A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a Phosphatidylinositol 3-Kinase Delta (PI3Kδ) Inhibitor, Combined With Zanubrutinib in Patients With Mature B-Cell Malignancies and Combined With Tislelizumab in Patients With Solid Tumors
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Diffuse Large B Cell Lymphoma, Advanced Solid Tumor
Sponsor: BeiGene

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a 
Phosphatidylinositol 3-Kinase Delta (PI3Kδ) Inhibitor, Combined With 
Zanubrutinib in Patients With Mature B-Cell Malignancies and 
Combined With Tislelizumab in Patients With Solid Tumors 
Protocol Identifier: 
BGB-A317-3111-10188-101 
Phase: 
1/2 
Investigational Product(s): 
BGB-10188, zanubrutinib (BGB-3111), tislelizumab (BGB-A317) 
Indication: 
Mature B-cell malignancies and advanced solid tumors 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive 
3rd Floor 
San Mateo, CA 94404 USA 
BeiGene (Suzhou) Co., Ltd* 
Building 9, Biological Industrial Park 
No. 218 Sangtian Street 
Suzhou Industrial Park 
China (Jiangsu) Pilot Free Trade Zone 
Suzhou, Jiangsu, 215123, China 
* China sponsor for this study
Sponsor Medical Monitor 
 
Telephone: 
 
Email: 
 
Original Protocol 
11 November 2019 
Version 1.0 
05 February 2020 
Version 2.0 
12 January 2021 
Version 3.0 
19 August 2021 
Version 4.0 
25 April 2022 
Version 5.0 
25 November 2022 
Version 6.0 
16 June 2023 
Version 7.0 
10 April 2024 
Approved Date
4/10/2024
NCT Number
NCT04282018

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 2 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd. and its 
affiliates.  This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s).  This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its affiliates.  Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without the prior written authorization 
from BeiGene, Ltd. or one of its affiliates. 
Approved Date
4/10/2024

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 3 
FINAL PROTOCOL APPROVAL SHEET  
 
A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a Phosphatidylinositol 
3-Kinase Delta (PI3Kδ) Inhibitor, Combined With Zanubrutinib in Patients With Mature B-Cell 
Malignancies and Combined With Tislelizumab in Patients With Solid Tumors 
BeiGene, Ltd. Approval: 
 
 
 
 
 
 
 
 
 
 
 
 
See electronic signature 
 
See electronic signature 
Sponsor Medical Monitor 
 
Date 
 
 
Approved Date
4/10/2024

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
The primary purposes of Amendment 7.0 are to reflect that Part C will not be initiated and that 
the higher doses of Part B will not enroll patients, and to add one condition for the end of study. 
The changes made in this amendment are described in the table below.  Editorial and formatting 
changes are not included in this summary.   
Protocol Amendment Summary of Changes Table  
Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 2.1, Section 3.1, 
Section 3.3, Section 7.7, 
Section 9.8  
Added or modified language to 
reflect that Part C (BGB-10188+ 
zanubrutinib dose expansion in 
patients with R/R FL, R/R 
MCL, R/R DLBCL) will not be 
initiated 
Dose escalation of combination 
therapy (Part B) was suspended 
and no further development for 
combination therapy. 
Section 5.5.1.1  
Added safety management 
guidelines for diarrhea/colitis, 
rash, and pneumonitis to 
BGB-10188 in heme parts 
Clarifying and improving safety 
management and monitoring 
regarding these potential safety 
risks. 
Section 7.14  
Added one condition for “the 
end of the study” for each part, 
which is at 12 months from 
C1D1 of the last enrolled patient 
in this part. 
Clarifying wording regarding 
study closure. 
Section 8.6.2.1, Section 8.6.2.2, 
Section 8.7.2  
Added reporting requirements of 
adverse events of special interest 
(ie, diarrhea ≥ Grade 2 or 
Grade 1 lasting more than 
7 days) for BGB-10188 
Clarifying and improving safety 
management and monitoring 
regarding these potential safety 
risks. 
Section 8.6.2  
Updated the Reporting Method 
to Email or fax SAE form 
More efficient reporting of 
SAEs. 
Section 7.12.2, Appendix 1  
Removed survival follow-up for 
patients in Part B 
Maintaining consistency with 
study endpoints for Part B 
throughout the protocol.  
Section 1.2.4, Section 1.5, and 
Section 8.1  
Updated Prior Clinical 
Experience with BGB-10188, 
Benefit-Risk Assessment, and 
Risks Associated with Study 
Drug  
Providing the most current 
available data. 
Section 1.2, Section 8.1  
Modified language on 
zanubrutinib and tislelizumab 
approval status 
Providing the most current 
available information. 
Section 8.6.5 and Section 8.6.6  
Updated with clarified language 
for reporting disease progression 
and death on study 
Providing clearer instructions 
for investigators. 
Approved Date
4/10/2024

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 5 
Section Number and Title 
Summary of Change 
Brief Rationale for Change 
Section 9.4.3  
Modified language on PFS 
estimation in Part E 
Clarifying planned analysis 
method 
Section 10.1  
Updated language on SMC 
meeting in Part E 
Better reflecting study 
committee practices 
Section 7.7, Section 7.8, 
Appendix 5  
“First 5 patients in Part C and 
Part E, phospho-AKT 
expression in blood samples will 
be determined and used as a 
direct pharmacodynamic 
biomarker for PI3Kδ 
inhibition”, changed to 
“approximately 5 patients…” 
Correction of typographical 
errors 
Approved Date
4/10/2024

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 6 
TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................14 
SYNOPSIS…… .............................................................................................................................15 
LIST OF ABBREVIATIONS AND TERMS ................................................................................27 
1. 
INTRODUCTION AND RATIONALE .....................................................................30 
1.1. 
Background on Phosphatidylinositol 3-Kinase δ........................................................30 
1.2. 
Background Information on BGB-10188 (PI3Kδ Inhibitor), Zanubrutinib 
(BTK Inhibitor), and Tislelizumab (PD-1 Antibody) .................................................31 
1.2.1. 
Pharmacology .............................................................................................................33 
1.2.2. 
Toxicology ..................................................................................................................33 
1.2.3. 
Clinical Pharmacology ................................................................................................35 
1.2.4. 
Prior Clinical Experience ............................................................................................36 
1.2.4.1. 
BGB-10188 .................................................................................................................36 
1.2.4.2. 
Zanubrutinib ...............................................................................................................36 
1.2.4.3. 
Tislelizumab ...............................................................................................................36 
1.3. 
Study Rationale ...........................................................................................................37 
1.3.1. 
Rationale for Combination of BGB-10188 and Zanubrutinib in the 
Treatment of B-Cell Malignancies .............................................................................37 
1.3.2. 
Rationale for Combination of BGB-10188 and Tislelizumab in the 
Treatment of Advanced Solid Tumors .......................................................................37 
1.3.2.1. 
Rationale for Combination of BGB-10188 and Tislelizumab in the 
Treatment of Platinum-Resistant Ovarian Cancer ......................................................38 
1.4. 
Dose Rationales ..........................................................................................................39 
1.4.1. 
BGB-10188 in Monotherapy Escalation Phase (Part A) ............................................39 
1.4.2. 
BGB-10188 With Zanubrutinib in Combination Escalation Phase (Part B) ..............39 
1.4.3. 
BGB-10188 With Tislelizumab in Combination Escalation Phase (Part D) ..............40 
1.4.4. 
BGB-10188 With Tislelizumab in Combination Expansion Phase (Part E) ..............40 
1.5. 
Benefit-Risk Assessment ............................................................................................40 
1.5.1. 
Benefit-Risk Assessment for BGB-10188 Monotherapy in the Treatment of 
B-Cell Malignancies ...................................................................................................40 
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BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 7 
1.5.2. 
Benefit-Risk Assessment for the Combination of BGB-10188 and 
Zanubrutinib in the Treatment of B-Cell Malignancies .............................................41 
1.5.3. 
Benefit-Risk Assessment for the Combination of BGB-10188 and 
Tislelizumab in the Treatment of Advanced Solid Tumors ........................................42 
1.6. 
Study Conduct ............................................................................................................43 
2. 
STUDY OBJECTIVES ..............................................................................................44 
2.1. 
Study Objectives .........................................................................................................44 
3. 
STUDY DESIGN .......................................................................................................48 
3.1. 
Summary of Study Design ..........................................................................................48 
3.2. 
Details of Dose Escalation ..........................................................................................52 
3.2.1. 
Starting Dose and Dose Escalation Approach ............................................................52 
3.2.2. 
Rules for Dose Escalation and Dose Verification ......................................................53 
3.2.3. 
Assessment of Dose-Limiting Toxicity ......................................................................55 
3.2.4. 
Dose-Limiting Toxicity Definition .............................................................................56 
3.2.5. 
Recommended Dose For Expansion Determination ...................................................57 
3.3. 
Details of Dose Expansion ..........................................................................................57 
3.3.1. 
Study Design of Part E ...............................................................................................57 
4. 
STUDY POPULATION .............................................................................................59 
4.1. 
Inclusion Criteria ........................................................................................................59 
4.2. 
Exclusion Criteria .......................................................................................................62 
5. 
STUDY TREATMENT ..............................................................................................71 
5.1. 
Study Treatment Preparation and Dispensation .........................................................71 
5.1.1. 
BGB-10188 .................................................................................................................71 
5.1.2. 
Zanubrutinib ...............................................................................................................71 
5.1.3. 
Tislelizumab ...............................................................................................................71 
5.2. 
Dosage and Administration ........................................................................................72 
5.2.1. 
BGB-10188 .................................................................................................................72 
5.2.2. 
Zanubrutinib ...............................................................................................................72 
5.2.3. 
Tislelizumab ...............................................................................................................73 
5.3. 
Compliance and Accountability .................................................................................73 
5.4. 
Overdose .....................................................................................................................74 
5.5. 
Dose Hold or Modification .........................................................................................74 
5.5.1. 
BGB-10188 .................................................................................................................74 
Approved Date
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BGB-A317-3111-10188-101 
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Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
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5.5.1.1. 
Dose Escalation ..........................................................................................................74 
5.5.1.2. 
Dose Expansion (Part E) .............................................................................................76 
5.5.2. 
Zanubrutinib ...............................................................................................................79 
5.5.2.1. 
Zanubrutinib Dose Reductions for Hematologic Toxicity .........................................79 
5.5.2.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity ...................................80 
5.5.3. 
Tislelizumab ...............................................................................................................81 
5.6. 
Management Guidelines for Treatment-Related Diarrhea or Colitis (Part E) ............81 
5.7. 
Precautions ..................................................................................................................83 
6. 
CONCOMITANT THERAPY ...................................................................................84 
6.1. 
Concomitant Therapy .................................................................................................84 
6.1.1. 
Permitted Concomitant Medications/Procedures .......................................................84 
6.1.1.1. 
Part A, Part B, and Part C ...........................................................................................84 
6.1.1.2. 
Part D and Part E ........................................................................................................85 
6.1.2. 
Prohibited Concomitant Medications/Procedures ......................................................86 
6.1.3. 
Restricted Concomitant Medications/Procedures .......................................................86 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................86 
7. 
ENROLLMENT AND STUDY PROCEDURES ......................................................88 
7.1. 
Screening Period .........................................................................................................88 
7.1.1. 
Informed Consent and Screening Log ........................................................................88 
7.1.2. 
Demographics .............................................................................................................88 
7.1.3. 
Patient Numbering ......................................................................................................89 
7.2. 
Enrollment ..................................................................................................................89 
7.2.1. 
Randomization (Part E) ..............................................................................................89 
7.3. 
Treatment Period ........................................................................................................89 
7.3.1. 
Treatment Period (Part E) ...........................................................................................90 
7.4. 
Visit Windows ............................................................................................................90 
7.5. 
Safety Assessments .....................................................................................................91 
7.5.1. 
Physical Examination and Vital Signs ........................................................................91 
7.5.2. 
Ophthalmologic Examination (Part D) .......................................................................91 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status ........................................91 
7.5.4. 
Laboratory Safety Tests ..............................................................................................92 
7.5.5. 
Electrocardiograms .....................................................................................................93 
Approved Date
4/10/2024

