except to treat a drug-related AE) 
• Systemic corticosteroid > 10 mg daily prednisone equivalent (except to treat a drug-
related AE) or requirement of prolonged corticosteroid treatment (ie, >12 weeks) for 
the treatment of a drug-related AE, including an irAE. Patients who require prolonged 
corticosteroid treatment of >12 weeks for a drug-related AE must permanently 
discontinue from study therapy.   
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive radiation therapy, standard or investigational agents for 
treatment of cancer) 
• Live vaccines within 28 days prior to the first dose of study drug and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, 
bacille Calmette-Guerin (BCG), and typhoid vaccine. Inactivated influenza vaccine is 
allowed. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES  
Study enrollment and procedures are summarized in the following subsections. The timing of all 
study procedures is provided in the Schedule of Assessments (Appendix 1). 
Visit Windows 
A study visit may be scheduled on any day within a specified study week. For any given day within 
the study week, the visit window is ± 7 days (ie, 7 days before or after the given day) unless 
otherwise stated in the Schedule of Assessments. The minimum amount of time between doses is 
10 days. Study drug supplies must be taken into account when scheduling visits during windows. 
Procedures for a given visit may be split across the window to allow for drug resupply and 
completion of study procedures.  
All assessments will be performed on the day of the specified visit unless an acceptable time 
window is specified. Assessments scheduled on the day of study treatment administration (Day 1) 
of each cycle should be performed prior to study treatment infusion unless otherwise noted. 
Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other event, 
the visit should be scheduled on the nearest feasible date (see Appendix 1), with subsequent visits 
conducted according to the planned schedule of every 3 weeks. 
7.1. 
Screening  
7.1.1. 
Informed Consent  
Study site personnel must explain to potential study participants all aspects of the study, including 
all scheduled visits and activities. A copy of the informed consent form will be given to the patient 
to read, and the patient must have adequate time to understand the content and ask questions. 
Study site personnel must obtain signed informed consent before any study-specific procedures 
are conducted unless the procedures are part of routine standard of care, and the informed consent 
process must be documented in the patient’s clinical record. Informed consent may be obtained 
before the 28-day screening period. Consent must be obtained using the most current version of 
the form approved by the Independent Ethics Committee. 
All screening procedures must be performed within 28 days prior to the first dose of study drug, 
unless noted otherwise; assessments not completed within this interval must be repeated. Once all 
screening assessments have been completed and study eligibility has been confirmed, study 
treatment must commence within 14 days of confirmation, which is within the 28-day screening 
window prior to the first dose of study treatment. Results of standard-of-care tests or examinations 
for echocardiogram/multigated acquisition scan performed prior to obtaining informed consent 
and ≤ 90 days prior to enrollment may be used for the purposes of screening rather than repeating 
the standard-of-care tests, subject to review and agreement by the medical monitor or designee. 
Repeating screening procedures or tests is allowed if the patient did not previously meet the 
inclusion and exclusion criteria or if needed to have a documented result within the protocol-
specified screening window.  
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For patients who provide informed consent and subsequently do not meet eligibility criteria or 
withdraw consent before enrollment, study site personnel should document the screen failure in 
the patient’s source documents. The documentation should include demographics and medical 
history, the reason for screen failure, the eligibility criteria reviewed, procedures performed, etc.  
7.1.2. 
Females of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer to 
Appendix 9 for contraception guidelines and definitions of “women of childbearing potential” and 
“no childbearing potential.” 
7.1.3. 
Medical and Cancer History  
All medical and cancer history will be reviewed after informed consent has been obtained, 
including the presence or absence of disease-related constitutional symptoms. Clinically 
significant medical history (ie, previous diagnoses, diseases, or surgeries) that does not pertain to 
the study indication but started before signing the informed consent and considered relevant to the 
patient’s study eligibility will be collected and captured in the eCRF. “Clinically significant” is 
defined as any event, diagnosis, or laboratory value requiring treatment or follow-up or the 
presence of signs or symptoms that require medical intervention. Concurrent medical signs and 
symptoms must be documented to establish baseline severities. 
Other background information to be collected include history of cHL (including the date of initial 
diagnosis and current disease status), staging, sites of disease, International Prognostic Score 
(Appendix 3), and presence or absence of disease-related constitutional symptoms. Prior 
medications/significant nondrug therapies will also be collected. 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 (ICH) guidance (ICH E5 1998, ICH E17 
2017) adopted by the European Medicines Agency (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 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. 
Nonserious AEs will be recorded during the screening period as medical history. 
7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient. All screening procedure 
results, and relevant medical history must be available before eligibility can be determined. All 
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inclusion criteria must be met and none of the exclusion criteria may apply. No eligibility waivers 
will be granted. 
In France, for any patient enrolling to Cohort 1 who has not received prior brentuximab vedotin 
and chemotherapy regimen, the investigator must document rationale for tislelizumab 
administration in the medical record. This is required by the French Health Authority, Agence 
nationale de sécurité du médicament et des produits de santé (ANSM). 
For sites in countries where BeiGene is the sponsor, after a patient is screened and the investigator 
determines that the patient is eligible for enrollment, study site personnel will complete an 
Eligibility Authorization Packet and send it, via secure transmission, to the medical monitor or 
designee to agree with the enrollment in writing. Study site personnel should ensure that the final 
Eligibility Authorization Packet is in the patient’s file before proceeding with study procedures. 
For all sites, either unstained tissue (block or unstained slides) or stained slides, together with 
pathology report, should be sent to a central pathology laboratory for confirmation of tissue 
diagnosis. If unstained tissue (block or unstained slides) or stained slides are not available, 
collection of a fresh tumor biopsy at screening is mandatory. Central pathology confirmation is 
not required prior to enrollment. If an archival tissue sample is available, it should be collected for 
central pathology and other biomarker analysis. Refer to Section 7.9 for details. 
7.2.2. 
Patient Numbering  
Patients will be identified by a patient number. Each patient enrolled in this study will receive a 
unique patient number that will be assigned when the patient is screened or enrolled in the study. 
Patient numbers will be assigned by the EDC tool in chronological order starting with the lowest 
number. Once a patient number has been assigned to a patient, it cannot be reassigned to any other 
patient. 
7.3. 
Study Drug Dispensation  
Tislelizumab will be dispensed and administered as described in Section 5.2. 
7.4. 
Safety Assessments  
Safety assessments should be performed by the investigator at all visits throughout the study. 
Safety assessments include monitoring of all AEs and SAEs, regular monitoring of blood tests, 
vital signs, weight, and performance status, and regular physical examinations. For the schedule 
of study visits, see the Schedule of Assessments (Appendix 1). 
7.4.1. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of (1) head, eyes, ears, nose, throat, (2) cardiovascular, (3) dermatological, 
(4) musculoskeletal, (5) respiratory, (6) gastrointestinal, and (7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. Height (baseline only) and weight 
will be measured and recorded in the eCRF. 
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At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. Changes from baseline will be recorded. New or worsened 
clinically significant abnormalities are to be recorded as AEs on the eCRF. See Section 8.3 
regarding AE definitions and reporting and follow-up requirements. 
7.4.2. 
Vital Signs Assessment  
Vital signs will include measurements of body temperature (˚C), heart rate, and blood pressure 
(systolic and diastolic) while the patient is in a seated position after resting for 10 minutes. 
7.4.3. 
ECOG Performance Status  
Eastern Cooperative Oncology Group (ECOG) performance status (Appendix 7) will be assessed 
during the study. 
7.4.4. 
Pulmonary Function Tests  
Pulmonary function tests include spirometry and lung diffusion capacity. Screening evaluations 
must be performed within 28 days prior to first dose of tislelizumab. Pulmonary function tests can 
also be performed when clinically indicated at the discretion of the investigator during the study. 
7.4.5. 
Electrocardiogram and Cardiac Function Tests  
ECG assessments are to be performed with the patient in a semi-recumbent or supine position and 
rested for at least 5 minutes. 
Cardiac function is assessed by either echocardiography or multigated acquisition scan. Screening 
evaluations may be performed within 90 days prior to enrollment, subject to review and agreement 
by the medical monitor or designee. ECG can also be performed when clinically indicated at the 
discretion of the investigator during the study. 
7.4.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, outcome, and time to onset. All AEs, 
including SAEs, will be collected as described in Section 8. 
7.4.7. 
Concomitant Medications Review  
Any new medications, changes in ongoing medications or procedures, and medications 
discontinued within 28 days before the first visit in Cycle 1 and since the prior study visit, 
thereafter, will be recorded. 
7.5. 
Tumor Assessments  
7.5.1. 
Imaging Studies  
Response assessments will be by PET-CT and CT with contrast and categorized as per the Lugano 
Classification (Appendix 4). Total body magnetic resonance imaging (MRI) is allowed if CT with 
contrast is contraindicated. At time points in which a CT scan with contrast is required, PET-CT 
may be adequate if the CT portion of the PET-CT is of diagnostic quality and contrast is 
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administered. Because PET-CT is considered to be the standard imaging modality for response 
assessment in HL as per the Lugano guidelines (Cheson et al 2014), when both PET-CT and CT 
are performed but results are discordant, overall response will generally be defined by PET-CT. 
Clinical suspicion of disease progression at any time will require a physical examination and 
radiological confirmation to be performed promptly, rather than waiting for the next scheduled 
tumor assessment. In case of an unscheduled or delayed tumor assessment for any reason, 
subsequent tumor assessments must be performed per the originally planned schedule. 
Imaging data may be uploaded to a central database for future review. 
7.5.1.1. 
PET-CT  
As per the Lugano guidelines (Cheson et al 2014), PET-CT is considered the standard imaging 
modality for response assessment in HL. Tumor assessment by PET-CT will be performed at 
screening, at Week 12 from Cycle 1 Day 1, every 12 weeks for 96 weeks, and then every 24 weeks 
thereafter until disease progression (Appendix 1). 
A banking of the PET-CT scans is mandatory and will be organized for this study. For each patient 
when applicable, PET-CT will be uploaded to the imaging platform. 
7.5.1.2. 
CT With Contrast  
Tumor assessment by CT with contrast of neck, chest, abdomen, and pelvis will be performed at 
screening and every 24 weeks starting from Cycle 1 Day 1 until disease progression. Total body 
MRI or CT without contrast of the chest plus MRI of the neck, abdomen, and pelvis is allowed if 
CT with contrast is contraindicated. At time points in which a CT scan with contrast is required, 
PET-CT may be adequate if the CT portion of the PET-CT is of diagnostic quality and contrast is 
administered. 
Thickness of CT scan slice should not exceed 8 mm cuts using a contiguous reconstruction 
algorithm. 
Banking of the CT scans is mandatory and will be organized for this study. For each patient, CT 
scans will be uploaded to the imaging platform, when applicable. 
7.5.2. 
Disease Progression With Immune Checkpoint Inhibitors  
During treatment with immune checkpoint inhibitors such as tislelizumab, pseudo-progression 
may occur due to immune cell infiltration and other mechanisms as manifested by the apparent 
increase of existing tumor masses or appearance of new tumor lesions. Patients are allowed to 
continue study treatment if there is suspicion of pseudo-progression, provided they are 
asymptomatic and have radiographic progression only, until follow-up imaging and/or biopsy 
demonstrates progressive disease, at which time study treatment will be discontinued permanently. 
If appropriate, the medical monitor may consult with the investigator (or vice versa) to review 
cases of potential pseudo-progression and determine if it is in the best interest of the patient to 
continue study treatment. 
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7.6. 
Laboratory Assessments  
Laboratory tests will be collected and analyzed as specified in Appendix 1. Screening blood tests 
performed within 3 days before the first study drug administration do not need to be repeated on 
Cycle 1 Day 1. Abnormal laboratory values will be considered AEs only if they are associated 
with clinical signs or symptoms that are clinically significant and/or require therapy and should be 
recorded on the AE eCRF. In addition, isolated abnormal laboratory values that are considered 
clinically significant (eg, any event, diagnosis, or laboratory value requiring treatment or follow-
up or the presence of signs or symptoms that require medical intervention) should be recorded on 
the AE eCRF. Local laboratory assessments of serum chemistry and hematology will be 
conducted, of which certain elements will be collected as specified in Appendix 2. 
7.6.1. 
Hematology  
Hematology laboratory studies include white blood cell count with differential (neutrophil, 
lymphocyte, monocyte, eosinophil, basophil), hemoglobin, hematocrit, and platelet count. In the 
event of ≥ Grade 3 neutropenia or thrombocytopenia that develops during study treatment, 
complete blood count monitoring will be conducted as often as clinically indicated per the 
investigator’s medical judgment to ensure patient safety. Close monitoring should occur until the 
toxicity resolves to ≤ Grade 2. Refer to Section 5.4 for dose modification of tislelizumab due to 
hematologic toxicity(s). 
7.6.2. 
Clinical Chemistry  
Clinical chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(if available), creatinine, glucose, calcium, magnesium, phosphorus, albumin, AST, ALT, total 
bilirubin, conjugated bilirubin, alkaline phosphatase, lactate dehydrogenase, total protein, uric 
acid, creatine kinase, and creatine kinase-cardiac muscle isoenzyme. In the event that creatine 
kinase-cardiac muscle isoenzyme fractionation is not available, troponin I and/or troponin T will 
be assessed instead. In the event a ≥ Grade 3 clinical chemistry toxicity develops during study 
treatment, the frequency of clinical chemistry monitoring will be conducted as often as clinically 
indicated per the investigator’s medical judgment to ensure patient safety. Close monitoring should 
occur until the toxicity resolves to ≤ Grade 2. 
7.6.3. 
Hepatitis B and Hepatitis C Testing  
These hepatitis B/C serologic markers and/or viral load will be tested at screening: 
• HBsAg, antibodies against HBsAg (HBsAb), antibodies against hepatitis B core 
antigen (HBcAb) 
• HCV serology (anti-HCV) 
• HBV DNA and HCV RNA 
Hepatitis B testing includes HBsAg, HBcAb, and HBsAb, as well as HBV DNA by polymerase 
chain reaction (PCR) if the patient is negative for HBsAg, but positive for HBcAb (regardless of 
HBsAb status). 
Hepatitis C testing includes HCV antibody as well as HCV RNA by PCR if the patient is positive 
for HCV antibody. 
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Patients who have detectable levels of HCV RNA (≥ 15 IU/mL) are not eligible. Patients who are 
positive for HBsAg and/or detectable HBV DNA are not eligible. 
Patients who are negative for HBsAg (required for study eligibility) and positive for HBcAb 
should have HBV DNA testing performed. If HBV DNA is detectable by an assay with a 
sensitivity of ≤ 20 IU/mL, the patient is not eligible for the study. If HBV DNA is not detected, 
patients may elect to: 
• Undergo HBV DNA testing by PCR every other cycle beginning in Cycle 2 
(ie, Cycles 2, 4, 6, 8, etc.) without beginning prophylactic antiviral medication, OR 
• Begin prophylactic dosing of antiviral therapy according to the regional standard of 
care. Patients will undergo HBV DNA testing by PCR every 4 cycles beginning in 
Cycle 4 (ie, Cycles 4, 8, 12, etc.). Medications recommended and excluded are 
described in Section 6. It is recommended that antiviral therapy be initiated at least 
2 weeks before the first dose of study treatment and continue until 6 months after 
discontinuation of study treatment. Patients may enter the study on HBV antiviral 
medication according to the regional standard of care. 
If HBV DNA is detectable at any time during the study, tislelizumab will be held until antiviral 
therapy is administered according to the regional standard of care. Resumption of study drug in 
patients whose HBV reactivation resolves (ie, HBV DNA is undetectable) should be discussed 
with and approved by physicians with expertise in managing hepatitis B and the medical monitor. 
Patients positive for HCV antibody but negative for HCV RNA (< 15 IU/mL) must undergo HCV 
RNA screening every other cycle, beginning in Cycle 2 (ie, Cycles 2, 4, 6, 8, etc.). Patients with 
detected HCV RNA should stop study drug and antiviral therapy should be initiated. 
Patients at risk for reactivation will also have HBV DNA and/or HCV RNA testing performed at 
the Safety Follow-up Visit. 
The medical monitor should be informed of any suspected hepatitis B or hepatitis C reactivation. 
Table 1 shows how the results for HBV/HCV and HBV/HCV testing at screening relate to 
inclusion and exclusion criteria. 
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Table 1: 
Active Hepatitis B Virus or Hepatitis C Virus Infection (Detected Positive by 
Polymerase Chain Reaction) 
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA undetectable by an assay with 
sensitivity ≤ 20 IU/mL and either of the 
following: 
 