BGB-A317-3111-10188-101 
BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 9 
7.5.6. 
Adverse Events ...........................................................................................................93 
7.5.7. 
Hepatitis B and C Testing ...........................................................................................93 
7.5.7.1. 
Part A, Part B, Part C, and Part D ...............................................................................93 
7.5.7.2. 
Part E ..........................................................................................................................95 
7.5.8. 
Cardiac Enzyme Monitoring (Part D and Part E) .......................................................95 
7.5.9. 
Cytomegalovirus Monitoring ......................................................................................95 
7.6. 
Tumor and Response Evaluations ..............................................................................95 
7.6.1. 
Treatment After Disease Progression (Part A) ...........................................................97 
7.6.2. 
Treatment After Primary Progression of Disease (Part D and Part E) .......................98 
7.6.3. 
CA-125 Tumor Evaluations (Part E) ..........................................................................98 
7.7. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................98 
7.8. 
Pharmacodynamics ...................................................................................................100 
7.9. 
Biomarkers ................................................................................................................101 
7.10. 
Unscheduled Visits ...................................................................................................102 
7.11. 
End-of-Treatment Visit .............................................................................................103 
7.12. 
Follow-up Periods .....................................................................................................103 
7.12.1. 
Safety Follow-up Period ...........................................................................................103 
7.12.2. 
Survival Follow-up ...................................................................................................104 
7.12.3. 
Lost to Follow-up .....................................................................................................104 
7.13. 
Discontinuation From Study Treatment or From the Study .....................................104 
7.13.1. 
Patient Discontinuation From Study Treatment .......................................................104 
7.13.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ......................................................................................................................104 
7.14. 
End of Study .............................................................................................................105 
8. 
SAFETY MONITORING AND REPORTING .......................................................107 
8.1. 
Risks Associated With Study Drug ..........................................................................107 
8.1.1. 
Risks Associated With BGB-10188 .........................................................................107 
8.1.1.1. 
Safety Data From Study BGB-10188-101 ................................................................108 
8.1.2. 
Risks Associated With Zanubrutinib ........................................................................110 
8.1.3. 
Risks Associated With Tislelizumab ........................................................................110 
8.2. 
General Plan to Manage Safety Concerns ................................................................110 
8.2.1. 
Eligibility Criteria .....................................................................................................110 
8.2.2. 
Safety Monitoring Plan .............................................................................................110 
Approved Date
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BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
Page 10 
8.3. 
Adverse Events .........................................................................................................111 
8.3.1. 
Definitions and Reporting .........................................................................................111 
8.3.2. 
Assessment of Severity .............................................................................................112 
8.3.3. 
Assessment of Causality ...........................................................................................112 
8.3.4. 
Following Adverse Events ........................................................................................113 
8.3.5. 
Laboratory Test Abnormalities .................................................................................114 
8.4. 
Definition of a Serious Adverse Event .....................................................................114 
8.5. 
Suspected Unexpected Serious Adverse Reaction ...................................................115 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events .........................................................................................................115 
8.6.1. 
Adverse Event Reporting Period ..............................................................................115 
8.6.2. 
Reporting Serious Adverse Events ...........................................................................116 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events and Adverse Events of Special 
Interest ......................................................................................................................116 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report and 
Adverse Events of Special Interest ...........................................................................117 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events ...........................117 
8.6.3. 
Eliciting Adverse Events ..........................................................................................117 
8.6.4. 
Diagnosis Versus Signs and Symptoms ...................................................................117 
8.6.5. 
Disease Progression ..................................................................................................118 
8.6.6. 
Death on Study .........................................................................................................118 
8.6.7. 
Pregnancies ...............................................................................................................118 
8.6.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ..............................................119 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events (Part D and 
Part E) .......................................................................................................................119 
8.6.10. 
Assessing and Recording Infusion-Related Reactions (Part D and Part E) ..............119 
8.7. 
Management of Adverse Event of Special Interest (AESI) (Part D and 
Part E) .......................................................................................................................119 
8.7.1. 
AESI of Tislelizumab ...............................................................................................119 
8.7.1.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ....................................119 
8.7.1.2. 
Immune-Mediated Adverse Events ..........................................................................120 
8.7.2. 
AESI of BGB-10188 .................................................................................................121 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...............122 
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BeiGene 
Protocol Amendment 7.0 
10 April 2024 
 
CONFIDENTIAL 
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9.1. 
Bayesian Model-based Dose Escalation Design .......................................................122 
9.1.1. 
Planned Dose/Combination Levels...........................................................................122 
9.1.2. 
Cohort Size ...............................................................................................................122 
9.1.3. 
Statistical Models ......................................................................................................123 
9.1.3.1. 
Bayesian Logistic Regression Model .......................................................................123 
9.1.3.2. 
Bayesian Proportional Hazard Model .......................................................................123 
9.1.4. 
Next Dose Recommendation Rules ..........................................................................124 
9.1.5. 
Escalation Phase Stopping and MTD Recommendation Rules ................................125 
9.2. 
Study Endpoints ........................................................................................................125 
9.3. 
Statistical Analysis ....................................................................................................129 
9.3.1. 
Analysis Sets .............................................................................................................129 
9.3.1.1. 
Part A, Part B, and Part C .........................................................................................129 
9.3.1.2. 
Part D ........................................................................................................................129 
9.3.1.3. 
Part E ........................................................................................................................129 
9.3.2. 
Randomization Method (Part E) ...............................................................................130 
9.3.3. 
Patient Disposition ....................................................................................................130 
9.3.4. 
Demographic and Other Baseline Characteristics ....................................................130 
9.3.5. 
Disease History .........................................................................................................130 
9.3.6. 
Prior and Concomitant Medications .........................................................................130 
9.3.7. 
Medical History ........................................................................................................131 
9.4. 
Efficacy Analyses .....................................................................................................131 
9.4.1. 
Part A, Part B, and Part C .........................................................................................131 
9.4.2. 
Part D ........................................................................................................................132 
9.4.3. 
Part E ........................................................................................................................132 
9.5. 
Safety Analyses ........................................................................................................133 
9.5.1. 
Extent of Exposure ...................................................................................................134 
9.5.2. 
Dose-Limiting Toxicities ..........................................................................................134 
9.5.3. 
Adverse Events .........................................................................................................134 
9.5.4. 
Laboratory Analyses .................................................................................................134 
9.5.5. 
Vital Signs Analyses .................................................................................................135 
9.5.6. 
Ophthalmologic Examination (Part D) .....................................................................135 
9.6. 
Pharmacokinetic Analyses ........................................................................................135 
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Protocol Amendment 7.0 
10 April 2024 
 
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9.7. 
Other Analyses ..........................................................................................................136 
9.7.1. 
Related PK Analyses ................................................................................................136 
9.7.2. 
Immunogenicity Analyses ........................................................................................136 
9.8. 
Determination of Sample Size ..................................................................................136 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................138 
10.1. 
Safety Monitoring Committee ..................................................................................138 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................139 
11.1. 
Access to Information for Monitoring ......................................................................139 
11.2. 
Access to Information for Auditing or Inspections ..................................................139 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................140 
12.1. 
Regulatory Authority Approval ................................................................................140 
12.2. 
Quality Assurance .....................................................................................................140 
12.3. 
Study Site Inspections...............................................................................................140 
12.4. 
Drug Accountability .................................................................................................140 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................142 
13.1. 
Ethical Standard ........................................................................................................142 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................142 
13.2.1. 
Protocol Amendments ..............................................................................................142 
13.3. 
Informed Consent .....................................................................................................143 
13.4. 
Patient and Data Confidentiality ...............................................................................143 
13.5. 
Financial Disclosure .................................................................................................145 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................146 
14.1. 
Data Collection and Management Responsibilities ..................................................146 
14.1.1. 
Data Collection .........................................................................................................146 
14.1.2. 
Data Management/Coding ........................................................................................146 
14.2. 
Study Records Retention ..........................................................................................146 
14.3. 
Protocol Deviations ..................................................................................................147 
14.4. 
Publication and Data-Sharing Policy ........................................................................148 
14.5. 
Study and Study Center Closure ...............................................................................148 
14.6. 
Information Disclosure and Inventions ....................................................................149 
15. 
REFERENCES .........................................................................................................151 
APPENDIX 1. PART A AND PART B SCHEDULE OF ASSESSMENTS ...........................156 
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APPENDIX 2. PART C SCHEDULE OF ASSESSMENTS ...................................................160 
APPENDIX 3. PART D SCHEDULE OF ASSESSMENTS ...................................................164 
APPENDIX 4. PART E SCHEDULE OF ASSESSMENTS ....................................................168 
APPENDIX 5. SCHEDULE OF PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS.......................................................................................................173 
APPENDIX 6. PART D AND PART E SCHEDULE OF PK/ADA ASSESSMENTS ...........176 
APPENDIX 7. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................178 
APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................180 
APPENDIX 9. INFUSION-RELATED REACTIONS, HYPERSENSITIVITY 
REACTIONS AND IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT .................................................................181 
APPENDIX 10. CYP3A INHIBITORS AND INDUCERS .....................................................200 
APPENDIX 11. DOSE MODIFICATION TABLE FOR ZANUBRUTINIB WHEN 
COADMINISTERED WITH STRONG/MODERATE CYP3A 
INHIBITORS OR INDUCERS ................................................................................201 
APPENDIX 12. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................202 
APPENDIX 13. THE LUGANO CLASSIFICATION FOR NON-HODGKIN 
LYMPHOMA (CHESON 2014) ..............................................................................203 
APPENDIX 14. CLL RESPONSE DEFINITIONS (IWCLL 2018) ........................................206 
APPENDIX 15. GRADING SCALE FOR HEMATOLOGIC TOXICITY IN CLL 
STUDIES ..................................................................................................................208 
APPENDIX 16. ECOG PERFORMANCE STATUS...............................................................209 
APPENDIX 17. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................210 
APPENDIX 18. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................220 
APPENDIX 19. SIGNATURE OF INVESTIGATOR .............................................................222 
APPENDIX 20. EVALUATION OF RESPONSE ACCORDING TO CA-125 ......................223 
 