Perform monitoring of HBV DNA 
(HBV DNA screening by PCR every other 
cycle, beginning in Cycle 2) 
OR 
Antiviral therapy administered and 
perform monitoring of HBV DNA (HBV 
DNA screening by PCR every 4 cycles, 
beginning in Cycle 4)  
HBsAg (-) and HBcAb (+) 
HBV DNA Detected 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not-detected” (<15 IU/mL) 
 
Perform monitoring of HCV RNA every 
other cycle, beginning in Cycle 2 
Antibody (+) 
HCV RNA Detected 
Abbreviations: HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; 
HCV, hepatitis C virus; PCR, polymerase chain reaction. 
7.6.4. 
Thyroid Function Test  
Evaluations of free triiodothyronine (T3), free thyroxine (T4), and thyroid-stimulating hormone 
will be performed as specified in Appendix 1. 
7.6.5. 
Liver Function Tests  
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total 
bilirubin, and conjugated bilirubin will be performed locally. Assessments should be as indicated 
in Appendix 1. 
7.6.6. 
Pancreatic Enzymes  
Pancreatic enzymes (amylase and lipase) will be tested locally if clinically indicated while on 
treatment. Assessments should be as indicated in Appendix 1. 
7.6.7. 
Pregnancy Test  
For women of childbearing potential, a serum pregnancy test will be performed at screening no 
more than 7 days before the first study drug administration. Any female patient who is pregnant 
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will not be eligible for the study. Urine pregnancy tests will be performed locally on Day 1 of 
every cycle starting with Cycle 2. Pregnancy tests must be continued during every cycle for at least 
30 days after the last dose of study drug. If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test. Serum pregnancy tests may be substituted for urine pregnancy tests if 
the site is not able to perform urine testing. A patient who has a positive pregnancy test result at 
any time after administration of the study drug will be immediately withdrawn from participation 
in the study. 
7.7. 
Pharmacokinetics  
The PK of tislelizumab will be characterized in this study. Blood samples will be collected from 
all patients at the time points described in Appendix 1. The time of study drug administration and 
actual PK collection time must be recorded on the eCRF. The actual time each sample is collected 
will be captured to the nearest minute in the eCRF and recorded in the database. Samples will be 
shipped to the designated bioanalytical laboratory for quantification of plasma tislelizumab 
concentrations using a validated method. 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK assays will be 
managed through a central laboratory. Serum samples will be tested for tislelizumab concentration 
using a validated immunoassay. Instruction manuals and supply kits will be provided for all central 
laboratory assessments. 
7.8. 
Antidrug Antibody Evaluation Procedures  
Tislelizumab might elicit an immune response, so patients with signs of any potential immune 
response to tislelizumab will be closely monitored for the development of antidrug antibody 
(ADA) during this study. 
Blood samples will be collected from all patients at the time points described in Appendix 1. 
Validated screening and confirmatory assays will be employed to detect ADAs at multiple time 
points throughout the study. Samples will be shipped to the designated bioanalytical laboratory for 
quantification of plasma tislelizumab concentrations using a validated method. 
Shipping, storage, and handling of samples for the assessment of tislelizumab ADAs will be 
managed through a central laboratory. Serum samples will be tested for the presence of ADAs to 
tislelizumab using a validated immunoassay. Instruction manuals and supply kits will be provided 
for all central laboratory assessments. 
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy (Bai et al 2012; 
Worobec and Rosenberg 2004) to characterize ADA responses to tislelizumab in support of the 
clinical development program. 
7.9. 
Biomarkers  
Tissue and optional blood samples for biomarker assessment will be collected as stated in 
Appendix 1. Shipping, storage, and handling of blood, archival tumor, fresh tumor, and tumor 
tissue for the assessment of biomarkers will be managed through a central laboratory. See the 
Laboratory Manual for sample handling details. 
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Archival tumor tissue (FFPE blocks or approximately 15 unstained slides) must be sent to a central 
laboratory for diagnosis confirmation and biomarker analysis, including but not limited to 
immunohistochemistry assay and/or fluorescence in situ hybridization to detect status of PD-L1, 
CD64, MHC II and other proteins related to disease or treatment mechanism, presence of immune 
cells in the tumor microenvironment, PD-L1/PD-L2 gene alteration, EBV infection status, etc. 
Gene mutation profiling and/or immune-related gene-expression profiling, and tumor-infiltrating 
immune cells that are related to response or clinical benefit of tislelizumab may also be evaluated. 
Tumor tissue submission is mandatory for all patients who consent to participate in the study, and 
an additional fresh baseline tumor biopsy (optional) at screening is strongly recommended. If a 
biopsy is not performed at screening, a sample of archival tumor tissue should be submitted from 
the confirmation of any relapse, with the most recent relapse sample being preferred. If tissue from 
a relapse is unavailable, archival tissue from the initial diagnosis may be submitted. 
An optional tumor biopsy will be taken from accessible tumor sites at the time of PR to explore 
tumor biomarkers of tislelizumab response and resistance. For patients who have confirmed 
disease progression during the study, optional biopsies will also be taken to explore resistance 
mechanisms. If feasible, any follow-up biopsy should be ideally taken from the same tumor lesion 
as the screening biopsy. Written patient consent is required prior to collecting a fresh tumor biopsy 
sample. 
Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. For 
fresh biopsy specimens, acceptable samples include core needle biopsies for deep tumor tissue or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
Optional blood samples will be taken at screening, at Weeks 3, 6, 12, 24, 48, and at the time of 
disease progression or 6 months after treatment to explore the association of blood-based 
biomarkers (such as ctDNA, cytokine, immune cell profiling, etc.) with response, resistance, and 
prognosis to tislelizumab. Written patient consent is required for blood sample collections. 
7.9.1. 
Archival Tissue Collection for Central Confirmation of Diagnosis and 
Biomarker Analysis  
Archival tumor tissue (FFPE blocks or approximately 15 unstained slides) will be collected at the 
Screening Visit and sent to a central laboratory for central confirmation of diagnosis and biomarker 
analysis. Central review of the tissue will be performed to confirm diagnosis of cHL (central 
confirmation of cHL diagnosis is not required for study entry). Enrollment will not be increased 
based on central review of pathology as patients will not be replaced in this study. 
7.10. 
Patient-Reported Outcomes  
Patient-reported outcomes will continue to be assessed until disease progression, death, or 
withdrawal of consent, regardless of study treatment discontinuation. Patients in both cohorts will 
be asked to complete the EQ-5D-5L and EORTC QLQ-C30 questionnaires per the Schedule of 
Assessments (Appendix 1) before study drug is administered. 
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EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(The EuroQol Group 1990, Herdman et al 2011). Patients will self rate their current state of 
mobility, self care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 
5 possible responses that record the level of severity (no problems, slight problems, moderate 
problems, severe problems, or extreme problems) within each dimension. The questionnaire also 
includes a visual analog scale to self rate general health state on a scale from “the worst health you 
can imagine” to “the best health you can imagine”. A sample questionnaire is provided in 
Appendix 10 as an example only. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients 
(Fayers et al 2001). It is a copyrighted instrument, which has been translated and validated in over 
100 languages and is used in more than 3,000 studies worldwide. The EORTC QLQ-C30 includes 
30 separate questions (items). The recall period is 1 week (the past week). The EORTC QLQ-C30 
has been widely used among cancer patients in general, and specifically in non-Hodgkin 
lymphoma patients. It is a reliable and valid measure of PRO in cancer patients and takes about 11 
minutes to administer. A sample questionnaire is provided in Appendix 11 as an example only. 
7.11. 
End of Treatment  
All patients, regardless of reason for discontinuation of study treatment, will undergo an End-of-
Treatment (EOT) Visit within 30 days (+ 7 days) of stopping study drug. This visit may be 
considered the Safety Follow-up Visit. The reason for discontinuation from treatment will be 
recorded on the eCRF. Section 7.13.1 describes the circumstances under which patients may 
discontinue study drug. 
Patients may voluntarily withdraw consent from the study at any time and may continue to 
participate in follow up, even if they withdraw consent from study treatment. 
See the Schedule of Assessments (Appendix 1) for further details. 
7.12. 
Follow-up Period  
All patients who discontinue treatment for any reason will be required to comply with the safety, 
efficacy, and survival follow-up assessments specified in Appendix 1. 
7.12.1. 
Safety Follow-up  
Patients who discontinue treatment for any reason will be asked to return to the clinic for a Safety 
Follow-up Visit (to occur within 30 days [+ 7 days]) after the last dose of study drug. In addition, 
telephone contacts (or clinic visit, if preferred) with patients should be conducted to assess AEs 
and concomitant medications (if appropriate, ie, associated with an AE or a new anti-lymphoma 
therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizumab. All AEs and SAEs are 
collected up to 90 days after the last dose of study drug. Beyond 90 days, investigators should 
continue to report any SAEs that are believed to be related to study drug if they become aware of 
them. 
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Patients who discontinue study treatment prior to PD will continue to have their tumors assessed 
as outlined in Section 7.5. 
7.12.2. 
Efficacy Follow-up  
For patients who discontinue from study drug for any reason other than PD (eg, AE), disease status 
will be assessed radiographically by the same imaging modality used during study treatment. 
Tumor imaging, physical examination, and complete blood count (CBC) will be performed per 
protocol until disease progression, withdrawal of consent, death, loss to follow-up, or end of study, 
whichever occurs first. 
7.12.3. 
Survival Follow-up  
Patients will be followed for survival and further anti-lymphoma therapy information after 
discontinuation of study treatment via telephone calls, patient medical records, and/or clinic visits 
approximately every 90 days (± 14 days) after the Safety Follow-up Visit or as directed by the 
sponsor until withdrawal of consent, death, loss to follow-up, or end of study, whichever occurs 
first. 
7.13. 
Discontinuation From Study Treatment or From the Study  
7.13.1. 
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 disease progression should be followed for 
tumor assessments (Section 7.5), safety (Section 7.12.1), and survival (Section 7.12.3), if possible. 
The primary reason for discontinuation from study treatment should be documented on the 
appropriate eCRF. Patients may discontinue study treatment for reasons which include, but are not 
limited to, the following: 
• Disease progression 
• AE(s) 
• Patient withdrawal of consent 
• Investigator decision 
• Other, including pregnancy, patient noncompliance, and 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 
7.13.2. 
Patient Discontinuation From the Study (End of Study for an Individual Patient)  
Patients may discontinue from the study for reasons that include but are not limited to the 
following:  
• Patient withdrawal of consent 
• Death 
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• Loss to follow-up 
• Study closure 
Premature discontinuation from the study (including all follow-up visits) will occur under the 
following circumstances: 
• Major protocol deviations 
• Patient withdrawal of consent 
• Loss to follow-up 
• Death 
• Study termination by sponsor 
• Investigator’s discretion 
Patients may voluntarily withdraw consent from the study at any time. 
Patients lost to follow-up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should document, in the source documents, steps taken to contact the 
patient (eg, dates of telephone calls, registered letters, etc.). 
7.14. 
End of Study  
The end of the study is expected to occur up to approximately 2 years after enrollment of the last 
patient. Patients who remain on study treatment at the end of the study may have an opportunity to 
receive tislelizumab in a separate rollover or extension study or post-trial supply program. 
The sponsors have the right to terminate this study at any time. Reasons for early termination of 
the study may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients (refer to Section 9.4.2 for the study safety stopping criteria) 
• Overall patient enrollment is unsatisfactory 
The sponsors will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for a final visit. 
Assessments performed should include those required for the Safety Follow-up. 
The investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator or 
sponsors will be responsible for informing Institutional Review Boards (IRBs) and/or Independent 
Ethics Committees (IECs) of the early termination of the trial. 
The sponsors have the right to close a site at any time. The site will be notified of this decision in 
advance. Reasons for closing a site may include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate, untimely, or incomplete data recording 
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• Good Clinical Practice (GCP) noncompliance 
• Study activity is completed (ie, all patients have completed all study related 
assessments and all obligations have been fulfilled) 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. Limited safety 
data are available in patients and the full safety profile has not been characterized. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
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 immune-related AEs (irAEs), specifically the induction or enhancement of 
autoimmune conditions. The irAEs observed with anti-PD-1 therapy are presented in 
Section 8.7.3. 
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, 
such events should be recognized early and treated promptly to avoid potential major 
complications. Suggested workup procedures for suspected irAEs are provided in Appendix 6. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with 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 within 28 days before first dose of study drug are excluded from the 
study. (See Section 4.2 for the full list of exclusion criteria.) 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to the 
start of each cycle. 
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory measurements 
(hematology, chemistry, etc.), and other assessments. In addition, patients will be closely 
monitored for the development of any signs or symptoms of autoimmune conditions and infection. 
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Serum samples will be drawn for determination of ADAs to tislelizumab in all patients. 
Administration of tislelizumab will be performed in a setting where emergency medical equipment 
and staff who are trained to respond to medical emergencies are available (see Section 5.2.1). 
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing of informed consent) and for up to 90 days after the last dose of study drug(s). At 
the end of treatment, ongoing AEs considered related to study treatment will be followed until the 
event has resolved to baseline level or ≤ Grade 1, the event is assessed by the investigator as stable, 
the patient is lost to follow-up, the patient withdraws consent, or it has been determined that study 
treatment or participation is not the cause of the AE. 
Immune-related AEs will be recorded up to 90 days after the last dose of tislelizumab, regardless 