LIST OF TABLES  
Table 1: 
Guidelines for Dose Modifications of BGB-10188 in Part A and B ..........................75 
Table 2: 
BGB-10188 Dose Reduction Levels in Part E ...........................................................76 
Approved Date
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Table 3: 
Guidelines for Dose Modifications of BGB-10188 in Part E .....................................77 
Table 4: 
Guidelines for Dose Modifications of BGB-10188 Regarding AEs not 
Mentioned in Table 3 in Part E ...................................................................................78 
Table 5: 
Zanubrutinib Dose Reduction Levels .........................................................................79 
Table 6: 
Zanubrutinib Dose Reduction Steps for Nonhematologic Toxicity ...........................80 
Table 7: 
Evaluation and Diagnostic Testing Recommendations for Subjects 
Presenting Diarrhea ....................................................................................................82 
Table 8: 
Diet Modification Recommendations for Subjects With Diarrhea .............................82 
Table 9: 
Management and Dose Modification Guidance for Treatment-Related 
Diarrhea/Colitis ...........................................................................................................82 
Table 10: Hepatitis B Eligibility Criteria ....................................................................................94 
Table 11: Hepatitis C Eligibility Criteria ....................................................................................94 
Table 12: Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms ..................................................................................................116 
Table 13: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events and Adverse Events of Special Interest to the Sponsor or Designee ............116 
Table 14: Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) .......................................................................................................120 
Table 15: Examples of Immune-Mediated Adverse Events .....................................................121 
Table 16: Two-Sided 95% Confidence Interval for ORR With 10/20/30 Patients ...................137 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................49 
Figure 2: 
Study Schema of Part E ..............................................................................................58 
 
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SYNOPSIS……   
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Products: BGB-10188, zanubrutinib (BGB-3111), and tislelizumab 
(BGB-A317) 
Title of Study: A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a 
Phosphatidylinositol 3-Kinase Delta (PI3Kδ) Inhibitor, Combined With Zanubrutinib in 
Patients With Mature B-Cell Malignancies and Combined With Tislelizumab in Patients With 
Solid Tumors 
Protocol Identifier: BGB-A317-3111-10188-101 
Phase of Development: 1/2 
Number of Patients: Part A (n = 3 to 30, approximately) plus China verification part (n ≥ 3); 
Part B (n = 3 to 18, approximately); Part D (n = 3 to 30, approximately) plus China 
verification part (n ≥ 3); Part E (n = 30 to 50, approximately) 
Study Centers: Approximately 35 in Australia and China (final site number may change) 
Study Objectives: 
Part A: BGB-10188 Monotherapy Dose Escalation in Patients With Relapsed/Refractory 
(R/R) Mature B-cell Malignancies 
Primary: 
• To determine the maximum tolerated dose (MTD) and the recommended dose for 
expansion (RDFE) of BGB-10188 as monotherapy  
• To assess the safety and tolerability of BGB-10188 as monotherapy  
Secondary: 
• To evaluate the preliminary antitumor activity of BGB-10188 monotherapy as 
measured by investigator-assessed overall response rate 
• To characterize the pharmacokinetic profiles of BGB-10188 as monotherapy  
Exploratory: 
• To explore relationships between BGB-10188 concentrations and corrected QTcF 
intervals 
• To characterize the pharmacodynamic profiles of BGB-10188 after a single dose 
and at steady state 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 monotherapy 
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Part B: BGB-10188 + Zanubrutinib Dose Escalation in Patients With R/R Follicular 
Lymphoma, R/R Mantle Cell Lymphoma, or R/R Diffuse Large B-cell Lymphoma  
Primary: 
• To determine the MTD and the RDFE of BGB-10188 in combination with 
zanubrutinib 
• To assess the safety and tolerability of BGB-10188 in combination with 
zanubrutinib 
Secondary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed overall response rate, duration 
of response (DOR), and time to response 
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
zanubrutinib 
Exploratory: 
• To characterize the pharmacokinetic profile of zanubrutinib when given in 
combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
zanubrutinib 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 in combination with zanubrutinib  
Part C: BGB-10188 + Zanubrutinib Dose Expansion in Patients With R/R Follicular 
Lymphoma, R/R Mantle Cell Lymphoma, or R/R Diffuse Large B-cell Lymphoma 
Primary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed overall response rate  
Secondary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed duration of response, time to 
response, and progression-free survival  
• To assess the safety and tolerability of BGB-10188 in combination with 
zanubrutinib  
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
zanubrutinib 
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Exploratory: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by overall survival  
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 in combination with zanubrutinib at 
RDFE  
• To characterize the pharmacokinetic profile of zanubrutinib when given in 
combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
zanubrutinib at RDFE  
 
Part D: BGB-10188 + Tislelizumab Dose Escalation in Patients With Advanced Solid 
Tumors 
Primary: 
• To determine the MTD and the RDFE of BGB-10188 in combination with 
tislelizumab  
• To assess the safety and tolerability of BGB-10188 in combination with 
tislelizumab  
Secondary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by investigator-assessed overall response rate, duration of 
response, disease control rate, and time to response  
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
tislelizumab 
Exploratory: 
• To assess host immunogenicity to tislelizumab in combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
tislelizumab 
• To explore the relationships between biomarkers and mechanisms of resistance and 
the preliminary anticancer activity of BGB-10188 in combination with tislelizumab 
Part E: BGB-10188 + Tislelizumab Dose Expansion in Patients With Platinum-Resistant 
Ovarian Cancer (PROC) 
Primary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab in PROC as measured by the investigator-assessed overall response 
rate  
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• To assess the safety and tolerability of BGB-10188 in combination with 
tislelizumab  
Secondary: 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by investigator-assessed duration of response, 
progression-free survival, disease control rate, clinical benefit rate, and time to 
response 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by locally assessed carcinoma antigen-125 (CA-125) 
response rate per Gynecological Cancer Intergroup for CA-125 changes 
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
tislelizumab 
Exploratory: 
• To assess host immunogenicity to tislelizumab in combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
tislelizumab at the recommended doses for expansion 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary anticancer activity of BGB-10188 in combination with tislelizumab at 
the RDFE 
Study Design: 
This is an open-label, multicenter, dose escalation and dose expansion study to evaluate the 
safety and tolerability, determine the MTD and RDFE, and evaluate the preliminary antitumor 
activity of the following: 
• BGB-10188 monotherapy in patients with mature B-cell malignancies, including 
R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 
R/R marginal zone lymphoma (MZL), R/R follicular lymphoma (FL), R/R mantle 
cell lymphoma (MCL), or R/R diffuse large B-cell lymphoma (DLBCL) 
• BGB-10188 in combination with zanubrutinib in patients with R/R FL, R/R MCL, 
or R/R DLBCL  
• BGB-10188 in combination with tislelizumab in patients with advanced solid 
tumors 
The study consists of 5 parts, which are as follows: 
• Part A, a dose escalation phase to determine the MTD/RDFE of BGB-10188 
monotherapy in patients with R/R mature B-cell malignancies 
• Part B, a dose escalation phase to determine the MTD/RDFE of BGB-10188 in 
combination with zanubrutinib in patients with R/R FL, R/R MCL, and R/R 
DLBCL 
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• Part C, a dose expansion phase for evaluation of BGB-10188 in combination with 
zanubrutinib at the RDFE in patients with R/R FL, R/R MCL, and R/R DLBCL. 
This Part was originally planned but was cancelled by the sponsor and will not be 
initiated. 
• Part D, a dose escalation phase to determine the MTD/RDFE of BGB-10188 in 
combination with tislelizumab in patients with advanced solid tumors 
• Part E, a dose expansion phase for evaluation of BGB-10188 in combination with 
tislelizumab at the RDFE in patients with platinum-resistant ovarian cancer 
(PROC) 
The study design schematic is presented in Figure 1. 
Part A is designed to test BGB-10188 monotherapy at 5 planned dose levels from 60 to 
540 mg.  Additional dose levels could be added per the Safety Monitoring Committee 
(SMC)’s recommendation based on safety, tolerability, and PK data.  A Bayesian model-based 
dose escalation approach will be used for dose escalation and MTD determination of 
BGB-10188 monotherapy.   
In Part B, approximately 3 dose levels will be tested to determine the MTD/RDFE of 
BGB-10188 in combination with zanubrutinib in patients with R/R FL, R/R MCL, and R/R 
DLBCL. The dose levels of BGB-10188 may be adjusted per SMC’s recommendation 
according to the safety, tolerability and PK data. Additional dose levels could be added per the 
SMC’s recommendation based on safety, tolerability, and PK data.  The initial dose of 
BGB-10188 for Part B will be the latest cleared dose of BGB-10188 monotherapy in Part A.  
After the subsequent dose is identified to be safe in Part A, the same dose level in combination 
with zanubrutinib will be explored in Part B.  A modified 3 + 3 design and dose escalation 
criteria will be used to determine the MTD for combination therapy of BGB-10188 and 
zanubrutinib. 
When the dose of 120 mg once daily in Part A has been demonstrated safe, Part D, 
BGB-10188 dose escalation in combination with tislelizumab in patients with advanced solid 
tumors, will be triggered.  In Part D, 6 planned dose levels of BGB-10188 will be tested with 
the initial dose of 20 mg once daily.  The dose levels and dosages of BGB-10188 may be 
adjusted according to the safety and exposure results in Part A, and additional dose levels 
could be added if deemed appropriate.  A Bayesian model-based-dose escalation approach will 
be used for dose escalation and MTD determination of the combination therapy with 
tislelizumab.  
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Dose expansion of BGB-10188 in combination with zanubrutinib (Part C) and BGB-10188 in 
combination with tislelizumab (Part E) will be explored after the RDFE of BGB-10188 in 
combination with zanubrutinib (Part B) or with tislelizumab (Part D) have been determined, 
respectively.  In Part C, patients with R/R FL, R/R MCL, or R/R DLBCL will be enrolled.  
Part E is an open-label, randomized, multicenter, dose expansion phase to evaluate the safety 
and preliminary efficacy of BGB-10188 combined with tislelizumab in patients with PROC.  
Approximately 30 to 50 patients with PROC that have progressed on/after prior anticancer 
treatment and are CPI naïve will be randomized at a 2:1 ratio to receive either BGB‑10188 
(160 mg once daily) plus tislelizumab (200 mg once every 3 weeks) or BGB‑10188 (320 mg 
once daily) plus tislelizumab (200 mg once every 3 weeks) until disease progression, 
intolerance, or patient withdrawal for other reasons.  
In Part A, Part B, and Part C, a cycle is defined as 28 days in length.  In Part D, a cycle is 
defined as 21 days in length except for Cycle 1, which is 28 days in length due to the 
dose-limiting toxicities (DLT) assessment period.  In Part E, a cycle is defined as 21 days in 
length. 
In Part A, Part B, and Part D, patients will be evaluated for DLT during Cycle 1.  Patients will 
continue to be evaluated for DLTs up to 8 weeks due to late-onset toxicities that have been 
found to be associated with PI3Kδ inhibitors.  A DLT is defined as an adverse event (AE) that 
meets one of the following criteria: 
• Event occurs within 4 weeks (28 days) after start of study drug administration on 
C1D1, is related to the investigational agent, and is not due to alternative causes 
(eg, underlying disease, concurrent disease, or concomitant treatment): 
o Hematologic toxicity: Grade 4 neutropenia lasting > 7 days, ≥ Grade 3 febrile 
neutropenia, ≥ Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, or Grade 4 
thrombocytopenia lasting > 7 days   
o Nonhematologic toxicity: ≥ Grade 3 event persistent for > 7 days or any Grade 
of intracranial hemorrhage 
o Any toxicity that does not meet the abovementioned DLT criteria, but which 
leads to discontinuation or dosing interruption of > 7 days of BGB-10188 or 
zanubrutinib prior to Day 28, is considered a DLT. 
• ≥ Grade 3 events of skin reaction, pneumonitis, colitis, diarrhea or increased 
alanine aminotransferase (ALT)/aspartate aminotransferase (AST) lasting > 7 days 
occur within a prolonged window up to 8 weeks (56 days) after starting 
BGB-10188 administration, is related to the investigational agent, and is not due to 
alternative causes (eg, underlying disease, concurrent disease, or concomitant 
treatment): 
Note: For Part D only, the following AEs will not be considered DLTs: Grade 3 
endocrinopathy that is adequately controlled by hormonal replacement, Grade 3 tumor 
flare (defined as local pain, irritation, or rash localized at sites of known or suspected 
tumors), or Grade 3 infusion-related AE that is transient (resolved within 6 hours of onset)  
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Study treatment will continue until disease progression, unacceptable toxicity, death, 
withdrawal of consent, lost to follow-up, end of study, investigator’s decision, or the study is 
terminated by sponsor, whichever comes first. 
Patients with disease progression in Part A can receive the cleared dose of BGB-10188 in 
combination with zanubrutinib at the investigator’s discretion based on the local guidance and 
zanubrutinib prescribing information that the patients can benefit from treatment in 
combination with zanubrutinib.  This should be discussed with and approved by the sponsor.  
The SMC will review the accumulated safety data and model result after the last patient 
(decided by the sponsor/SMC) or ≥ 3 DLT-evaluable patients of the current cohort, whichever 
occurs earlier, have completed the 28-day DLT observation period and make the 
recommendation on the dose level for the next cohort.  Sponsor will make the final decision 
based on the recommendation of the SMC.  The RDFE may not be the MTD since targeted 
therapies can achieve the desired antitumor effect at doses lower than the MTD. 
Dose Verification in Chinese Patients (Part A and Part D) 
Before enrollment of patients in China for Part B, Part C, and Part E of the study, the safety 
and tolerability of BGB-10188 as monotherapy (Part A) and in combination with tislelizumab 
(200 mg once every 3 weeks) (Part D) will be assessed in Chinese patients in accordance with 
detailed verification rules.  For each cohort, approximately 3 to 6 Chinese patients will be 
enrolled to assess the safety and tolerability starting at the dose most recently identified as safe 
or the RDFE identified in Australian patients as outlined in Section 3.2.2.  The DLT 
observation period will be 28 days, with a prolonged window of up to 8 weeks (ie, up to 56 
days) for some specific events.  After reviewing the accumulated safety data, including AEs 
and laboratory assessments, the SMC will recommend the RDFE for Chinese patients.  The 
RDFE for Chinese patients will be determined based on the totality of the safety data and 
preliminary efficacy data of BGB-10188 as monotherapy and when combined with 
tislelizumab 200 mg before Chinese patients join Part B, Part C, and Part E.  
Study Assessments: 
Assessments of disease status during the study will include symptom-directed physical 
examination; disease-related constitutional symptoms (as necessary); complete blood count; 
bone marrow examination (as necessary); gastrointestinal examination (as necessary); and 
imaging scans. 
Efficacy will be assessed by the investigators.  For patients with chronic lymphocytic 
leukemia, disease response will be determined in accordance with the 2018 International 
Workshop on Chronic Lymphocytic Leukemia guidelines (Hallek et al 2018) with 
modification for treatment-related lymphocytosis (Cheson et al 2012).  For patients with 
non-Hodgkin lymphoma (NHL) (including SLL, MCL, MZL, DLBCL, and FL), disease 
response will be determined in accordance with the Lugano Classification for non-Hodgkin 
lymphoma (Cheson et al 2014).  For patients with advanced solid tumors, disease response 
will be determined per Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1) (Eisenhauer et al 2009). 
Computed tomography (CT) scan with contrast of neck, chest, abdomen, and pelvis, plus any 
other disease sites will be performed at screening and, every 8 weeks for first 24 weeks, every 
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12 weeks for the next 24 weeks, and then every 16 weeks, and at End-of-Treatment (EOT) for 
Part A, Part B, and Part C.  Patients in Parts A, B, and C with non-Hodgkin lymphoma (ie, 
MZL, MCL, FL, or DLBCL) will undergo positron emission tomography (PET)/CT imaging 
at baseline; a separate CT scan of diagnostic quality should be performed in addition to the 
PET/CT imaging if the PET/CT imaging is not of diagnostic quality.  If PET-avid disease is 
detected, then subsequent tumor assessments should be conducted with PET/CT-based 