of whether the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by 
the investigator after treatment discontinuation until patient death, withdrawal of consent, or loss 
to follow up, whichever occurs first. 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, or duration, and/or has an association with a significantly worse 
outcome 
• New condition(s) detected or diagnosed after study drug administration even though 
it may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this instance, all patient identifiers will be blinded on the copies of the medical 
records prior to submission to the sponsor. 
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8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
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 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the 
AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the Tislelizumab Investigator’s Brochure in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal information 
to include in the initial report to the sponsor. However, it is very important that the investigator 
always make an assessment of causality for every SAE prior to transmission of the SAE report to 
the sponsor, since causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality after considering 
follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or “not 
related.” An AE is considered related if there is “a reasonable possibility” that the AE may have 
been caused by the study drug (ie, there are facts, evidence, or arguments to suggest possible 
causation). A number of factors should be considered in making this assessment, including:  
• Temporal relationship of the AE to the administration of study treatment/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
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• Biological plausibility 
An AE should be considered “related” to study drug if any of the following criteria are met, 
otherwise the event should be assessed as not related: 
• There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
• There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
• There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs). 
8.3.4. 
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 indicated to elucidate the nature and/or causality of the AE or SAE. This may 
include additional laboratory tests or investigations, histopathological examinations, radiographic 
imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the 
AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the study 
or during a recognized follow-up period, the sponsor will be provided with a copy of any post-
mortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry or 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 significantly worsen during the study. The definition of “clinically significant” is left to the 
judgement of the investigator. In general, clinically significant findings are the laboratory test 
abnormalities or other abnormal assessments that: 
• are associated with clinical signs or symptoms, or 
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• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or 
• require further diagnostic investigation. 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Planned hospital admissions or surgical procedures for an illness or disease which 
existed before the patient was enrolled in the study or before study drug was given are 
not to be considered SAEs unless the condition deteriorated in an unexpected manner 
during the study (eg, surgery was performed earlier than planned) 
• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
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• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information) and meets the 
definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the Tislelizumab Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Reporting Period  
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, AEs and SAEs, regardless of relationship to study drug, will be 
reported until 90 days after last dose of study treatment or until initiation of new anticancer therapy. 
For patients who begin new anticancer therapy, only irAEs will be reported during the 90-day 
period after the last dose of study treatment. Clinical symptoms that are determined by the 
investigator to be clearly due to disease progression and are not considered serious in nature should 
not be reported as AEs. The symptoms, signs, or clinical sequelae, if considered serious in nature, 
that result from disease progression should be reported as SAE term(s). Further, after this period, 
the investigator should report any SAEs that are assessed as related to tislelizumab treatment, at 
any time after treatment discontinuation.  
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 2. 
Table 2: 
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 h of 
first knowledge 
of the SAE 
SAE report 
As 
expeditiously 
as possible 
SAE report 
Email or fax 
SAE form 
Abbreviations: h, hours; SAE, serious adverse event. 
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8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours, as outlined above in Section 8.6.2.1. The SAE Report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE and completing the 
form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE, as described in 
Section 8.3.3.  
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board/Independent Ethics Committee (IRB/IEC). 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for 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 Institutional Review Board or Independent Ethics 
Committee. The investigator should place copies of safety reports from the sponsor in the 
Investigator Site File. 
8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask about AEs by asking the following standard questions:  
• How are you feeling?  
• Have you had any medical problems since your last visit?  
• Have you taken any new medicines since your last visit?  
8.6.4. 
Disease Progression  
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, 
the symptoms, signs or clinical sequelae, if considered serious in nature that result from disease 
progression should be reported as SAE term(s). However, clinical symptoms that are determined 
by the investigator to be clearly due to disease progression and are not considered serious in nature 
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should not be reported as AEs. If the symptoms cannot be determined as exclusively due to the 
progression of the underlying malignancy, then the term(s) should be reported as AE(s) or SAE(s) 
accordingly. 
For instance, if a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression.”  
8.6.5. 
Deaths  
Death is an outcome and not usually considered an event. If the only information available is death 
and the cause of death is unknown, then the death is reported as an event, eg, “death,” “death of 
unknown cause,” or “death unexplained.” 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab, a pregnancy report 
form is required to be completed and expeditiously submitted to the sponsor to facilitate outcome 
follow-up. Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study 
drug should be recorded and reported as an SAE.  
8.6.7. 
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, 
Institutional Review Boards, and Independent Ethics Committees 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 document: 
• Tislelizumab Investigator’s Brochure 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events  
Since treatment with anti-PD-1 therapy can cause or worsen autoimmune disorders, AEs 
considered by the investigator to be immune-related (see Section 8.7.3) should be classified as 
irAEs and identified as such on the eCRF AE page until Day 90, after treatment discontinuation.  
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 6. 
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A list of potential irAEs appears in Section 8.7.3. All conditions similar to those listed should be 
evaluated to determine whether they are irAEs, based on a similar diagnostic process to those 
reactions that are presented in more detail in Appendix 6. 
8.7. 
Management of Adverse Events of Special Interest  
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 2 hours afterward in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a minimum of a 30-minute monitoring period is required 
in an area with resuscitation equipment and emergency agents.  
The management of infusion-related reactions, severe hypersensitivity reactions, and irAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Infusion-Related Reactions  
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Patients should be closely monitored for 
such reactions. Immediate access to an Intensive Care Unit or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, IV antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 
Treatment modification for symptoms of infusion-related reactions due to study drug is provided 
in Table 3. 
Table 3: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 h 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
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Grade 4 – life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: h, hours; IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued, and the patient should be withdrawn from 
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), and, if considered 
indicated, oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen. In the next cycle, 
patients should receive oral premedication with an antihistamine (eg, diphenhydramine or 
equivalent) and an antipyretic (eg, paracetamol or equivalent), and they should be closely 
monitored for clinical signs and symptoms of an infusion reaction.  
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 IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If a hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction, the infusion must be immediately 
stopped and the patient discontinued from the study. Such reactions typically manifest within 
minutes following administration of the drug/antigen and are characterized by respiratory distress; 
laryngeal edema; and/or intense bronchospasm (which 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 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(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
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Tumor Lysis Syndrome 
Patients with a high tumor burden (presence of a leukemic phase, multiple organ involvement, or 
marrow infiltration) are recommended to receive prophylaxis for tumor lysis syndrome prior to the 
initiation of study treatment. These patients must be well hydrated. It is desirable to maintain a 
fluid intake of approximately 3 L/day, 1 to 2 days before the first dose of tislelizumab. All such 
patients with high tumor burden must be treated with a xanthine oxidase inhibitor (allopurinol) of 
> 300 mg/day orally. It is recommended that patients of Asian descent have HLA-B5801 testing 
before allopurinol therapy. If testing is not available, febuxostat 80 mg/day may be used or a 
suitable alternative treatment (eg, rasburicase) starting at least 12 to 24 hours prior to the first dose 
of tislelizumab. Patients should continue to receive prophylaxis with a xanthine oxidase inhibitor 
and adequate hydration prior to each infusion of tislelizumab, if deemed appropriate by the 
investigator. 
Cytokine Release Syndrome 
Although infrequent in incidence, cytokine release syndrome (CRS) has been observed in cancer 
patients treated with PD-1 checkpoint inhibitors (Chen et al 2017; Rotz et al 2017). Representing 
a constellation of inflammatory reactions that result from cytokine elevations associated with 
T-cell engagement and activation, patients with cytokine release syndrome may present with 
symptoms that include sepsis, fever, tachycardia, hypotension, coagulopathies, and deranged liver 
function tests. Often these symptoms can mimic disease progression or infection. 
If CRS is suspected, patients should undergo evaluation as soon as possible. If needed, in-patient 
admission is recommended to fully evaluate patients for CRS as well as rule out infection, which 
can exacerbate CRS. Patients with a suspected infection should be aggressively treated with 
antibiotics and antifungal medication as needed. Serum ferritin, IL-6, CRP, LDH, and 
procalcitonin (Maakaron et al 2018) can be valuable tests in this setting. 
Patients should be managed appropriately according to local institutional standard of care. The 
recommended treatment for CRS typically includes high-dose corticosteroids, use of the IL-6 
inhibitor tocilizumab, and intensive supportive care. A thorough benefit-risk evaluation should be 
made by the investigator on the possibility of rechallenge with study treatment for patients who 
experience severe CRS and subsequently recover. Although there have been anecdotal reports of 
response to PD-1 inhibitors after rechallenge in extranodal natural killer/T-cell lymphoma (ENKL) 
patients with drug-induced CRS, the decision to resume study treatment should be weighed against 
a variety of factors and may involve consultation with additional specialists and also informing the 
medical monitor. 
8.7.3. 
Immune-Related Adverse Events  
Immune-related AEs (irAEs) 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, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but are not limited to serologic, immunologic, and 
histologic (biopsy) data. The irAE indicator on the eCRF AE page should be checked if alternative 
causes of the irAE have been ruled out; the irAE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy; and the irAE is consistent with an immune-mediated 
mechanism of action. 
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A list of potential irAEs is shown in Table 4. All conditions similar to those listed should be 
evaluated in patients receiving tislelizumab to determine whether they are immune-related.  
Recommendation for diagnostic evaluation and management of irAEs is based on European 
Society for Medical Oncology (ESMO) and ASCO guidelines (Haanen et al 2017; 
Brahmer et al 2018) and common immune-related toxicities are detailed in Appendix 6. For any 
AEs not included in Appendix 6, see the ASCO Clinical Practice Guideline (Brahmer et al 2018) 
for further guidance on diagnostic evaluation and management of immune-related toxicities. 
Table 4: 
Immune-Related Adverse Events  
Body System Affected 
Examples of Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s 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 irAEs are detailed in Appendix 6. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor. Patients who experience a recurrence of any event at the same 
or higher severity grade with rechallenge should permanently discontinue treatment. 
8.7.4. 
Recording Diagnosis Versus Signs and Symptoms  
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF (and SAE 
report, as applicable), rather than the individual signs and symptoms (eg, record only “hepatitis” 
rather than “elevated transaminases,” “bilirubin,” or “jaundice”).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual AE should be recorded as an SAE 
or AE on the eCRF (and SAE report, if applicable). If a diagnosis is subsequently established, it 
should replace the individual signs and/or symptoms as the AE term on the eCRF (and SAE report, 
if applicable). 
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8.7.5. 
Recording Adverse Events Occurring Secondary to Other Events  
In general, AEs occurring secondary to other AEs (eg, clinical sequelae or a cascade of AEs) 
should be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as the SAE or AE on the eCRF (and SAE 
report, if applicable). However, if a patient initially has a nonserious AE, and it subsequently 
becomes an SAE, both AEs should be reported separately on the eCRF. The onset date of the 
nonserious AE should be recorded as the start date of the nonserious AE. The onset date of the 
SAE should be recorded as the date that the nonserious AE became serious (eg, due to hospital 
admission). 
8.7.6. 
Recording Persistent or Recurring Adverse Events  
A persistent AE is one that extends continuously without resolution between patient evaluation 
time points. Such AEs should be recorded only once on the AE eCRF (and SAE report, if 
applicable). If an AE worsens in grade, with the exception of an AE that is related and requires 
dose modification (ie, treatment discontinuation or dose interruption/delay), the worst grade should 
be recorded for the entire event. A persistent AE that is related and requires dose modification 
should be recorded separately on the eCRF (and SAE report, if applicable). 
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded separately on the eCRF (and SAE 
report, if applicable). 
8.7.7. 
Recording Poststudy Adverse Events  
A poststudy AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period 
that is defined in Section 8.6.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will notify 
the sponsor. 
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9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN  
Details of the statistical analyses will be included in a separate Statistical Analysis Plan (SAP). 
9.1. 
Primary, Secondary and Exploratory Study Endpoints  
9.1.1. 
Primary Endpoint  
• ORR, defined as the proportion of patients who achieve a best response of CR or PR 
per the Lugano Classification (Cheson et al 2014) (Appendix 4) and determined by 
the investigator 
9.1.2. 
Secondary Endpoints  
• Efficacy endpoints assessed by the investigator using the Lugano Classification: 
− Complete response rate, defined as the proportion of patients who achieve a best 
response of complete response 
− Duration of response, defined as the time from the date that response criteria are 
first met to the date that disease progression is objectively documented or death, 
whichever occurs first  
− Time to response, defined as the time from the date of the first dose of 
tislelizumab to the time the response criteria are first met  
• Safety and tolerability of tislelizumab, as defined by: 
− The incidence and severity of AEs according to NCI-CTCAE v5.0 
− Changes in vital signs, physical findings, and clinical laboratory results 
9.1.3. 
Exploratory Endpoints  
• Progression-free survival, as assessed by the investigator using the Lugano 
Classification and defined as the time from the first dose of tislelizumab to the date of 
disease progression or death, whichever occurs first  
• Overall survival, defined as the time from the first dose of tislelizumab to the date of 
death from any cause 
• Patient-reported outcomes, as measured using EQ-5D-5L and EORTC QLQ-C30 
• Clinical outcomes (eg, PFS and duration of response) per the LYRIC criteria 
(Cheson et al 2016) (Appendix 5) and as determined by the investigator, and ancillary 
exploratory studies by centralized imaging for a subset of patients (to be determined 
at the time of the primary analysis) 
• Status of exploratory biomarkers in the study population, and their association with 
disease status, response, and/or resistance mechanisms of tislelizumab 
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• PK of tislelizumab: Summary of serum concentrations of tislelizumab including but 
not limited to tislelizumab Ctrough 
• Immunogenicity of tislelizumab: assessment of the incidence of ADAs 
9.2. 
Statistical Analysis  
9.2.1. 
Analysis Sets  
The Safety Analysis Set includes all patients who receive at least 1 dose of tislelizumab.  
This will be the primary analysis set for the efficacy and safety analyses, which will be performed 
for both cohorts combined. 
The PK Analysis Set includes all patients for whom valid tislelizumab PK parameters can be 
estimated. 
9.2.2. 
Patient Disposition  
The number of patients enrolled, treated, and discontinued from study drug will be counted by 
cohort and overall. The primary reason for study drug discontinuation will be summarized 
according to the categories in the eCRF. The end of study status (alive, death, withdrew consent 
or lost to follow-up) at the data cutoff date will be summarized using the data from the eCRF. 
Major protocol deviations will be summarized and listed by each category. 
9.2.3. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized by cohort and overall using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial cHL 
diagnosis, number of prior lines of therapy for cHL; categorical variables include gender, ECOG, 
systemic symptoms (B symptoms), International Prognostic Score (Appendix 3) at diagnosis, 
bulky disease defined as mediastinal mass ratio of 0.33 or size of any single node/nodal mass is 
≥ 10 cm in diameter, and erythrocyte sedimentation rate. 
9.2.4. 
Prior and Concomitant Therapy  
Concomitant medications will be assigned an 11-digit code using the WHO 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 by cohort and overall and listed by drug and drug class in the clinical study report for 
this protocol. Prior medications will be defined as medications that stopped before the 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. A 
listing of prior and concomitant medications will be included in the clinical study report of this 
protocol. 
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9.3. 
Efficacy Analyses  
9.3.1. 
Primary Efficacy Endpoint Analysis  
The primary endpoint is ORR assessed by the investigator per the Lugano Classification 
(Cheson et al 2014) (Appendix 4). The ORR is defined as the proportion of patients achieving a 
best response of CR or PR.  
Best overall response is defined as the best response recorded from the first dose of tislelizumab 
until data cut or the start of a new anti-lymphoma therapy. Patients with no post-baseline response 
assessment (due to any reason) will be considered non-responders. For each cohort, estimate of 
ORR and its corresponding Clopper-Pearson 95% confidence interval (CI) will be presented. The 
proportion for each of the response categories will also be summarized. 
The primary efficacy analysis for both cohorts combined will be conducted at least 12 weeks after 
the last patient has been dosed, either having undergone the first response assessment or having 
withdrawn prior to the first response assessment. A separate end-of-study analysis will be 
performed, details of which will be provided in the Statistical Analysis Plan (SAP).  
In the event that some patients do not have central confirmation of cHL diagnosis, a sensitivity 
analysis may be performed on the patients in the Safety Analysis Set with central confirmation of 
cHL diagnosis. 
The historical control ORR is assumed to be approximately 45% based on previous clinical trials 
(Moskowitz et al 2013). The null and alternative hypotheses are set as follows: 
H0: ORR = 0.45 for Cohort 1 and Cohort 2 combined 
Ha: ORR > 0.45 for Cohort 1 and Cohort 2 combined 
A binomial exact test will be performed to test the hypothesis. If the 1-sided p-value is less than 
or equal to 0.05 (which is equivalent to observing 25 or more responders out of 42 patients), it will 
be concluded that single agent tislelizumab statistically significantly increases ORR compared to 
the historical control. The superiority of single agent tislelizumab will be demonstrated at a 1-sided 
level alpha of 0.05. A 2-sided Clopper-Pearson 95% CI of ORR will be constructed to assess the 
precision of the rate estimate; a 2-sided 90% CI will also be constructed to be consistent with the 
1-sided 95% confidence bound. 
9.3.2. 
Secondary Efficacy Endpoint Analysis  
The rate of complete response as determined by the investigator and the corresponding Clopper-
Pearson 95% CI will be presented for the cohorts combined. Patients with no post-baseline 
response assessment (due to any reason) will be considered non-responders. 
Duration of response will be analyzed using the Kaplan-Meier method. Patients who receive other 
anticancer therapies, including HSCT (in Cohort 2), before having an event (disease progression 
or death, whichever occurs first), will be censored. Time to response will be analyzed using 
descriptive statistics such as mean, median, and standard deviation. Only patients who have 
achieved an overall response will be included in the analysis of duration of response and time to 
response. In addition, sensitivity analyses will be performed using the European Medicines 
Agency (EMA) censoring rules and censoring only for HSCT. 
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9.3.3. 
Exploratory Analyses  
The distribution of PFS will be estimated overall using the Kaplan-Meier method. Patients who 
receive other anticancer therapies, including HSCT (in Cohort 2), before having an event (disease 
progression or death, whichever occurs first), will be censored. Median and other quartiles of PFS 
will 
be 
estimated 
with 
95% 
CI 
using 
the 
Brookmeyer 
and 
Crowley 
method 
(Brookmeyer and Crowley 1982). In addition, sensitivity analyses will be performed using EMA 
censoring rules and censoring only for HSCT. PFS rate at selected time points will be estimated 
with its 95% CI using Greenwood’s formula. Details of the censoring rules for PFS will be 
provided in the SAP. 
Overall survival will be censored at the last date known to be alive. Overall survival will be 
analyzed using the same methods employed on the PFS analysis.  
Descriptive analyses (mean, standard deviation, median, range) and mean changes (standard 
deviation) from baseline for the scores from the EORTC QLQ-C30 scales, and the scores of the 
visual analog scale (VAS) of the EQ-5D-5L will be computed and summarized for each assessment 
time point. 
Clinical outcomes by tumor assessment will be summarized using the LYRIC criteria 
(Cheson et al 2016) (Appendix 5). 
Efficacy variables (eg, ORR and PFS) will be correlated to biomarker expression level to identify 
a potential biomarker defining a subset that is more sensitive to the PD-1 treatment. 
Correlation between steady-state trough serum concentration of tislelizumab and efficacy or safety 
endpoints may be explored. 
9.4. 
Safety Analysis  
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry), vital signs, and physical examination 
assessments will also be used in determining safety. Descriptive statistics will be used to analyze 
all safety data by cohort and overall. 
9.4.1. 
Extent of Exposure  
Extent of exposure to study drug will be summarized descriptively by cohort and overall as the 
number of cycles received (number and percentage of patients), duration of exposure (days), 
cumulative total dose received per patient (mg), dose intensity (mg/day), and relative dose 
intensity. 
The number (percentage) of patients requiring dose interruption, dose delay, and drug 
discontinuation due to AEs will be summarized. The cycle in which the first dose interruption 
occurred will be summarized using descriptive statistics. Frequency of dose interruptions will be 
summarized by categories.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
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9.4.2. 
Adverse Events  
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be coded to MedDRA lower level term closest to the verbatim 
term. The linked MedDRA Preferred Term and primary System Organ Class are also captured in 
the database. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline (pre-
treatment) on or after the first dose of study drug up to 90 days following study drug 
discontinuation, regardless of whether or not the patient starts a new anti-lymphoma therapy. 
TEAEs also include all irAEs and drug-related serious AEs recorded up to 90 days after the last 
dose of study drug. For patients who begin new anticancer therapy, only irAEs will be reported 
during the 90-day period after the last dose of study treatment. Only those AEs that were treatment 
emergent will be included in summary tables. All AEs, treatment emergent or otherwise, will be 
presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
System Organ Class and Preferred Term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE v5.0 within a System Organ Class and Preferred Term, even if the 
patient experienced more than 1 TEAE within a specific System Organ Class and Preferred Term. 
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug. Treatment-related AEs include those events considered by the investigator to be 
definitely, possibly, or probably related to study treatment or with missing assessment of the causal 
relationship. SAEs, deaths, TEAEs with Grade 3 or above, irAEs, treatment-related TEAEs, and 
TEAEs that led to treatment discontinuation or dose interruption will be summarized. 
Safety data will be monitored throughout the study. At approximately 9 weeks after the 20th patient 
has been dosed, data from the first 20 patients in the combined cohorts will be compared against 
pre-specified safety stopping criteria. The stopping criteria will be applied for deaths from causes 
other than disease progression (non-PD), treatment-emergent SAEs, and treatment-emergent 
Grade 3 or higher immune-related AEs. The stopping criteria for the aforementioned types of 
safety events are summarized in Table 5 and are based on cutoffs representing a greater than 85% 
Bayesian posterior probability of exceeding a set event rate threshold where each event rate 
threshold is based approximately in reference to the results of approved anti-PD1 treatments, 
including nivolumab (Armand et al 2018, Opdivo® US Prescribing Information). For non-PD 
deaths, the stopping criterion is defined as having a greater than 85% Bayesian posterior 
probability of exceeding the event rate of 5%. Similarly, for treatment-emergent SAEs and 
treatment-emergent Grade 3 or higher immune-related AEs, the event rates for comparison are 
35% and 20%, respectively. The prior distributions for non-PD deaths, treatment-emergent SAEs 
and treatment-emergent Grade 3 or higher immune-related AEs are based approximately on the 
results of the BGB-A317-203 trial (data on file) and are Beta (0.05, 4.95), Beta (0.85, 4.15) and 
Beta (0.6, 4.4), respectively. 
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Table 5: 
Safety Stopping Criteria  
Event type 
Event rate 
threshold 
Prior 
distribution 
Number of patients with event 
where posterior probability of 
event rate exceeding threshold is 
greater than 85% among 20 
subjects 
Deaths from causes other than 
disease progression  
5% 
Beta (0.05, 4.95) ≥ 3 
Treatment-emergent SAEs 
35% 
Beta (0.85, 4.15) ≥ 11 
Treatment-emergent Grade 3 
or higher immune-related AEs 
20% 
Beta (0.6, 4.4) 
≥ 7 
9.4.3. 
Laboratory Analyses  
Clinical laboratory values (eg, hematology, serum chemistry) will be evaluated for each laboratory 
parameter as appropriate. Abnormal laboratory values will be flagged and identified as those 
outside (above or below) the normal range. Reference (normal) ranges for laboratory parameters 
will be included in the clinical study report for this protocol. Descriptive summary statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables, n[%] for 
categorical variables) for laboratory parameters and their changes from baseline will be calculated. 
Laboratory values will be summarized by visit and by worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 will be summarized by CTCAE grade. 
In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading in 
both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
9.4.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse, 
temperature) and changes from baseline will be presented by visit for all visits. Vital signs will be 
listed by patient and visit. 
9.5. 
Pharmacokinetics Analysis  
PK samples will be collected in this study as outlined in Appendix 1. 
The tislelizumab Ctrough will be tabulated and summarized for each cycle at which PK is to be 
measured. Descriptive statistics will include means, medians, ranges, and standard deviations, as 
appropriate. 
Additional PK analyses may be conducted as appropriate. 
9.6. 
Immunogenicity Analysis  
Immunogenicity samples will be collected in this study as outlined in Appendix 1.  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
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neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
9.7. 
Sample Size Consideration  
A total of approximately 42 patients will be enrolled. 
The results from a previous clinical trial of tislelizumab (Song et al 2018) yielded an ORR of 
85.7% in a predominantly brentuximab vedotin-naive population. Assuming an alternative ORR 
of 65% compared to the null ORR of 45% in Cohort 1 and Cohort 2 combined, using a binomial 
exact test, the power to reject the null hypothesis with 42 patients at a 1-sided alpha of 0.05 is 
greater than 80%. 
9.8. 
Interim Analysis  
No interim analysis is planned for this study. 
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10. 
STUDY COMMITTEES AND COMMUNICATIONS  
10.1. 
Safety Monitoring Committee  
The first safety review will occur after at least 20 patients have been on treatment for at least 
9 weeks in order to determine if the proposed dosing schedule of tislelizumab is safe and tolerable. 
As enrollment will be discontinued at approximately 42 patients dosed, safety monitoring analysis 