imaging.  Patients in Parts A, B, and C with non-Hodgkin lymphoma without PET-avid 
disease, as well as patients with CLL/SLL, should undergo tumor assessments with CT-based 
imaging.  Combined PET/CT may be used in lieu of a CT with contrast only if the CT of the 
combined PET/CT has been performed with diagnostic quality, adheres to the specified slice 
thickness/scan parameters, and IV contrast is administered.  Magnetic resonance imaging 
(MRI) may be substituted for patients with serious contrast allergy but should be used 
consistently.  In Part D and Part E, tumor imaging will be performed at screening, Week 10 
(Part D) or Week 9 (Part E), then every 9 weeks thereafter, and at EOT. 
For patients who have mantle cell lymphoma with baseline gastrointestinal lymphoma 
involvement documented by endoscopic examination prior to first dose, a follow-up 
endoscopic examination will be performed at the time of suspected complete response to 
confirm complete response.   
For patients who have bone marrow involvement of lymphoma by bone marrow biopsy at 
baseline, a bone marrow examination will be performed to confirm complete response.  If a 
follow-up biopsy cannot be obtained, a PET scan that clearly documents continued disease 
clearance from bone marrow may be used in lieu of the repeated biopsy. 
Assessments of safety will include AEs, serious adverse events, clinical laboratory tests, 
physical examinations, and vital signs.  Adverse events will be graded for severity per the 
current version of the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAT v5.0). 
Blood samples for pharmacokinetics (PK) and pharmacodynamics analyses will be collected 
after single and repeat doses at specified timepoints in Parts A through Part E.  In Part A only, 
all patients will receive a single dose of BGB-10188 followed by a washout period of 7 days. 
For patients enrolled in Part A, Part B, or Part D, and approximately 5 patients in Part E, 
phospho-AKT expression in blood samples will be determined and used as a direct 
pharmacodynamic biomarker for PI3Kδ inhibition.  Proportion and number of immune cells in 
blood samples will also be assessed to monitor pharmacodynamic changes by BGB-10188 
treatment as monotherapy or in combination with zanubrutinib or tislelizumab. 
Key Eligibility Criteria 
For all parts of the study, eligible patients must be ≥ 18 years of age on the day of signing the 
informed consent form (or the legal age of consent in the jurisdiction in which the study is 
taking place); have an ECOG Performance Status of 0 or 1; and adequate organ function. 
Part A, Part B, and Part C 
Eligible patients must have a confirmed diagnosis of one of the following:  
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• Part A: R/R CLL/SLL, R/R MZL, R/R FL, R/R MCL, or R/R DLBCL 
• Part B and Part C: R/R FL, R/R MCL, or R/R DLBCL  
R/R disease is defined for patients who must have either: 1) disease progression after CR or 
PR of the last line of systemic therapy, or 2) failure to achieve CR or PR to the most recent 
appropriate systemic therapy.   
Patients with SLL, FL, MZL, MCL, or DLBCL must have ≥ 1 bidimensionally measurable 
nodal lesion > 1.5 cm in the longest diameter or extranodal lesion that is > 1 cm in the longest 
diameter by CT scan or MRI, as defined by the Lugano Classification.  Patients must have a 
life expectancy of > 4 months. 
Patients should have no history of allogeneic stem-cell transplantation; prior exposure to PI3K 
inhibitor (or Bruton tyrosine kinase inhibitor for patients in Part B and Part C); no 
histologically confirmed transformed lymphoma; no clinically significant cardiovascular 
disease; no uncontrolled systemic infection requiring parenteral intravenous anti-infective 
therapy; and no active hepatitis B or C or HIV. 
Part D and Part E 
Eligible patients must have one of the following: 
• Part D: Histologically or cytologically confirmed unresectable locally advanced or 
metastatic solid tumors previously treated with standard systemic therapy or for 
which effective standard treatment is not available or not tolerated.  Patients must 
have ≥ 1 measurable lesion as defined by RECIST v1.1 
• Part E: Histologically or cytologically confirmed epithelial ovarian cancer 
previously treated with 1 to 3 lines of systemic anticancer treatment and that is 
platinum-resistant and CPI naïve.  Patients must have ≥ 1 measurable disease as 
assessed by RECIST v1.1. 
Baseline tumor biopsy or available archived formalin-fixed paraffin-embedded (FFPE) tumor 
tissue sample (block or approximately 10 to 15 freshly cut unstained FFPE slides) is required.  
If a fresh tumor biopsy collected at screening is not available, archival samples are required. 
Patients should have no prior exposure to PI3K inhibitor; no recent exposure to chemotherapy, 
immunotherapy (eg, interleukin, interferon, or thymosin), hormonal therapy, or any 
investigational agent or participation in another clinical study with therapeutic intent within 
14 days or 5 half-lives (whichever is shorter) before first dose; no clinically uncontrolled 
pleural effusion, pericardial effusion, or ascites that requires drainage procedures within 
14 days before first dose (Part D), or recurrence ≤ 14 days after intervention (Part E); no active 
leptomeningeal disease or uncontrolled brain metastasis; and no severe chronic or active 
infections, including active hepatitis B or C or HIV. 
Test Product, Dose, and Mode of Administration 
BGB-10188 will be administered orally, daily, in the morning on and with a glass of water 
(approximately 240 mL).  In Part A, 5 proposed dose levels will be tested: 60 mg once daily, 
120 mg once daily, 240 mg once daily, 360 mg once daily, and 540 mg once daily.  The dose 
levels of BGB-10188 may be adjusted per SMC’s recommendation according to the safety, 
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tolerability and PK data when combined with zanubrutinib. In Part B, approximately 3 dose 
levels will be tested: the latest cleared dose in Part A and the subsequent higher doses of Part 
A. In Part C, the RDFE determined in Part B will be tested. In Part D, 6 proposed dose levels 
will be tested: 20 mg once daily, 40 mg once daily, 80 mg once daily, 160 mg once daily, 320 
mg once daily, and 540 mg once daily.  In Part E, 2 proposed dose levels will be tested: 160 
mg once daily and 320 mg once daily.  Additional dose levels may be added if, based on 
emerging safety and tolerability data, exploration of additional doses (eg, 80 mg) is warranted 
and agreed by the SMC. 
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice 
daily) with or without food, with water at approximately the same time every day, with a 
minimum of 8 hours between consecutive doses.  Zanubrutinib capsules should not be opened, 
broken, or chewed at any time.  
Tislelizumab 200 mg will be administered on Day 8 of Cycle 1, and Day 1 of each subsequent 
cycle in Part D.  In Part E, tislelizumab 200 mg will be administered on Day 1 of each cycle. 
Statistical Methods 
Analysis Sets: 
Part A, Part B and Part C 
• The DLT-Evaluable Set is defined as all patients who received ≥ 75% of the 
scheduled dose of each study treatment during the first 28-day treatment cycle.  
Additionally, patients who had a DLT event during the corresponding DLT 
observation window despite having received < 75% of the scheduled dose will also 
be considered evaluable. 
• The Safety Analysis Set is defined as all patients who received ≥ 1 medication of 
BGB-10188 and/or zanubrutinib (for combination therapy part).  This will be the 
primary analysis set used for safety analyses.  
• The Efficacy Analysis Set is defined in the same way as the Safety Analysis Set 
and will be the primary analysis set used for efficacy analyses. 
• The PK Analysis Set is defined as all patients who had ≥ 1 postdose plasma 
concentration and no important protocol deviation affecting PK. 
Part D and Part E 
• For Part D, the DLT-Evaluable Set is defined as all patients who received ≥ 75% of 
the scheduled dose of BGB-10188, ≥ 75% of the scheduled dose of tislelizumab 
during the first 28-day treatment cycle.  Additionally, patients who had a DLT 
event during the corresponding DLT observation window despite having received 
< 75% of scheduled dose of tislelizumab or < 75% of the scheduled dose of 
BGB-10188 will also be considered evaluable. 
• The Safety Analysis Set is defined as all patients who received at least one 
medication of BGB-10188 and/or tislelizumab.  Patients are analyzed according to 
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the treatment they actually received.  The Safety Analysis Set will be the primary 
analysis set used for safety analyses.  
• The Efficacy Analysis Set is defined in the same way as the Safety Analysis Set in 
Part D.  In Part E, the Efficacy Analysis Set follows the modified intent-to-treat 
principle and includes all patients who are randomized/enrolled and treated.   The 
patients will be analyzed according to the treatment group to which they were 
randomized/enrolled to.  The Efficacy Analysis Set will be the primary analysis set 
used for efficacy analyses. 
• In Part E, the Efficacy Evaluable Analysis Set includes all patients who received at 
least one dose of study drugs, have evaluable disease at baseline, and have at least 
one evaluable postbaseline tumor response assessment unless any clinical disease 
progression or death occurred before the first postbaseline tumor assessment.  The 
Efficacy Evaluable Analysis Set will be the sensitivity analysis set for efficacy 
analyses. 
• The PK Analysis Set is defined as all patients who had at least one postdose plasma 
concentration and no major protocol deviation affecting PK. 
Efficacy Analysis: 
Efficacy analyses will be conducted by study part (where applicable) and indication based on 
the Efficacy Analysis Set.  Overall response rate (ORR), disease control rate (DCR), clinical 
benefit rate, and CA-125 response rate will be summarized along with 95% CI using Clopper-
Pearson method.  Kaplan-Meier methodology will be used to estimate medians or other 
quartiles of duration of response (DOR) and progression-free survival (PFS), and their 95% CI 
will be constructed using Brookmeyer and Crowley method.  Kaplan-Meier curves will also be 
provided.  Time to response (TTR) will be summarized by descriptive statistics.  DOR and 
TTR will be only analyzed for responders. 
Safety Analysis: 
Safety analyses will be conducted by study part, indication, dose level, and overall as 
appropriate based on the Safety Analysis Set.  DLT events will be summarized by dose level 
for the dose escalation phase of each part.  All treatment-emergent adverse events will be 
summarized.  Serious adverse events, deaths, treatment-emergent adverse events ≥ Grade 3, 
immune-mediated adverse events (for Part D and Part E), treatment-related 
treatment-emergent adverse events, treatment-emergent adverse events that led to treatment 
discontinuation and/or dose modification, dose interruption, or dose delay will be summarized. 
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.  Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. 
Descriptive statistics for vital sign parameters (eg, systolic and diastolic BP, heart rate, 
temperature) and changes from baseline will be presented by visit. 
For Part D, ophthalmologic examination results will be listed by patient. 
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PK Analysis: 
Blood samples will be collected to characterize the PK (and immunogenicity, if applicable) 
profiles of specified compounds.  All blood sampling (plasma or serum) for PK assessment 
and antidrug antibody (ADA) testing (if applicable) will be collected at the timepoints 
specified in the Schedule of Assessments.  The actual collection date and time of each blood 
sample will be recorded.  The timing of PK and ADA samples may be altered and/or PK and 
ADA samples may be obtained at additional timepoints upon sponsor approval to ensure 
thorough PK and ADA monitoring. 
Sample Size: 
For Part A, Part B, and Part D, the number of dose levels examined, the dose escalation cohort 
size, and the emerging toxicities of the therapy will determine the sample size.  Patients will 
be recruited with a targeted cohort size of 3, although flexibility in cohort size is allowed with 
the model-based dose escalation as well as for a modified 3 + 3 design.  
Approximately 5 dose levels are planned for the dose escalation path of BGB-10188 
monotherapy in Part A.  A total of approximately 30 patients are expected to be enrolled for 