will be conducted at the time of primary analysis. 
The Safety Monitoring Committee may recommend study modification including termination of 
the study due to safety and/or efficacy concerns. The function and membership of the Safety 
Monitoring Committee will be described in the Safety Monitoring Committee Charter. 
In addition to the planned review(s), ad hoc reviews may take place based on new information.  
Following Safety Monitoring Committee review and discussion, the sponsor will make all final 
decisions regarding any change in study conduct. Please see the details in the Safety Monitoring 
Committee Charter.  
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
11.1. 
Access to Information for Monitoring  
In accordance with ICH Good Clinical Practice (GCP) guidelines, the study monitor must have 
direct access to the investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to verify 
the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure that any 
problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits of the 
clinical study. BeiGene will provide thirty calendar days’ prior written notice of any audit to ensure 
that all members of the LYSARC Team involved in the study will be present. If the investigator is 
notified of an inspection by a regulatory authority, the investigator agrees to notify the sponsor or 
its designee immediately. The investigator agrees to provide to representatives of a regulatory 
agency or BeiGene access to records, facilities, and personnel for the effective conduct of any 
inspection or audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements before the study is 
initiated at a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the study. 
If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of his/her personnel 
to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, BeiGene 
and LYSARC 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 Institutional Review 
Board/Independent Ethics Committee members to inspect all facilities and records relevant to this 
study.  
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient dispensing records, and returned or destroyed study 
product. Dispensing records will document quantities received from BeiGene and quantities 
dispensed to patients, including lot number, date dispensed, patient identifier number, patient 
initials (if allowed), and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction in order to ensure that it complies with BeiGene requirements. At the end of 
the study, following final drug inventory reconciliation by the monitor, the study site will return 
to sponsor and/or dispose of and/or destroy all unused study drug supplies, including empty 
containers, according to these procedures. If the site cannot meet BeiGene’s requirements for 
disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. All drug supplies and associated 
documentation will be periodically reviewed and verified by the study monitor over the course of 
the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full conformance 
with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the informed consent forms, any information to be given to the patient, and relevant 
supporting information must be submitted to the Institutional Review Board/Independent Ethics 
Committee by the principal investigator/the sponsor, unless local laws and regulations require 
otherwise, and reviewed and approved by the Institutional Review Board/Independent Ethics 
Committee before the study is initiated. In addition, any patient recruitment materials must be 
approved by the Institutional Review Board/Independent Ethics Committee. 
The principal investigator/the sponsor is responsible for providing written summaries of the status 
of the study to the Institutional Review Board/Independent Ethics Committee annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
Institutional Review Board/Independent Ethics Committee. Investigators/the sponsor are/is also 
responsible for promptly informing the Institutional Review Board/Independent Ethics Committee 
of any protocol amendments. In addition to the requirements for reporting all AEs to the sponsor, 
investigators/the sponsor must comply with requirements for reporting SAEs to the local health 
authority and Institutional Review Board/Independent Ethics Committee. 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 Institutional Review Board/Independent Ethics Committee and archived in the 
site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the Institutional Review 
Board/Independent Ethics Committee together with, if applicable, a revised model informed 
consent form in accordance with local requirements. Written documentation from competent 
authorities (according to local requirements) and from the Institutional Review Board/Independent 
Ethics Committee 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). 
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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 informed 
consent form confirming their willingness to remain in the study. 
13.3. 
Informed Consent  
The sponsor’s sample informed consent form will be provided to each site. If applicable, it will be 
provided in a certified translation of the local language. The final Institutional Review 
Board/Independent Ethics Committee-approved informed consent forms must be provided to the 
sponsor for health authority submission purposes according to local requirements.  
The investigator is responsible for obtaining written informed consent from everyone participating 
in this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures. The informed consent forms must 
be signed and dated by the patient or the patient’s legally authorized representative before his or 
her participation in the study. The case history or clinical records for each patient shall document 
the informed consent process and that written informed consent was obtained prior to participation 
in the study.  
The informed consent forms 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 Institutional Review Board/Independent Ethics Committee -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 informed consent forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
Institutional Review Board/Independent Ethics Committee policy) during their participation in the 
study. For any updated or revised informed consent forms, 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 informed consent forms for continued participation in the 
study. 
A copy of each signed informed consent form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated informed consent forms must remain in 
each patient’s study file or in the site file and must be available for verification by study monitors 
at any time. 
13.4. 
Patient and Data Confidentiality  
The sponsor will maintain confidentiality and privacy standards by coding each patient enrolled in 
the study through assignment of a unique patient identification number. This approach ensures that 
patients’ names are not included in any data set transmitted to any sponsor location. The 
investigator must keep a screening log showing codes, names, and addresses for all patients 
screened and for all patients enrolled in the trial. 
Patient medical information obtained during this study is confidential and may be disclosed only 
to third parties as permitted by the signed informed consent form (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.  
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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.  
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Information on maintaining patient 
confidentiality in accordance to applicable national and international (such as the EU General Data 
Protection Regulation) patient privacy regulations must be provided to each patient as part of the 
informed consent process, either as part of the informed consent form or as a separate signed 
document (for example, in the US, a study-center specific Health Insurance Portability and 
Accountability Act [HIPAA] consent may be used). 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational new drug, and any other 
study information, remain the sole and exclusive property of BeiGene 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 BeiGene. The investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
If a written contract for the conduct of the study includes confidentiality provisions inconsistent 
with this section is executed, that contract’s provisions shall apply to the extent they are 
inconsistent with this section. 
13.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators and/or disclose those financial 
interests, as required to the appropriate health authorities. This is intended to ensure financial 
interests and arrangements of the clinical investigators with the sponsor that could affect reliability 
of data submitted to health authorities are identified and disclosed by the sponsor. Investigators 
are responsible for providing information about their financial interests before participation in the 
study, and to update this information if any relevant changes occur during the study and for 1 year 
after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture system. Data required 
by the protocol includes the first letter of the first name, the first letter of the last name, and month 
and year of birth, for patients included in France and Belgium in order to optimize the collection 
of tumor blocks from anatomopathology laboratories and to facilitate biological samples 
reconciliation.  
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The investigator or designee as identified on the Statement of 
Investigator Form must sign the completed casebooks to attest to its accuracy, authenticity, and 
completeness. 
Data contained in the eCRFs should not be made available in any form to third parties, except for 
authorized representatives of the sponsor or appropriate regulatory authorities. 
14.1.2. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored at LYSARC at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure that 
the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records will 
be performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs 
for completeness, clarity, and cross-checking with source documents is required to monitor the 
progress of the study. Direct access to source data is also required for inspections and audits and 
will be carried out giving due consideration to data protection and medical confidentiality. 
AEs will be coded using MedDRA. Concomitant medications will be coded using the World 
Health Organization Drug Dictionary. Concomitant diseases/medical history will be coded using 
MedDRA. 
14.2. 
Data Integrity and In-House Blinding  
Due to the open-label design of the study, access to the patient-level clinical data in the electronic 
data capture system will only be assigned to predefined study personnel. Functions/persons with 
access to the electronic data capture system shall be prohibited from using the electronic data 
capture system to generate unnecessary listings/summaries that may introduce unwanted bias or 
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sharing such outputs from the electronic data capture system with other functions/persons who do 
not have access to the electronic data capture. Although the trial is open label, analyses or 
summaries generated by randomized treatment assignment and actual treatment received will be 
limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 
classified into at least the following 2 categories: (1) investigator’s study file, and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
Institutional Review Board/Independent Ethics Committee, and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, 
and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECG, electroencephalogram, x-ray, pathology and special assessment 
reports, consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval when needed (eg, audit 
or inspection) and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and personnel. Where permitted by local 
laws/regulations or institutional policy, some or all of these records can be maintained in a format 
other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be exercised 
before such action is taken. The investigator must assure that all reproductions are legible, are a 
true and accurate copy of the original, and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an 
acceptable backup of these reproductions and that an acceptable quality control process exists for 
making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional requirements 
or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the retention period 
will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility and 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 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 
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in case of a regulatory audit. When source documents are required for the continued care of the 
patient, appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the sponsor for a 
period up to 1 year for purposes of this study. 
14.4. 
Protocol Deviations  
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and, if applicable, to the Institutional Review Board/Independent 
Ethics Committee, in accordance with established Institutional Review Board/Independent Ethics 
Committee policies and procedures. 
14.5. 
Publication and Data Sharing Policy  
A clinical study report will be prepared and provided to the regulatory agency(ies). BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, objective, 
and clinically meaningful manner that is consistent with good science, industry and regulatory 
guidance, and the need to protect the intellectual property of BeiGene and LYSARC (co-sponsors), 
regardless of the outcome of the study. The data generated in this clinical study are confidential. 
As this is a multicenter study, the first publication or disclosure of study results shall be a complete, 
joint multicenter publication or disclosure coordinated by the sponsor. Thereafter, any secondary 
publications will reference the original publication(s). Authorship will be determined by mutual 
agreement and all authors must meet the criteria for authorship established by the International 
Committee of Medical Journal Editors Uniform Requirements for Manuscripts or stricter local 
criteria (International Committee of Medical Journal Editors 2023). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. 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 in advance of 
the publication/presentation. 
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14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Shipment of all samples to a central laboratory 
In addition, the sponsor reserves the right to suspend or prematurely discontinue this study either 
at a single study center or at all study centers at any time for reasons including, but not limited to, 
safety or ethical issues or severe non-compliance with this protocol, GCP, 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 prior to its taking effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action. If required 
by 
applicable regulations, 
the investigator must inform 
the 
Institutional Review 
Board/Independent Ethics Committee 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 drug(s) in accordance with the applicable 
sponsor procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study, whether patentable or not, are the sole property of BeiGene, 
and are hereby assigned to BeiGene.  
If a written contract for the conduct of the study which includes ownership provisions inconsistent 
with this statement is executed between the sponsor and the study center, that contract’s ownership 
provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) will be kept by the investigator and 
other study center personnel. This information and data will not be used by the investigator or 
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other study center personnel for any purpose other than conducting the study, without the prior 
written consent of BeiGene. 
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 Institutional Review 
Board/Independent Ethics Committee 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. 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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15. 
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16. 
 APPENDICES  
APPENDIX 1. SCHEDULE OF ASSESSMENTS  
 
Screening 1 
Treatment Period 
Safety 
Follow-up 4 
Safety/Survival/Efficacy 
Follow-up 5 
Cycle 1  
(21 Days) 2 
Cycle 2 and 
additional 
cycles  
(every 21 
days) 
EOT 3 
Days 
-28 to -1 
1 
 
1 ± 7 
 
Within 30 
days (+ 7) 
of last dose 
Within 30 
days (+ 7) 
of last dose 
Every 90 days (± 14) 
after Safety Follow-up 
Informed consent 6 
x 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
Demographics /Medical 
history / Prior medications 7 
x 
 
 
 
 
 
Vital signs 8 
x 
x 
x 
x 
x 
 
Height and weight 9 
x 
x 
x 
x 
 
 
Physical examination 
x 
x 
x 
x 
x 
x 29 
ECOG performance status 
x 
x 
x 
x 
x 
 
12-lead ECG 10 
x 
 
 
 
 
 
Pulmonary function test 11 
x 
 
 
 
 
 
Review adverse events 12 
x 
x 
x 
x 
x 
x 
Review concomitant 
medications 13 
x 
x 
x 
x 
x 
x 
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Screening 1 
Treatment Period 
Safety 
Follow-up 4 
Safety/Survival/Efficacy 
Follow-up 5 
Cycle 1  
(21 Days) 2 
Cycle 2 and 
additional 
cycles  
(every 21 
days) 
EOT 3 
CBC with differential 14 
x 
x 
x 27 
x 
x 
x 29 
Serum chemistry panel 14 
x 
x 
x 27 
x 
x 
 
Hepatitis B and C and HIV 15 
x 
 
 
 
 
 
ESR 
 
x 27 
 
 
 
 
Pregnancy test (if 
applicable)16 
x 
 
x 
x 
x 
 
Thyroid function test 17 
 
x 27 
x 27 
(after C2D1, 
repeat every 
odd-numbered 
cycle) 
x 
x 
 
Liver function tests 18 
x 
x 
x 
 
x 
 
Pancreatic enzymes 19 
x 
 
 
 
 
 
Tumor tissue 20 
x 
x 20 
 
x 20 
 
 
Optional blood collection 21 
x 
x 
x 
x 
 
 
Tumor imaging (note separate 
schedule for PET-CT and CT 
with contrast)22 
x 
PET-CT: At Week 12 from 
C1D1, then every 12 weeks for 
96 weeks, and every 24 weeks 
thereafter, ± 14 days 
CT w/contrast: Every 24 weeks 
from C1D1, +/- 14 days 
x 23 
 
x 23 
ECHO or MUGA 24 
x 
 
 
 
 
 
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Screening 1 
Treatment Period 
Safety 
Follow-up 4 
Safety/Survival/Efficacy 
Follow-up 5 
Cycle 1  
(21 Days) 2 
Cycle 2 and 
additional 
cycles  
(every 21 
days) 
EOT 3 
Survival status 
 
 
 
 
 
x 
Study drug administration 
 
x 
x 
 
 
 
Pharmacokinetics 25 
 
x 
x 
 
x 
 
Anti-drug antibody 26 
 
x 
x 
 
x 
 
Patient-reported outcomes 28 
 
x 28 
x 28 
 
x 28 
 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, cycle; CBC, complete blood count; cHL, classical 
Hodgkin lymphoma; CR, complete response; CT, computed tomography; D, day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative 
Oncology Group; eCRF, electronic case report form; EOS, end of study; EOT, end-of-treatment; ESR, erythrocyte sedimentation rate; FFPE, formalin fixed 
paraffin-embedded; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; MRI, magnetic resonance imaging; irAE, immune-
related adverse event; MUGA, multigated acquisition scan; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; PCR, 
polymerase chain reaction; PD, progressive disease; PET, positron emission tomography; PK, pharmacokinetics; SAE, serious adverse event; TSH, thyroid 
stimulating hormone; T3, triiodothyronine; T4, thyroxine. 
 
1. All assessments mandated throughout the study must be performed on a calendar schedule. Screening procedures must be performed within 28 days prior to 
the first dose of treatment, unless noted otherwise. Once all screening assessments have been completed and study eligibility has been confirmed, study treatment 
must commence within 14 days of confirmation, which is within the 28-day screening window prior to the first dose of study treatment. Screening procedures 
that have a different visit window are indicated in parentheses.  
2. If screening lab assessment for eligibility is completed within 3 days of study drug administration, they do not need to be performed again for C1D1. Rescreening 
of patients will not be allowed, but laboratory parameters which do not meet the inclusion criteria may be re-tested within the screening window (Day -28 to 
Day -1). For C2D1 and all subsequent cycles, hematology and serum chemistry (including liver function tests) should be performed within 48 hours before 
study drug administration. For serum chemistry panel, a fasting blood sample is taken when possible, unless it is urgent.  
3. When patients go off treatment, they will need to have an EOT Visit within 30 days (+ 7 days) of last dose of tislelizumab. This visit may be considered the 
Safety Follow-up Visit.  
4. The mandatory Safety Follow-up Visit should be conducted within 30 days (+ 7 days) of the last dose of study treatment. In addition, telephone contacts (or 
clinic visit, if preferred) with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or a new anti-
lymphoma therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizumab. All AEs and SAEs, regardless of relationship to study drug, will be reported 
until 90 days after last dose of study treatment. Patients with an ongoing AE that leads to treatment discontinuation will be followed until either the event 
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resolves, the investigator assesses the event as stable, or the patient is lost to follow up, whichever comes first. Beyond 90 days, investigators should continue 
to report any SAEs that are believed to be related to study drug if they become aware of them. 
5. Following completion of the Safety follow-up phase, every effort should be made to follow patients for survival and for SAEs as described in Section 7.12 
approximately every 90 days (± 14 days) until PD, withdrawal of consent, death, loss to follow-up, or EOS, whichever occurs first. 
6. Written consent must be obtained prior to performing any protocol specific procedure except those done as standard of care. Results of a test performed as part 
of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 28 days prior to C1D1). Assign 
patient number when the study informed consent is signed. 
7. Includes history for the primary diagnosis (date of HL diagnosis and last recurrence, HL subtype, stage, International Prognostic Score [IPS], and biopsy 
details), treatment of HL including prior systemic, radiation and surgical treatment. Date of last prior cancer treatment must be documented. Report complete 
medication history for 28 days prior to the Screening Visit (Visit 1). 
8. Vital signs to include temperature, blood pressure, and pulse.  
9. Height is to be measured only on Day 1 of Cycle 1.  
10. A single 12-lead ECG will be performed by qualified site personnel after the patient has rested in a semi-recumbent or supine position for at least 5 minutes. 
Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the patient’s medical chart and the second copy will be 
kept in the study file for retrospective collection by the sponsor if necessary. The Screening ECG may be performed on Day 1 before the first dose. A single 
12-lead ECG can also be performed when clinically indicated at the discretion of the investigator during the study. 
11. Pulmonary function tests will include spirometry and lung diffusion capacity and must be performed within 4 weeks prior to first dose of tislelizumab. 
Pulmonary function tests can also be performed when clinically indicated at the discretion of the investigator during the study.  
12. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v5.0. All adverse experiences, whether gradable by CTCAE or not, 
will also be evaluated for seriousness. 
13. All concomitant medications within 28 days prior to first study treatment and 90 days after the last dose of study treatment should be recorded in the eCRFs. In 
addition, telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or a new 
anti-lymphoma therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizumab. Any new anti-lymphoma therapy, if taken after treatment 
discontinuation, will also be recorded. 
14. CBC and comprehensive serum chemistry panel, if obtained ≤ 3 days prior to Day 1 of Cycle 1 as part of screening, may be used as baseline, in which case 
retesting on Day 1 of Cycle 1 is not required. 
15. Testing will be performed at screening and includes Hepatitis C virus (HCV) antibody, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(HBsAb) and Hepatitis B core antibody (HBcAb). HIV results will be recorded if previously known. Patients who are HBcAb positive or HCV antibody positive 
at screening must not be enrolled until further testing by PCR to assess Hepatitis B or HCV viral load for determination of study eligibility as per 
Inclusion/Exclusion Criteria. (See Section 4 and Section 7.6.3 for additional information.)  
16. For all women of childbearing potential (including those who have had a tubal ligation), a serum pregnancy test will be performed at screening no more than 7 
days before the first dose of study drug. Urine pregnancy tests will be performed every cycle beginning with Cycle 2 during the treatment phase of the study. 
Pregnancy tests must be continued every 3 weeks for at least 30 days after the last dose of study drug. Pregnancy tests will be evaluated by local laboratories. 
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
17. TSH, free T4, and free T3 evaluations will be performed during the treatment period, at the EOT Visit and at the Safety Follow-up Visit.  
18. Liver function tests include ALT, AST, alkaline phosphatase, total bilirubin, and conjugated bilirubin and will be evaluated by a local laboratory. Liver function 
tests are required weekly during Cycles 1 and 2, with further monitoring if increases are observed in the first 2 cycles, according to Appendix 6. 
19. Pancreatic enzymes (amylase and lipase) will be tested if clinically indicated while on treatment.  
20. Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 unstained slides) for central confirmation of cHL diagnosis (central 
confirmation of diagnosis is not required for study entry) and biomarker analysis. Tumor tissue submission is mandatory for all patients who consent to 
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participate in the study, and an additional fresh baseline tumor biopsy (optional) at screening is strongly recommended. If a biopsy is not performed at screening, 
a sample of archival tumor tissue should be submitted from the confirmation of any relapse, with the most recent relapse sample being preferred. If tissue from 
a relapse is unavailable, archival tissue from the initial diagnosis may be submitted. An optional tumor biopsy will be taken from accessible tumor sites at the 
time of partial response to explore tumor biomarkers of tislelizumab response and resistance. For patients who have a confirmed disease progression during the 
study, optional biopsies will also be taken to explore resistance mechanisms (written informed consent is required prior to fresh tumor biopsy). If feasible, any 
follow-up biopsy should be ideally taken from the same tumor lesion as the screening biopsy.  
21. Optional blood samples will be taken at screening, at Weeks 3, 6, 12, 24, 48, and at the time of PD or 6 months after treatment to explore the association of 
blood-based biomarkers with response, resistance and prognosis to tislelizumab. 
22. Tumor imaging (PET-CT and CT with contrast of neck, chest, abdomen and pelvis) will be performed within 28 days prior to the first dose of study drug 
treatment. Any qualified imaging assessments already completed during the regular work-up of the patient are accepted within 28 days prior to start of treatment, 
including before signing the informed consent form, and can be considered as the screening/baseline image for this study. Imaging timing should follow calendar 
days and should not be adjusted for treatment delays. Tumor assessments by CT with contrast should be performed at screening and every 24 weeks (± 14 days) 
starting from Cycle 1 Day 1, until PD or treatment discontinuation, whichever is earlier. Target and non-target lesions must be identified at the time of screening 
and the same lesion(s) must be re-assessed by the investigator at each time point in a consistent manner in accordance with the Lugano Classification (Cheson 
et al 2014). The same diagnostic modality must be used throughout the study. At time points in which a CT scan with contrast is required, PET-CT may be 
adequate if the CT portion of the PET-CT is of diagnostic quality and contrast is administered. Total body MRI or CT without contrast of the chest plus MRI 
of the neck, abdomen, and pelvis may be substituted for CT if CT with contrast is contraindicated. PET-CT should be performed, in addition to during screening, 
at Week 12 from C1D1, then every 12 weeks for 96 weeks, and every 24 weeks thereafter (± 14 days). PET-CT should also be performed for PD suspected 
clinically and CR suspected clinically or by CT.  
23. Tumor imaging for the EOT Visit does not have to be performed if the most recent tumor imaging was performed within the previous 6 weeks. For patients 
who discontinue study treatment for reason other than PD, tumor imaging will be performed every 90 days (± 7 days) until PD, withdrawal of consent, death, 
loss to follow-up, or EOS, whichever occurs first. 
24. ECHO or MUGA is required at screening unless performed within 90 days of enrollment, subject to review and agreement by the medical monitor or designee. 
25. Samples for PK analysis will be collected only at sites that are able to adequately follow the sampling, handling, and processing procedures described in the 
Laboratory Manual. Samples for PK analysis will be collected predose (within 60 minutes before start of infusion) on Day 1 of Cycles 1, 2, 5, 9, and 17 and 
postdose (within 30 minutes after the end of infusion) on Day 1 of Cycles 1 and 5. Additional PK samples will be collected at the Safety Follow-up Visit. 
Should a patient experience any ≥ Grade 3 irAE, additional blood PK samples may be taken to determine the serum concentration of tislelizumab. 
26. Samples for anti-tislelizumab antibody analysis will be collected only at sites that are able to adequately follow the sampling, handling, and processing 
procedures. Procedures for collection of these samples are described in the Laboratory Manual. Blood for anti-tislelizumab antibodies should be collected within 
60 minutes before start of infusion on Day 1 of Cycles 1, 2, 5, 9, and 17, and at the mandatory Safety Follow-up Visit. All samples should be drawn at the same 
time as blood collection for PK predose sampling. In patients who discontinue study treatment before 6 months, every effort should be made to analyze anti-
tislelizumab antibodies approximately 6 months after the first dose. Analysis will be performed by a central laboratory. 
27. These tests should be completed within 3 days before the start of next cycle. 
28. All patients should complete the EQ-5D-5L and EORTC QLQ-C30 questionnaires before the first dose of study drug on C1D1, then every 12 weeks for 96 
weeks, then every 24 weeks thereafter until PD or treatment discontinuation, whichever is earlier, and at the Safety Follow-up Visit.  
29. Physical examination and CBC will be performed only for Efficacy Follow-up.  
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Serum Chemistry 
CBC With Differential 
Sodium 
Hematocrit 
Potassium 
Hemoglobin 
Chloride 
Platelet 
Bicarbonate 
WBC with differential: 
BUN 
 Neutrophil 
Creatinine 
 Lymphocyte 
LDH 
 Monocyte 
Glucose 
 Eosinophil 
Calcium 
 Basophil 
AST (SGOT) 
  
ALT (SGPT) 
  
Total bilirubin 
  
Conjugated bilirubin 
  
Alkaline phosphatase 
  
Total protein 
 
Magnesium 
 
Phosphorus 
 
Uric acid 
 
Albumin 
 
Creatine kinase (CK) 
 