the BGB-10188 monotherapy dose escalation.  The dose levels of BGB-10188 for the 
combination therapy in Part B with zanubrutinib 160 mg twice daily will be the latest cleared 
dose and subsequent higher dose levels from the monotherapy dose escalation.  Therefore, a 
total of approximately 18 patients are expected to be enrolled for the combination therapy dose 
escalation.  
Approximately 6 dose levels of BGB-10188 are planned for the combination therapy dose 
escalation with tislelizumab 200 mg once every 3 weeks in Part D.  A total of approximately 
36 patients are expected to be enrolled.  
The total sample size in Part A, Part B, and Part D is expected to be approximately 84, 
excluding patients for the China verification parts.  Part E is expected to have approximately 
30 to 50 patients.  Part C was designed to have approximately 20 patients but will not be 
initiated. The sample size for China verification parts will be based on the escalation status in 
Part A and Part D. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ALT 
alanine aminotransferase 
ADA 
antidrug antibody 
AE 
adverse event 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration curve 
BGB-3111 
zanubrutinib 
BGB-A317 
tislelizumab 
BLRM 
Bayesian logistic regression model 
BPH 
Bayesian proportional hazard 
BTK 
Bruton tyrosine kinase 
CBC 
complete blood count 
CD 
cluster of differentiation 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CPI 
checkpoint inhibitor 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T lymphocyte-associated antigen-4 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLBCL 
diffuse large B-cell lymphoma 
DLCO 
carbon monoxide diffusion capacity 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End-of-Treatment (Visit) 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FFPE 
formalin-fixed paraffin-embedded 
FEV1 
forced expiratory volume in 1 second 
FL 
follicular lymphoma 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IB 
investigator’s brochure  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
iwCLL 
International Workshop on CLL 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NMPA 
National Medical Products Administration 
NOAEL 
no observed adverse effect level  
NSCLC 
non-small cell lung cancer 
OC 
ovarian cancer 
ORR 
overall response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
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Abbreviation 
Definition 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI3Kδ 
phosphatidylinositol 3-kinase delta 
PJP 
pneumocystis jirovecii pneumonia 
PK 
pharmacokinetic(s) 
PR 
partial response 
PROC 
platinum-resistant ovarian cancer 
PT 
preferred term 
RDFE 
recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SLL 
small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TGI 
tumor growth inhibition 
Treg 
T-regulatory (cell) 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
WM 
Waldenström macroglobulinemia 
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1. 
INTRODUCTION AND RATIONALE  
1.1. 
Background on Phosphatidylinositol 3-Kinase δ  
Phosphatidylinositol 3-kinase δ (PI3Kδ) is frequently active in B-cell malignancies and is central 
to multiple signaling pathways that drive proliferation, survival, homing, and retention of 
malignant B-cells in lymphoid tissue and bone marrow.  In B-cell malignancies, PI3K pathway 
activity is significantly elevated, which is driven by altered B-cell receptor signaling together 
with other co-stimulatory signals present in lymphoid tissues such as chemokines and cytokines 
(Puri and Gold 2012; Okkenhaug and Vanhaesebroeck 2003).  PI3Kδ functions to integrate and 
transduce these signals from the microenvironment, thus promoting malignant B-cell 
proliferation, growth, survival, adhesion, and homing, making it an attractive drug target for B-
cell malignancies (Yang et al 2015). 
PI3Kδ is also important for the homeostasis and function of T-regulatory (Treg) cells 
(Lim and Okkenhaug 2019).  The inactivation of PI3Kδ in mice can stimulate immune responses 
against solid tumors via the inhibition of Treg cells (Ali et al 2014).  With PI3Kδ expression at 
low or undetectable levels in most organs, inhibitors against PI3Kδ should be selective for the 
immune system and less toxic (Okkenhaug and Fruman 2010). 
Because of the specific and critical functions of PI3Kδ in adaptive immune responses, inhibitors 
of PI3Kδ are being developed for the treatment of autoimmune and inflammatory disorders, 
hematologic and solid tumors, and activated PI3Kδ syndrome (Lucas et al 2016; 
Okkenhaug and Burger 2016).  PI3Kδ inhibitors are also being developed for the treatment of 
solid tumors because PI3Kδ is essential for the homeostasis and function of Foxp3+ Treg cells 
(Patton et al 2006).  Loss of PI3Kδ activity, especially by specific deletion in Treg cells, can 
restrict the growth of transplanted tumors in mice (Ali et al 2014), providing a rationale for the 
evaluation of PI3Kδ inhibitors in solid tumors. 
Since 2014, PI3Kδ inhibitors have been approved for treatment against B-cell malignancies.  
Zydelig® (idelalisib), the first PI3Kδ inhibitor approved in the USA, is indicated in combination 
with rituximab for the treatment of adult patients with relapsed chronic lymphocytic leukemia 
(CLL) (Brown et al 2014; Furman et al 2014; Zydelig® 2022).  Response rates for CLL in a 
Phase 1 trial evaluating several dose levels (50 to 350 mg once or twice daily) were reported as 
72% (95% CI: 58.4% to 83.5%) (39/54), with 39% (21/54) of patients meeting the criteria for 
partial response (PR) per International Workshop on CLL (iwCLL) 2008 criteria and 33% 
(18/54) meeting the criteria of PR in the presence of treatment-induced lymphocytosis (Brown et 
al 2014). 
Copanlisib was approved by the United States (US) Food and Drug Administration (FDA) in 
2017 for the treatment of adult patients with relapsed follicular lymphoma (FL) who have 
received ≥ 2 prior systemic therapies, and granted conditional approval by the China National 
Medical Products Administration (NMPA) in May 2023 for the treatment of patients with 
relapsed/refractory (R/R) FL after ≥ 2 prior therapies.  It was granted breakthrough therapy 
designation by the FDA for relapsed marginal zone lymphoma (MZL) with ≥ 2 prior therapies 
based on data from the Phase 2 CHRONOS-1 study.  In the FL subset, the overall response rate 
(ORR) was 58.7%, including 14.4% complete response (CR) and 44.2% PR.  In the MZL subset, 
the ORR was 69.6%, including 8.7% CR and 60.9% PR.  The estimated Kaplan-Meier median 
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duration of response (DOR) in the full analysis set was 687 days (range: 0 to 687 days) and 370 
days (range: 0 to 687 days) in the FL subset.  The Kaplan-Meier estimate of median progression-
free survival (PFS) was 340 days (range: 0 to 736 days).  The median overall survival (OS) had 
not yet been reached (Dreyling et al 2017). 
Duvelisib was approved by the US FDA in 2018 for the treatment of R/R CLL or small 
lymphocytic lymphoma (SLL) after ≥ 2 prior therapies, and approved by the China NMPA in 
March 2022 for the treatment of patients with R/R FL after ≥ 2 prior therapies.  The CLL and 
SLL indication is based on a randomized, multicenter, open-label trial (NCT02004522) 
comparing duvelisib to ofatumumab in patients with R/R CLL or SLL the estimated median PFS, 
as assessed by an Independent Review Committee (IRC), was 16.4 months in the duvelisib arm 
and 9.1 months in the ofatumumab arm (hazard ratio of 0.40; standard error 0.2).  The ORR per 
IRC was 78% and 39% for the duvelisib and ofatumumab arms, respectively (39% difference, 
standard error 6.5%) (Flinn et al 2018).  Duvelisib results in an ORR of 83% per the IRC for 
Chinese patients with R/R FL.  Median DOR, PFS, and OS have not been reached. Median time 
to response (TTR) was 1.8 (range: 1.6 to 5.5) months by the IRC. Treatment-related adverse 
events (TRAEs) of any grade occurred in 21 (91%) of 23 patients, in which 12 (52%) were 
≥ Grade 3 (Zheng et al 2021). 
Linperlisib was granted conditional approval by the China NMPA for adult patients with R/R FL 
who have failed at least two prior systemic therapies in November 2022 based on the Phase 2 
YY-20394 study (NCT04370405).  The results of the study indicated an ORR of 80.9% and a 
disease control rate (DCR) of 96.6% in 89 evaluable patients with R/R FL (Yingli Pharma 2021). 
Parsaclisib was granted breakthrough therapy designation by the China NMPA for R/R FL in 
March 2021 based on the Phase 2 study (CTR20192392).  Parsaclisib demonstrated an ORR of 
69.8% and a CR of 13.5% in 96 evaluable patients with R/R FL (Lynch et al 2020). 
TQ-B3525, a novel and selective oral PI3K α/δ inhibitor, was granted breakthrough therapy 
designation by the China NMPA for R/R FL in July 2021 based on the Phase 1 study 
(NCT03510767).  The results of the study indicated an ORR of 72.7% in 11 evaluable patients 
with R/R FL, and the longest DOR of 11.8 months at data cutoff in a patient with FL 
(Wang et al 2020). 
Although the approved agents have impressive clinical activity in CLL/SLL, MZL, and FL, some 
are associated with substantial toxicity.  In particular, fatal or life-threatening hepatotoxicity, 
colitis, and pneumonitis for idelalisib and fatal or serious infection, colitis, cutaneous reactions, 
and pneumonitis for duvelisib.  A PI3Kδ inhibitor with an improved therapeutic index would 
represent an important advance for these patients.  
1.2. 
Background Information on BGB-10188 (PI3Kδ Inhibitor), 
Zanubrutinib (BTK Inhibitor), and Tislelizumab (PD-1 Antibody)   
BGB-10188 
BGB-10188 is a potent, selective, orally active inhibitor of PI3Kδ with more than 3000-fold 
selectivity against other Class I PI3K isoforms and no inhibitory effect on 17 lipid kinases, 
376 protein kinases, and 87 non-kinase enzymes, including G-protein-coupled receptors, 
transporters, ion channels, and nuclear receptors.  BGB-10188 is about 10- to 20-fold more 
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potent than idelalisib in whole blood assays with an IC50 of 9.2 nM versus 189 nM.  BGB-10188 
has low permeability, but its solubility is high.  It has no effect on cytochrome P450 (CYP) 
inhibition or induction, it is a P-glycoprotein (P-gp) substrate and does not penetrate the blood-
brain-barrier.  The results of nonclinical efficacy studies suggest that BGB-10188 (BGB-10188 
Investigator’s Brochure [IB]) as monotherapy or in combination with the Bruton tyrosine 
kinase (BTK) inhibitors could significantly inhibit the growth of B-cell malignancies.  In Farage 
diffuse large B-cell lymphoma (DLBCL) and JeKo-1 mantle cell lymphoma (MCL) xenograft 
models, BGB-10188, as a single agent, showed significant antitumor activities with tumor 
growth inhibition (TGI) of 22% to 62% at doses ranging from 10 to 100 mg/kg.  In combination 
with BGB-3111 (2.5 mg/kg) in TMD-8 DLBCL model, BGB-10188 treatment increased the TGI 
from 77% to 101% (versus 68% for BGB-3111 alone) on treatment Day 14, and tumor shrinkage 
was observed in all combination treatment groups after treatment for 20 days.  In combination 
with BGB-3111 (7.5 mg/kg) in Jeko-1 MCL model, the TGI in combination treatment groups 
was increased from 75% to 84% (versus 43% for BGB-3111 alone) at doses of 10 to 30 mg/kg 
for BGB-10188.  BGB-10188 could also inhibit the growth of solid tumors in combination with 
the programmed cell death protein-1 (PD-1) antibodies.  In the CT26WT mouse colon cancer 
syngeneic model, BGB-10188 combined with anti-mouse PD-1 antibody muCh15mt 
significantly increased the TGI and tumor free animal percentage (TF%) compared with single 
agent alone at doses of 10 to 30 mg/kg (TGI increased to 72% to 88% versus 21% to 56% in 
single agent groups; TF% increased to 54% to 71% versus 0 to 37% in single agent groups).  In 
Good Laboratory Practice (GLP) toxicity studies, BGB-10188 had greater safety margins than 
idelalisib and the PI3Kα,δ inhibitor copanlisib, which was approved for the treatment of B-cell 
malignancies in 2017 (Krause et al 2018). 
BGB-10188 is a novel PI3Kδ inhibitor with high selectivity and a safety profile that in 
nonclinical studies is improved over the safety of approved inhibitors of PI3K enzymes.  These 
characteristics of BGB-10188 are encouraging and warrant its testing in humans. 
Zanubrutinib 
Zanubrutinib (also known as BGB-3111) is a novel, irreversible, second-generation BTK 
inhibitor with great potency and selectivity.  In both biochemical and cellular assays, 
zanubrutinib has demonstrated potent BTK inhibition activity.  Zanubrutinib is more selective 