Creatine kinase-cardiac muscle isoenzyme 
(CK-MB)* 
 
* In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; CBC, 
complete blood count; LDH: lactate dehydrogenase; SGOT: glutamic-oxaloacetic transaminase; SGPT: glutamic-
pyruvic transaminase; WBC: white blood cell (count). 
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APPENDIX 3. INTERNATIONAL PROGNOSTIC SCORE  
• Male sex 
• Age ≥ 45 years 
• Stage IV 
• Hemoglobin < 10.5 g/dL 
• White blood count ≥ 15 x 109/L 
• Lymphocyte count < 0.6 x 109/L or < 8% of differential 
• Albumin < 4 g/dL 
 
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APPENDIX 4. THE LUGANO CLASSIFICATION  
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the following): 
 Lymph nodes and 
 extra-lymphatic sites 
Score 1, 2, 3* with or without a residual mass on 
5PS□ 
It is recognized that in Waldeyer’s ring or extra-
nodal sites with physiologic uptake or with 
activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
• 
Target nodes/nodal masses must regress to ≤ 
1.5 cm in LDi 
• 
No extra-lymphatic sites of disease 
 Non-measured  
 lesion 
Not applicable 
Absent 
 Organ enlargement** 
Not applicable 
Regress to normal 
 New lesions 
None 
None 
 Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology, if indeterminate, IHC negative 
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
Partial 
Partial metabolic response 
Partial remission (all of the following): 
 Lymph nodes and 
 extra-lymphatic sites 
 
Score 4 or 5□ with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding 
disease 
 
At end of treatment, these findings indicate 
residual disease 
• 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extra-nodal sites 
• 
When a lesion is too small to measure on CT, 
assign 5 mm x 5 mm as the default value 
• 
When no longer visible, 0 x 0 mm 
• 
For a node > 5 mm x 5 mm, but smaller than 
normal, use actual measurement for calculation 
 Non-measured 
 lesions 
Not applicable 
Absent/normal, regressed, but no increase 
 Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal 
 New lesions 
None 
None 
 Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration should 
be given to further evaluation with MRI or biopsy 
or an interval scan 
Not applicable 
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
No response or stable disease 
No metabolic response 
Stable disease 
 Target nodes/nodal  
 masses, extra-nodal 
 lesions 
Score 4 or 5□ with no significant change in FDG 
uptake from baseline at interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extra-nodal sites; no 
criteria for progressive disease are met 
 Non-measured 
 lesions 
Not applicable 
No increase consistent with progression 
 Organ enlargement 
Not applicable 
No increase consistent with progression 
 New lesions 
None 
None 
 Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the following:  
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
Individual target  
 nodes/nodal masses 
Extranodal lesions 
 
Score 4 or 5□ with an increase in intensity of 
uptake from baseline and/or  
New FDG-avid foci consistent with lymphoma at 
interim or end of treatment assessment 
PPD progression: 
An individual node/lesion must be abnormal with: 
• 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
o 0.5 cm for lesions ≤ 2 cm 
o 1.0 cm for lesions > 2 cm 
• 
In the setting of splenomegaly, the splenic length 
must increase by > 50% of the extent of its prior 
increase beyond baseline (eg, a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 2 cm 
from baseline 
• 
New or recurrent splenomegaly 
Non-measured lesions 
None 
New or clear progression of pre-existing non-measured 
lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered 
• 
Regrowth of previously resolved lesions; a new 
node > 1.5 cm in any axis; 
• 
A new extra-nodal site > 1.0 cm in any axis; if < 
1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma; 
• 
Assessable disease of any size unequivocally 
attributable to lymphoma. 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
As published by Cheson et al 2014. 
 
Abbreviations: CT: Computed tomography; FDG: fluorodeoxyglucose; GI: gastrointestinal; IHC: immunohistochemistry; LDi: longest transverse diameter of a 
lesion; MRI, magnetic resonance imaging; PET: positron emission tomography; PET-CT: positron emission tomography-computed tomography; PPD: product of 
the LDi and perpendicular diameter; SDi: shortest axis perpendicular to LDi; SPD: sum of the product of the perpendicular diameters for multiple lesions 
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* Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extra-nodal lesions selected to be clearly measurable in two diameters. 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (eg, liver, spleen, kidneys, lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted on palpation. Non-measured 
lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, 
nodal masses, and extra-nodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extra-nodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
** Splenomegaly defined as vertical spleen length > 13 cm.  
□ PET 5-point scale (Deauville Criteria): 
1: no uptake above background 
2: uptake ≤ mediastinum 
3: uptake > mediastinum but ≤ liver 
4: uptake moderately > liver 
5: uptake markedly higher than liver and/or new lesions 
X: new areas of uptake unlikely to be related to lymphoma 
 
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APPENDIX 5. COMPARISON OF LYRIC CRITERIA AND LUGANO 
CLASSIFICATION  
Criteria 
CR 
PR 
PD** 
LYRIC 
Same as Lugano 
Same as Lugano 
As with Lugano with the 
following exceptions: 
Indeterminate Response 
(IR) - 
IR1: ≥ 50% increase in 
SPD* in first 12 weeks 
IR2: < 50% increase in 
SPD with: 
New lesion(s), OR 
≥ 50% increase in PPD of 
a lesion or set of lesions at 
any time during treatment 
IR3: Increase in FDG 
uptake without a 
concomitant increase in 
lesion size meeting 
criteria for PD 
As published by Cheson et al 2016. 
Abbreviations: CR: complete response; FDG: fluorodeoxyglucose; IR: indeterminate response; LDi, longest 
transverse diameter of a lesion; LYRIC, Lymphoma Response to Immunomodulatory Therapy Criteria; PD: disease 
progression; PPD: product of the LDi and perpendicular diameter; PR: partial response. 
 
Note: The study will use a modified version of the LYRIC criteria and Lugano Classification. For instances of 
observed indeterminate response (IR1, IR2, or IR3) as assessed by the investigator, pseudo-progression will be 
documented in the case report form to collectively represent all of the scenarios of indeterminate response. 
 
* SPD: sum of the product of the diameters 
** In patients categorized as having any of the above types of IR, it is mandatory to obtain a repeat imaging after an 
additional 12 weeks (or earlier if clinically indicated). At that time, response should be re-evaluated and the patient 
should be considered to have true disease progression if the SPD of the target lesion has increased further. Finally, 
if a patient is assessed as having IR (or pseudo-progression) and then true PD at a subsequent time point, the initial 
IR (or pseudo-progression) assessment should be corrected to PD.  
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APPENDIX 6. IMMUNE-RELATED ADVERSE EVENTS EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any irAE are intended as a 
guidance. This document should be used in conjunction with expert clinical judgement (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies. 
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, and 
adverse effects of concomitant drugs. In addition to the results of these tests, the following factors 
should be considered when making an irAE diagnosis:  
• What was the temporal relationship between the initiation of tislelizumab and the 
adverse event? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field, 
associated with the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of Possible Immune-related Adverse 
Events 
Immune-Related 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. 
Perform pituitary and whole brain MRI in patients with headache, visual 
disturbance, unexplained fatigue, asthenia, weight loss and unexplained 
constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or 
signs, such as an upper respiratory infection, new cough, shortness of 
breath or hypoxia should be assessed by high-resolution CT. Consider 
pulmonary function test including DLCO.  
Radiographic appearance is often nonspecific. Depending on the location 
of the abnormality, bronchoscopy and bronchoalveolar lavage or lung 
biopsy may be considered. Consult with a respiratory medicine physician 
for cases of uncertain cause.  
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Immune-Related 
Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all 
CNS symptoms; review alcohol history and other medications. Conduct a 
diabetic screen, and assess blood B12/folate, HIV status, TFTs, and 
consider autoimmune serology. Consider the need for brain/spine 
MRI/MRA and nerve conduction study for peripheral neuropathy. Consult 
with a neurologist if there are abnormal findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive 
testing, including the following: FBC, UEC, LFTs, CRP, TFTs, stool 
microscopy and culture, viral PCR, clostridium difficile toxin, 
cryptosporidia (drug-resistant organism).  
In case of abdominal discomfort, consider imaging (eg, X-ray, CT scan). If 
a patient experiences bleeding, pain or distension, consider colonoscopy 
with biopsy and surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye 
inflammation, blurred vision or other visual disturbances, refer the patient 
urgently to an ophthalmologist for evaluation and management.  
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend 
on severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, 
until recovering). Review medications (eg, statins, antibiotics) and alcohol 
history. Perform liver screen including: Hepatitis A/B/C serology, Hepatitis 
E PCR and assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. 
Consider imaging (eg, ultrasound scan for metastases or thromboembolism. 
Consult with a hepatologist and consider liver biopsy).  
Renal toxicity 
Review hydration status, and medication history. Test and culture urine. 
Consider renal ultrasound scan, protein assessment (dipstick/24-hour urine 
collection), or phase-contrast microscopy. Refer to nephrology for further 
management assistance.  
Dermatology 
Consider other causes by conducting a physical examination. Consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to 
rheumatology for further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, 
CRP, troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Primary adrenal 
insufficiency 
Evaluate ACTH (AM), cortisol level (AM), basic metabolic panel (sodium, 
potassium, carbon dioxide, glucose).  
Consider ACTH stimulation test for indeterminate results.  
If primary adrenal insufficiency (high ACTH, low cortisol) is found 
biochemically: 
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Immune-Related 
Toxicity 
Diagnostic Evaluation Guideline 
Evaluate for precipitating cause of crisis such as infection 
Perform an adrenal CT for metastasis/hemorrhage 
Hematologic toxicity 
May refer to ASCO guidelines (Brahmer et al 2018) for the diagnostic 
work-up of the following toxicities. Evaluation by a hematologist (may be 
treating physician, if appropriate) is strongly recommended. 
• 
Autoimmune hemolytic anemia 
• 
Acquired TTP 
• 
Hemolytic uremic syndrome 
• 
Aplastic anemia 
• 
Immune thrombocytopenia 
• 
Acquired hemophilia 
 
Abbreviations: ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AM, morning; ANA, 
antinuclear antibody; ASCO, American Society of Clinical Oncology; AST, aspartate aminotransferase; CK, creatine 
kinase; CK-MB, creatine kinase - cardiac muscle isozyme; CNS, central nervous system; CRP, C-reactive protein; 
CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, electrocardiogram; ESR, 
erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency virus; INR, international 
normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney microsomal antibody; LP, 
liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; PCR, polymerase 
chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, thyroxine; TFT, thyroid function tests; 
TSH, thyroid-stimulating hormone; TTP, thrombotic thrombocytopenia purpura; UEC, urea, electrolytes, and 
creatinine. 
Treatment of Immune-Related Adverse Events 
• Immune-related AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, with 
patients is required 
• Immune-related 
AEs 
should 
improve 
promptly 
after 
introduction 
of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice and contact the study medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor.  
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF] or 
azathioprine) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy 
• Patients who require prolonged corticosteroid treatment of >12 weeks for a drug-
related AE must permanently discontinue from study therapy  
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Thyroid Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to 
normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with 
a beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study treatment or 
withhold treatment in cases 
with systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization 
required 
Refer patient to an endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with comorbidities, 
the suggested starting dose is 0.5 
µg/kg/day). Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker and 
may require carbimazole until 
thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to Grade 
0-1. 
Hypophysitis 
1-2 
Mild-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary 
inflammation. Taper corticosteroids 
over at least 1 month. If there is no 
improvement in 48 hours, treat as 
Grade 3-4. Taper corticosteroids 
over at least 1 month. 
Continue study treatment. 
3-4 
Severe or life- 
threatening 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.  
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
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, or in the event of 
recurrent pneumonitis. 
3-4 
Severe or life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 
2 months. Cover with empiric 
antibiotics and consider prophylaxis 
for pneumocystis infection and 
other adverse steroid effects (eg, 
blood glucose monitoring, vitamin 
D/calcium supplement). 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
 
Continue study treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day. Taper over at least 4 
weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to Grade 
0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms. Taper 
corticosteroids over at least 4 
weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72 - 96 hours. 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Guillain-Barré 
syndrome 
Treat with intravenous 
immunoglobulin 0.4 g/kg/day for 
5 days or plasmapheresis. 
Consider corticosteroids 
(methylprednisolone 2 to 
4 mg/kg/day) followed by slow 
taper.  
 
Monitor for concurrent autonomic 
nervous system dysfunction. 
 
Discontinue study 
treatment. 
 
 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event 
Continue study treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day over 
baseline, or abdominal 
pain, or blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
Initiate IV methylprednisolone 1-
2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Consider prophylaxis for adverse 
steroid effects (eg, blood glucose 
monitoring, vitamin D/calcium 
supplement). 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, hepatitis, 
NYHA Grade III/IV CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the study 
medical monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Treat with topical emollients and/or 
mild to moderate potency topical 
corticosteroids. Counsel patients to 
avoid skin irritants and sun 
exposure. 
Continue study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Rash covers 10%-30% of 
BSA 
Consider initiating prednisone (or 
equivalent) at 1 mg/kg, tapering for 
a period of ≥ 4 weeks.  
In addition, treat with topical 
emollients, oral antihistamines, and 
medium to high potency topical 
corticosteroids. 
 
 
Consider holding 
tislelizumab and monitor 
weekly for improvement. If 
not resolved, interrupt 
treatment until dermatitis 
has improved to Grade 1. 
 
3 
Rash covers > 30% BSA 
or grade 2 with 
substantial symptoms 
Treat with topical emollients, oral 
antihistamines, and high-potency 
topical corticosteroids.  
Initiate (methyl)prednisolone (or 
equivalent) 1 to 2 mg/kg, tapering 
for a period of ≥ 4 weeks. 
 
 
Hold study treatment and 
consult with a dermatologist 
as needed. 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment) 
 
Hospitalize the patient and treat in 
collaboration with dermatology. 
Treat with intravenous 
(methyl)prednisolone 1 to 2 mg/kg 
(or equivalent) with tapering for a 
period of ≥ 4 weeks once toxicity 
resolves. 
 
Permanently discontinue 
study treatment and 
hospitalize the patient.  
 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
 
Refer the patient for specialized 
assessment and treatment. 
Hold study treatment if 
signs and symptoms of 
Stevens-Johnson syndrome 
or toxic epidermal 
necrolysis.  
 
If Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis of any 
grade is confirmed, 
permanently discontinue 
tislelizumab. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study treatment if 
LFTs are unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening until 
improvement is seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:  
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper 
over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Withhold study treatment 
until the event has resolved 
or improved to baseline 
grade and prednisolone has 
been tapered to 
≤ 10 mg/day.  
 
Tislelizumab may be 
reintroduced only:  
1) after the patient’s signs 
and symptoms of hepatitis 
return to baseline, and 
 2) if after careful 
consideration, the expected 
benefit of a rechallenge 
outweighs the risk to the 
patient. 
 
3 
ALT or AST 5-20X ULN 
Immediately start 
methylprednisolone 1 to 2 mg/kg 
(or equivalent). Monitor closely. If 
no improvement after 3 days, 
consider additional treatment 
options (mycophenolate mofetil or 
azathioprine). 
 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 to 2 mg/kg (or 
equivalent) 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. 
 
Permanently discontinue 
study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
4 
ALT or AST > 20X ULN 
Immediately begin treatment with 
methylprednisolone 2 mg/kg (or 
equivalent).  
 
Monitor closely. Obtain hepatology 
consultation. Consider additional 
treatment options (mycophenolate 
mofetil or azathioprine). 
Permanently discontinue 
study treatment. 
Hy’s Law: 
ALT or AST > 3X ULN 
and total bilirubin > 2X 
ULN; absence of initial 
findings of cholestasis or 
other reason(s) for 
concurrent increased 
AST or ALT, and total 
bilirubin 
Hepatology consultation 
Manage per hepatology consultation 
and per institutional guidance 
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone (Grade 2) change to pulsed IV methylprednisolone 
• 
If on IV add mycophenolate mofetil (MMF) 500-1000 mg twice a day or azathioprine 
(Grade 3 and 4) 
• 
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 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes 
Continue study treatment  
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management. Initiate IV 
(methyl)prednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone when amylase/lipase 
improved to Grade 2, and taper over 
at least 4 weeks 
Hold study treatment; 
reintroduce only after 
discussion with the study 
medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate 
referral.  
Discontinue study treatment 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study treatment 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental (fine 
motor) activities 
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms 
worsen on treatment manage as a 
Grade 3 event. 
Continue treatment or, if 
symptoms continue 
worsens, hold study 
treatment until symptoms 
improve to baseline or 
Grade 0-1 
3 and 4 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment unless 
improved to Grade 0-1; 
reintroduce only after 
discussion with the study 
medical monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline 
Continue study treatment 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage 
as a Grade 3 event. 
Continue study treatment 
3 
Severe pain, limited food 
and fluid intake, daily 
living activity limited 
Admit to hospital for appropriate 
management. Initiate IV 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone when symptoms 
improved to Grade 2 and taper over 
at least 4 weeks 
Hold study treatment until 
improved to grade 0-1. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider IV corticosteroids if 
not contraindicated by infection 
Discontinue study treatment 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2 
Continue study treatment 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment until 
improved to Grade 0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. If symptoms do not 
improve add immunosuppressant 
therapy. Taper oral steroids over at 
least 4 weeks 
Hold study treatment until 
improved to Grade 0-1. 
Discontinue if any evidence 
of myocardial involvement. 
Myocarditis 
1 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
If a diagnosis of myocarditis 
is confirmed, permanently 
discontinue study treatment 
in patients with moderate or 
severe symptoms. Patients 
with no symptoms or mild 
symptoms may not restart 
tislelizumab unless cardiac 
parameters have returned to 
baseline and after 
discussion with the study 
medical monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 1-2 
mg/kg/day. Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of 
(methyl)prednisolone 1g/day and 
add MMF, infliximab or anti-
thymocyte globulin 
Follow the same study drug 
management for Grade 1 
3 
Severe symptoms with 
mild exertion 
Discontinue study treatment 
4 
Life-threatening 
Discontinue study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Primary adrenal 
insufficiency 
1 
Asymptomatic or mild 
symptoms 
Endocrine consultation 
 
Replacement therapy with 
prednisone (5-10 mg daily) or 
hydrocortisone (10-20 mg orally 
every morning, 5-10 mg orally in 
early afternoon) 
 
May require fludrocortisone (0.1 
mg/day) for mineralocorticoid 
replacement in primary adrenal 
insufficiency. Titrate dose up or 
down as symptoms dictate. 
Consider holding study 
treatment until patient is 
stabilized on replacement 
hormone 
2 
Moderate symptoms, able 
to perform ADL 
Endocrine consultation 
 
Initiate outpatient treatment at 2-3 
times maintenance (if prednisone, 
20 mg daily; if hydrocortisone, 20-
30 mg in the morning, and 10-20 
mg in the afternoon) to manage 
acute symptoms. 
 
Taper stress-dose corticosteroids 
down to maintenance doses over 
5-10 days 
 
Maintenance therapy as in Grade 1. 
Consider holding study 
treatment until patient is 
stabilized on replacement 
hormone 
3-4 
Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL 
Endocrine consultation 
 
See in clinic or, for after hours, 
make an emergency department 
referral for normal saline (at least 2 
L) and IV stress-dose 
corticosteroids on presentation 
(hydrocortisone 100 mg or 
dexamethasone 4 mg [if the 
diagnosis is not clear and 
stimulation testing will be needed]) 
 
Taper stress-dose corticosteroids 
down to maintenance doses over 
7-14 days after discharge 
 
Maintenance therapy as in Grade 1 
Hold study treatment until 
patient is stabilized on 
replacement hormone 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Hematologic  
 
In general, refer to the ASCO 
practice guidelines on diagnostic 
work-up and management of these 
immune-related hematologic 
toxicities (Brahmer et al 2018). 
Treatment algorithms may vary 
according to individual institutional 
guidelines. 
In all cases of confirmed diagnosis, 
report to principal investigator of 
institution and Sponsors’ 
coordinating investigator(s) and 
medical monitor(s).  
 
Autoimmune 
hemolytic anemia 
(AHA) 
1 
Hgb < LLN to  
10.0 g/dL; < LLN to 6.2 
mmol/L; < LLN to 100 
g/L 
Close clinical follow-up and 
laboratory evaluation 
Continue study treatment 
2 
Hgb < 10.0 to  
8.0 g/dL; < 6.2 to 4.9 
mmol/L; < 100 to 80 g/L 
due to AHA 
Administer 0.5-1 mg/kg/d 
prednisone equivalents or as 
directed by treating hematologist 
and/or the principal investigator 
Hold study treatment and 
consider permanent 
discontinuation 
3 
Hgb < 8.0 g/dL;  
< 4.9 mmol/L;  
< 80 g/L; transfusion 
indicated due to AHA 
Hematology evaluation and hospital 
admission if indicated 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines 
Permanently discontinue 
study treatment 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
Hematology evaluation and hospital 
admission 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines 
Permanently discontinue 
study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Hemolytic uremic 
syndrome 
1-2 
Evidence of RBC 
destruction without 
clinical consequences or 
anemia, 
thrombocytopenia Grade 
2 
Close clinical follow-up and 
laboratory evaluation 
Supportive care 
Continue study treatment  
3 
Laboratory findings with 
clinical consequences 
Hematology evaluation and hospital 
admission if indicated 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines 
Permanently discontinue 
study treatment 
4 
Life-threatening 
consequences 
Acquired 
hemophilia 
1 
Mild, 5-40% of normal 
factor activity in blood, 
0.05-0.4 IU/mL of whole 
blood 
Administer 0.5-1 mg/kg/d 
prednisone or as directed by treating 
hematologist and/or the principal 
investigator 
Transfusion support as required 
Treatment of bleeding disorders  
Hold study treatment and 
discuss resumption with 
patient only after taking into 
account the risks and 
benefits 
2 
Moderate, 1-5% of 
normal factor activity in 
blood, 0.01-0.05 IU/mL 
of whole blood 
Hematology evaluation 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines  
3-4 
Severe, < 1% of normal 
factor activity in blood,  
< 0.01 IU/mL of whole 
blood 
Hematology evaluation and hospital 
admission 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines 
Permanently discontinue 
study treatment 
Acquired TTP 
1 
Evidence of RBC 
destruction without 
anemia, renal 
insufficiency, or 
thrombocytopenia 
clinically 
Stabilize patient (if needed) with 
any critical organ dysfunction 
stabilized 
 
Hematology evaluation 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
Hold study treatment and 
discuss resumption only 
after taking account the 
risks/benefits, noting that 
there are currently no data 
to recommend restarting 
ICPi therapy 
2 
Evidence of RBC 
destruction without 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
clinical consequence with 
Grade 2 anemia and 
thrombocytopenia 
investigator; consult ASCO 
guidelines  
 
For Grade 4, in conjunction with 
hematology, initiate plasma 
exchange according to existing 
guidelines 
3 
Laboratory findings with 
clinical consequences 
(Grade 3 
thrombocytopenia, 
anemia, renal 
insufficiency > Grade 2) 
4 
Life-threatening 
consequences (eg, CNS 
hemorrhage or 
thrombosis/ 
embolism or renal 
failure) 
Aplastic anemia 
1 
Nonsevere, > 0.5 
polymorphonuclear cells 
x 109/L hypocellular 
marrow, with cellularity  
< 25%, peripheral platelet 
count 
> 20,000, reticulocyte 
count > 20,000 
Provide growth factor support and 
close clinical follow-up, and 
laboratory evaluation 
 
Supportive transfusions per existing 
guidelines 
Hold study treatment 
2 
Severe, hypocellular 
marrow < 25% and two 
of the following: ANC  
< 500, peripheral platelet 
< 20,000, and 
reticulocyte  
< 20,000 
Hematology evaluation 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines 
3-4 
Very severe, ANC  
< 200, platelet count  
< 20,000, reticulocyte 
count  
< 20,000, plus 
hypocellular marrow  
< 25% 
Hematology evaluation 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines  
 
Monitor for weekly improvement 
Hold study treatment; if not 
improved to Grade 1, 
discontinue study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Immune 
thrombocytopenia 
1 
Platelet count  
< 100/µL 
Close clinical follow-up and 
laboratory evaluation 
Continue study treatment 
2 
Platelet count  
< 75/µL 
Administer prednisone 1mg/kg/d 
(range, 0.5-2 mg/kg/d) orally for 2-
4 weeks before tapering over 4-6 
weeks to lowest effective dose (or 
as directed by treating hematologist 
and/or the principal investigator); 
IVIG may be added if more rapid 
platelet increase is required 
Hold study treatment; may 
resume when Grade 1 or 
baseline 
3 
Platelet count  
< 50/µL 
Hematology evaluation 
 
Administer treatment based on 
recommendation from the treating 
hematologist and/or the principal 
investigator; consult ASCO 
guidelines  
4 
Platelet count  
< 25/µL 
 
Abbreviations: ADL, activities of daily living; AE, adverse event; ALT, alanine aminotransferase; ASCO, American 
Society of Clinical Oncology; AST, aspartate aminotransferase; BSA, body surface area; CHF, chronic heart failure; 
CK, creatine kinase; CK-MB, creatine kinase-cardiac muscle isoenzyme; ICPi, immune checkpoint inhibitor; INR, 
international normalized ratio; IV, intravenous; IVIG, intravenous immunoglobulin; LFT, liver function test; MMF, 
mycophenolate mofetil; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid 
function test; TTP, thrombotic thrombocytopenia purpura; TSH, thyroid-stimulating hormone; U&E, urea and 
electrolytes; ULN, upper limit of normal. 
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APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX 8. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease.  
Please contact the sponsor medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control. These methods 
include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized male partner is considered highly effective form of birth control only 
under the following preconditions:  
− Vasectomized partner is the sole sexual partner of the WOCBP trial participant 
− Vasectomized partner has received medical assessment of surgical success.  
− NOTE: Sterile males are those for whom azoospermia, in a semen sample 
examination, has been demonstrated as definitive evidence of infertility.  
− Males with ‘low sperm counts’ (consistent with ‘sub-fertility’) are not to be 
considered sterile for purposes of this study.  
• 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, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is 
not considered a highly effective method of contraception and if used, this method must be 
combined with a highly effective form of birth control, listed above. 
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Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
• ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
• < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
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APPENDIX 10. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 
5-LEVELS HEALTH QUESTIONNAIRE  
 
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APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30  
 
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