than ibrutinib (an approved BTK inhibitor) against off-target kinases, including EGFR, JAK3, 
HER2, TEC, ITK, and others.  Zanubrutinib has also demonstrated better antitumor activity than 
ibrutinib in human MCL and DLBCL xenograft models.  Unlike ibrutinib, zanubrutinib has not 
been shown to interfere with the anti-cluster of differentiation (CD)20 antibody-induced 
antibody-dependent cellular cytotoxicity effect.  Zanubrutinib has received approvals for the 
indications of MCL, WM, MZL, CLL/SLL, and FL in over 65 countries/regions worldwide 
(including all EU states). 
Tislelizumab 
Tislelizumab (also known as BGB-A317) is a humanized immunoglobulin G4 variant 
monoclonal antibody against the immune checkpoint-inhibitory receptor, PD-1.  Tislelizumab 
binds to the extracellular domain of human PD-1 with high specificity and affinity.  Also, with 
an edited gamma fragment crystallizable region receptor IIIA, tislelizumab had low or no 
antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity effects in 
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humans (Labrijn et al 2009).  Tislelizumab has been approved in China, Macao China, US, 
Europe, and South Korea. In China and Macao China, it has been approved as monotherapy or in 
combination with chemotherapy, for the treatment of patients with R/R classical Hodgkin 
lymphoma, locally advanced or metastatic urothelial carcinoma, locally advanced or metastatic 
squamous non-small cell lung cancer (NSCLC), locally advanced or metastatic nonsquamous 
NSCLC, previously treated hepatocellular carcinoma, advanced unresectable or metastatic 
microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, 
previously treated locally advanced or metastatic esophageal squamous cell carcinoma (ESCC), 
and metastatic nasopharyngeal cancer. In China, it has also been approved as the first line 
treatment with chemotherapy in locally advanced unresectable or metastatic gastric or 
gastroesophageal junction adenocarcinoma with high PD-L1 expression; first line treatment in 
locally advanced, recurrent, or metastatic ESCC; and as monotherapy in first line treatment of 
unresectable or metastatic HCC.  In US, Europe, and South Korea, tislelizumab has been 
approved for treatment in previously treated ESCC.  
1.2.1. 
Pharmacology  
BGB-10188 
BGB-10188 is a potent and selective inhibitor of PI3Kδ in biochemical and cellular assays.  
BGB-10188 inhibited cellular growth of several DLBCL and MCL cell lines in vitro. 
In vivo studies showed that BGB-10188 induced dose-dependent antitumor effects against 
Farage DLBCL xenografts engrafted either subcutaneously or systemically in mice.  In addition, 
BGB-10188 showed combination therapeutic effects with a BTK inhibitor (zanubrutinib) in 
Farage and TMD8 DLBCL, as well as JEKO-1 and MINO MCL subcutaneous xenografts at 
doses of 10 to 30 mg/kg.  In the CT26WT syngeneic mouse colon tumor model, BGB-10188 
showed combination inhibitory effects with anti-mouse PD-1 antibody on tumor growth at doses 
from 3 to 30 mg/kg in a dose-dependent manner. 
Zanubrutinib 
Zanubrutinib has been administered to approximately 2772 patients.  Refer to Section 1.2.3 for 
the clinical pharmacology data. 
Tislelizumab 
Tislelizumab has been administered to 3220 patients (as a monotherapy or in combination with 
chemotherapy), refer to Section 1.2.3 for the clinical pharmacology data. 
1.2.2. 
Toxicology  
BGB-10188 
In the 28-day repeat dose study in rats, mortalities were only noted in 7/15 females at the high 
dose of 500 mg/kg/day with similar changes and more severity as compared to the surviving 
animals in this group.  At the dose of 500 mg/kg/day, adverse histopathological changes were 
noted in the liver, brain, heart, non-glandular stomach, esophagus, thymus and mesenteric lymph 
node, skeletal muscle, and female reproductive organs, which were mainly characterized by 
hypertrophy/atrophy/hyperplasia, degeneration/necrosis/cell loss, mixed cell infiltration, 
decreased lymphocytes, and/or vacuolation and correlated with clinical pathology changes.  
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Non-adverse changes in other multiple tissues and/or organs were mainly characterized by 
hypertrophy, vacuolation, and macrophage aggregation/vacuolation/infiltration, apoptosis, 
neutrophilic inflammation, increased myeloid cellularity, decreased lymphocytes.  At the dose of 
150 mg/kg/day, adverse changes in the liver were characterized by mild hypertrophy/hyperplasia 
in the biliary.  No test article-related changes were noted in animals at the dose of 50 mg/kg/day 
except for lymphoid depletion, increased tingible body macrophages in peripheral lymphoid 
tissues, vacuolated macrophage infiltration in the testes, and minimal changes in the liver, which 
were not considered adverse.  All above changes were reversible.  The maximum tolerated dose 
(MTD) was considered to be 150 mg/kg/day, and the no observed adverse effect level (NOAEL) 
was considered to be 50 mg/kg/day.  
While dogs were orally administered BGB-10188 at single doses up to 300 mg/kg, or at 28-day 
repeated doses up to 60 mg/kg/day, no mortality was noted.  Dose-dependent hypersensitive-like 
clinical signs or changes, including red skin discoloration, swelling, salivation, decreased 
activity, vomitus, increased respiratory rate, prostration, tremors, and/or increased heart rate and 
decreased BP were noted in dogs after dosing from 30 to 300 mg/kg/day.  Those 
findings/changes were not noted at the dose of 10 mg/kg/day.  The histopathological changes 
were noted in liver, gallbladder, heart, bone marrow, and lymphoid tissues that were correlated 
with decreases in body weights; increases in white blood cells (WBCs) and/or its differential 
(monocytes, lymphocytes, neutrophils), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase, and total 
bilirubin; and decrease in reticulocytes.  All changes were reversible, and only changes in liver 
and gallbladder at the dose of 60 mg/kg/day were considered adverse.  Based on the results, the 
MTD was considered to be 60 mg/kg/day; the NOAEL was considered to be 30 mg/kg/day.   
The systemic exposure increased dose proportionally in rats with 1.7- to 2.7-fold higher exposure 
in females than males, while it increased more than dose proportionally in dogs and without 
marked sex difference.  Slight accumulation (area under the concentration curve [AUC] indices: 
1.1 to 3.5) was indicated after repeated doses in both rats and dogs.   
Based on genotoxicity core battery studies, BGB-10188 is considered lack of genotoxic potential 
and low concern for human safety (International Council for Harmonisation [ICH] S2[R1]).  
The phototoxic potential is considered based on the photochemical properties with molar 
extinction coefficient greater than 1000 L⋅mol-1⋅cm-1 between 290 and 347 nm.  
In summary, the toxicity and toxicokinetic profiles of BGB-10188 were well characterized in 
both rats and dogs.  Based on ICH S9, all the available toxicology studies and data are 
considered adequate to support the first in patient dosing and the clinical development of 
BGB-10188 for treatment of patients with advanced cancer.  
Zanubrutinib 
Zanubrutinib has been administered to approximately 2772 patients as of the data cutoff date of 
30 November 2022.  Refer to Section 1.2.4 for prior clinical experience information.  Please 
refer to the zanubrutinib IB for more detailed information on the toxicology of zanubrutinib. 
Tislelizumab 
Tislelizumab has been administered to 2377 patients as a monotherapy and 2019 in combination 
with chemotherapy as of the data cutoff date of 27 October 2023.  Refer to Section 1.2.4 for prior 
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clinical experience information.  Please refer to the tislelizumab IB for more detailed information 
on the toxicology of tislelizumab. 
1.2.3. 
Clinical Pharmacology  
BGB-10188 
The pharmacokinetics (PK) of BGB-10188 is being studied in this first-in-human study 
BGB-A317-3111-10188-101, which consists of 5 Parts (A to E).  As of 06 March 2023, 
preliminary PK parameters showed that BGB-10188 was rapidly absorbed with Tmax of 
approximately 2 hours.  The PK of BGB-10188 was characterized with a fast distribution phase 
followed by an elimination phase with mean terminal half-life ranging from 8 to 31 hours across 
the cohorts.  The dose normalized observed maximum plasma concentration (Cmax) and AUC0-24h 
of BGB-10188 are comparable between monotherapy in Part A and in combination therapy with 
tislelizumab (Part D), indicating tislelizumab had no significant impact on BGB-10188 PK. 
Little or low accumulation of BGB-10188 plasma AUC was observed after repeated dosing once 
daily compared to that after a single dose.  BGB-10188 exposure increased with each dose level 
in more than a dose-proportional manner both after the single dose and at steady state when the 
dose increased to 240 mg. 
For more detailed information on the clinical pharmacology of BGB-10188, refer to the IB 
(BGB-10188 IB). 
Zanubrutinib 
Zanubrutinib is rapidly absorbed and eliminated after oral administration in human subjects.  The 
mean elimination half-life (t½) was between 2 and 4 hours, and peak concentrations occurred 
around 2 hours postdose.  The Cmax and AUC increased in a nearly dose-proportional manner 
from 40 to 320 mg, after single-dose or repeated-dose administrations.  Zanubrutinib was 
primarily eliminated by hepatic metabolism and fecal excretion.  The food-effect study showed 
that the increase in Cmax (51%) and AUC0-inf (12%) observed when zanubrutinib was given with 
a low-fat meal compared to the fasted state are not considered to be clinically relevant; therefore, 
zanubrutinib can be administered with or without food.  
Single oral doses of zanubrutinib at 160 and 480 mg did not have a clinically relevant effect on 
electrocardiogram (ECG) parameters, including QTc intervals and other ECG intervals. 
Clinical drug-drug interaction study showed that the dose of zanubrutinib needs to be modified 
when coadministered with moderate or strong CYP3A inhibitors, and to be avoided when 
coadministered with moderate or strong CYP3A inducers (refer to Zanubrutinib Prescribing 
Information 2019).  
A dedicated hepatic impairment study (BGB-3111-107) showed that there was no substantial 
difference in PK profiles between patients with mild/moderate hepatic impairment and healthy 
subjects. 
Dosage modification of zanubrutinib is recommended in patients with severe hepatic 
impairment.  No dosage modification is recommended in patients with mild to moderate renal 
impairment.  
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For more detailed information on the clinical pharmacology experience for zanubrutinib, please 
refer to the IB (zanubrutinib IB). 
Tislelizumab 
A population PK analysis was performed based on pooled data (PK, dosing information, 
demographics, and patient or disease characteristics) from 2596 patients across 12 clinical 
studies (BGB-A317_Study_001, BGB-A317-102, BGB-A317-203, BGB-A317-204, 
BGB-A317-205, BGB-A317-206, BGB-A317-208, BGB-A317-209, BGB-A317-302, 
BGB-A317-303, BGB-A317-304, and BGB-A317-307).  The PK of tislelizumab was best 
characterized using a 3-compartmental linear population PK model with linear clearance 
mechanisms.  No time-varying clearance was observed in tislelizumab PK.  The typical estimates 
of clearance (CL), central volume of distribution (Vc), and peripheral volumes 2 and 3 (V2 and 
V3, respectively), were 0.153 L/day, 3.05 L, 1.27 L, and 2.10 L, respectively, with 
interindividual variability in CL (26.3%), Vc (16.7%), V2 (74.7%), and V3 (99.9%).  The 
terminal t½ was estimated to be approximately 23.8 days. 
The population PK analyses demonstrated that race, baseline ALT, AST, bilirubin, lactate 
dehydrogenase, estimated glomerular filtration rate (eGFR), ECOG Performance Status score, 
and sum of products of perpendicular diameters of classical Hodgkin lymphoma did not have 
statistically significant influences on tislelizumab PK.  Baseline body weight, tumor size of solid 
tumors, albumin, age, sex, immunogenicity, and tumor type were found to be statistically 
significant covariates on the PK of tislelizumab; however, the exposure changes by these 
covariates were small compared to the overall estimated PK exposures range and hence are not 
considered clinically meaningful. 
For more detailed information on the clinical pharmacology experience for tislelizumab, please 
refer to the IB (tislelizumab IB). 
1.2.4. 
Prior Clinical Experience  
1.2.4.1. 
BGB-10188  
BGB-10188 is being studied in this 1 ongoing clinical trial in Australia and China. For details on 
the clinical efficacy of BGB-10188, refer to the BGB-10188 Investigator’s Brochure.  
1.2.4.2. 
Zanubrutinib  
For details on the clinical efficacy of zanubrutinib, refer to the zanubrutinib Prescribing 
Information (Brukinsa [zanubrutinib] US prescribing information 2019).  
1.2.4.3. 
Tislelizumab  
For details on the clinical efficacy of tislelizumab, refer to the tislelizumab Prescribing 
Information (Tevimbra [tislelizumab] US prescribing information 2024). 
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1.3. 
Study Rationale  
1.3.1. 
Rationale for Combination of BGB-10188 and Zanubrutinib in the Treatment of 
B-Cell Malignancies  
PI3Kδ and BTK are downstream intermediaries of B-cell receptor signaling and are essential for 
B-cell activation, proliferation, and survival.  Both have unique roles in B-cell receptor signal 
transduction pathways and loss of PI3Kδ and BTK results in a profound B-cell defect.  PI3Kδ 
and BTK also transmit signals from chemokine receptors (CXCR4/5) and adhesion molecules 
critical for malignant B-cell adhesion, migration, and retention in the tumor microenvironment.  
Disruption of PI3Kδ and BTK signaling has a synergistic effect on key biological activities 
necessary for malignant B-cell growth, survival, and migration. 
Dual inhibition of PI3Kδ and BTK is also expected to induce a more pronounced expulsion of 
malignant B-cells from the protective tumor microenvironment.  In a study done with idelalisib 
and ibrutinib, dual inhibition of PI3Kδ and BTK achieves greater inhibition of B-cell receptor- 
and chemokine receptor-stimulated adhesion compared with either agent alone.  This occurs in a 
strongly synergistic manner, including at suboptimal drug concentrations.  The PI3Kδ and BTK 
inhibitors target B-cell receptor signaling by different means; therefore, they may enhance each 
other’s anticancer effect.  Furthermore, the targeting of more than 1 key component of a pathway 
may overcome innate and overcome or prevent acquired (mono) therapy resistance. 
BGB-10188 and zanubrutinib are highly selective and potent PI3Kδ and BTK inhibitors, 
respectively (Section 1.2.1).  Improved antitumor activity was found with the combined 
treatment of BGB-10188 and zanubrutinib in mice subcutaneously xenografting TMD8 DLBL or 
JeKo-1 MCL tumor cells, and further improved antitumor activity was observed with a 
prolonged combination treatment (refer to BGB-10188 IB).  Therefore, it is possibly optimal to 
explore the efficacy and safety of this combination.  
1.3.2. 
Rationale for Combination of BGB-10188 and Tislelizumab in the Treatment of 
Advanced Solid Tumors  
Inhibitors of PI3Kδ are being developed for the treatment of solid tumors because of the specific 
and critical functions of PI3Kδ in adaptive immune responses. 
PI3Kδ is essential for the homeostasis and function of Foxp3+ Treg cells (Patton et al 2006).  
PI3Kδ-deficient mice develop colitis due to the reduced Treg cell functions (Patton et al 2006).  
Additionally, it was shown that PI3Kδ-inactivated Treg cells are impaired in mediating tumor 
immunosuppression.  Loss of PI3Kδ activity, especially by specific deletion in Treg cells, can 
restrict the growth of transplanted tumors in mice (Ali et al 2014), providing a rationale for the 
evaluation of PI3Kδ inhibitors in solid tumors. 
PD-1 is mainly expressed in activated T-cells, including CD8+ cytotoxic T-lymphocytes and 
CD4+ T-helper lymphocytes (McDermott and Atkins 2013).  The PD-1 signaling cascade 
negatively regulates the T-cell receptor and attenuates T-cell proliferation and functional 
activities, leading to T-cell exhaustion.  PD-1 expression is markedly up-regulated on tumor-
infiltrating lymphocytes, while the expression of PD-L1 is significantly increased on tumor cells 
and tumor-associated immune cells in the presence of stimulating cytokines, such as interferon-
gamma and interferon-alpha in the tumor microenvironment (Riley 2009), which is observed in 
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many types of human solid tumors.  This body of evidence provides the basis for cancer 
immunotherapeutic intervention via the approach of antagonizing PD-1.  
Significantly improved antitumor activity and prolonged survival were observed in the 
combination of BGB-10188 and mouse anti-PD-1 antibody in a CT26 colorectal tumor model 
(refer to BGB-10188 IB).  The results of these nonclinical efficacy studies suggest that the 
PI3Kδ inhibitor BGB-10188 could significantly inhibit the growth of solid tumors in 
combination with PD-1 antibody. 
1.3.2.1. 
Rationale for Combination of BGB-10188 and Tislelizumab in the Treatment of 
Platinum-Resistant Ovarian Cancer  
Ovarian cancer (OC) is the eighth most common cancer in women worldwide.  Globally, there 
were about 295,414 new cases and 184,799 deaths in 2018 (Bray et al 2018).  Patients who 
developed disease progression < 6 months after the last dose of platinum are characterized as 
having platinum-resistant OC (PROC).  The PROC population accumulates with lines of 
additional therapy, and almost all patients become resistant after 3 to 6 lines of prior 
chemotherapy. 
For patients with PROC, standard cytotoxic chemotherapy with or without bevacizumab are 
generally recommended.  The benefits of these agents are very limited, typically with an ORR of 
approximately 10%, a median PFS of 2.1 to 3.7 months, and median OS of 8.4 to 16.8 months.  
For the combination of chemotherapy with bevacizumab, the ORR improved to 27% for patients 
with PROC who received no more than 2 prior lines.  However, the addition of bevacizumab 
resulted in an increased rate of Grade 2 or greater AEs, including hypertension (20% versus 7%) 
and proteinuria (2 versus 0%), as well as gastrointestinal perforation (2% versus 0%) (Stockler et 
al 2014).  Thus, a more tolerable and effective alternative to the present therapy for patients with 
PROC is an urgent clinical need. 
OC is a “cold tumor,” characterized by low infiltration by CD8+ T cells, activated CD4+ T cells 
and increased infiltration by PD-L1+ cells, known to promote peritoneal dissemination 
(Hamanishi et al 2015).  The increased PD-L1 expression in post-chemotherapy ovarian tumor 
tissues indicates an opportunity of checkpoint inhibition in late-line setting of OC.  However, 
single-agent pembrolizumab showed limited activity in heavily pretreated OC, with ORR as 5% 
in tumors with combined positive score<1 and 10.2% in tumors with combined positive score≥1 
(Matulonis et al 2019).  Up to date, anti-PD-1 monotherapy was only approved in limited 
patients with MSI-H or dMMR, or tumor mutational burden-high tumors (KEYTRUDA 
[pembrolizumab] [US Prescribing Information] 2023).  
Studies have suggested that the frequencies of Treg cells in the epithelial OC samples are higher 
than those in the benign ovarian tumor samples (Zhu et al 2016).  Large-scale meta-analysis 
suggested that increased Tregs was associated with poorer survival and correlated with more 
advanced stages of OC (Hao et al 2018).  Those findings suggest that inhibition of Treg might 
bring clinical benefit in patients with OC.  A recent study (NCT03860272) investigated the 
combination of balstilimab (anti-PD-1) and botensilimab (anti-CTLA-4) in PROC.  With 24 
patients enrolled, the results showed ORR as 33% and DOR not reached (median follow-up 6.9 
months) (Bruno et al 2023).  The promising antitumor activity indicates that Treg inhibition 
might has the potential to reverse immune cold environment and extend efficacy of checkpoint 
inhibition to immunotherapy insensitive tumors.  
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As of 05 April 2023, 4 patients with pretreated OC were enrolled in Part D of the current study.  
Two responders were reported.  The preliminary efficacy of the study supported further 
evaluation of BGB-10188 combined with tislelizumab in the treatment of patients with PROC.  
1.4. 
Dose Rationales  
1.4.1. 
BGB-10188 in Monotherapy Escalation Phase (Part A)  
Determination of the Starting Dose 
The starting dose of BGB-10188 was determined based on animal toxicology results (detailed in 
Section 1.3.2).  With a 10-fold safety margin, the maximum recommended starting dose (MRSD) 
in humans is calculated from rat MTD to be 145 mg once/day or 200 mg once/day (from dog 
MTD).  By applying a more conservative approach using animal NOAEL, the MRSD was 48 mg 
once/day (from rat NOAEL) or 100 mg once/day (from dog NOAEL).  Taken together, 60 mg 
once/day (being close to 48 mg once/day) is selected to be the starting dose in Part A 
monotherapy escalation phase.  This dose level has more than 5 to 20 safety factors based on 
toxicity studies.  The PK of BGB-10188 is being studied in the first-in-human study 
BGB-A317-3111-10188-101.  The mean t½ following a single dose was 7.3 hours in the 60 mg 
group and 11.2 hours in the 120 mg group.  PK results showed that 2 peaks in the plasma 
concentration-time curve were observed in 7 of 9 patients after dosing (refer to Section 1.2.3).  
One ≥ Grade 3 treatment-related TEAE (upper respiratory tract infection) and 1 serious TEAE 
(acute myocardial infraction) were reported in 1 patient (7.1%) each as of the data cutoff date of 
19 July 2021.  No TEAEs leading to death were reported (refer to Section 1.2.4).  
Prediction of Human Efficacious Dose Level for BGB-10188 
The human PK parameters were predicted from animal PK results using classic allometric 
scaling methods; the efficacious plasma concentration levels of BGB-10188 were predicted from 
a panel of nonclinical pharmacodynamic or antitumor models.  The simulated PK profiles at 
multiple dose levels suggested that at least 120 mg to 240 mg once daily of BGB-10188 were 
needed to achieve significant antitumor activity in the targeted population.  Daily dose levels of 
360 and 540 mg are also planned to evaluate safety and tolerability over a wide dose range.   
1.4.2. 
BGB-10188 With Zanubrutinib in Combination Escalation Phase (Part B)  
Approximately 3 dose levels of BGB-10188 will be selected based on data from the Part A 
monotherapy escalation phase and used in combination with zanubrutinib (160 mg twice daily) 
in the combination escalation phase of Part B. The dose levels of BGB-10188 may be adjusted 
per SMC’s recommendation according to the safety, tolerability and PK data when combined 
with zanubrutinib. Both BGB-10188 and zanubrutinib are substrates of CYP3A and P-gp.  
Zanubrutinib is also a weak CYP3A inducer and may interact with BGB-10188 when given 
together.  Therefore, while fixing the therapeutic dose level of zanubrutinib, the dose level of 
BGB-10188 will be further optimized and confirmed in the escalation cohorts, which will be 
used for the expansion phase.   
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1.4.3. 
BGB-10188 With Tislelizumab in Combination Escalation Phase (Part D)  
When given with tislelizumab in the mouse model, the efficacious BGB-10188 concentration 
was about 3-fold lower than that using BGB-10188 alone.  Simulated human PK profiles 
suggested that a daily dose level of 40 mg is sufficient to achieve predicted efficacious human 
exposure.  Therefore, in Part D, which includes patients with solid tumor, 20 mg once/day of 
BGB-10188 was selected as the starting dose, ie, half of the predicted efficacious level of 40 mg 
once daily.  The clinical exposure at the dose level of 120 mg, measured as AUC and Cmax is 
45.5- and 33.3-fold, respectively, lower than the nonclinical MTD exposure from the most 
sensitive species.  Additional dose levels of 40, 80, 160, 320, and 540 mg in combination with 
tislelizumab (200 mg once every 3 weeks) will be evaluated to explore the optimal therapeutic 
dose of BGB-10188. 
1.4.4. 
BGB-10188 With Tislelizumab in Combination Expansion Phase (Part E)  
Two dose levels of BGB-10188 320 mg (orally daily) and 160 mg (orally daily) in combination 
with tislelizumab (200 mg intravenously once every 3 weeks) in patients with PROC have been 
selected for dose expansion.  Dose selection of BGB-10188 in Part E was based on the totality of 
evidence available for clinical activity and safety from Part D, clinical PK/pharmacodynamics 
and supportive preclinical results.  Refer to Section 1.5.3 and BGB-10188 IB for more detailed 
information.  Both 160 and 320 mg were considered tolerable with preliminary efficacy, minimal 
PK overlapping, and fair target engagement.  Alternate doses of BGB-10188 (eg, 80 mg orally 
once daily) or dose schedules may be added to Part E, depending on the benefit-risk of study 
drug and the various purposes of dose expansion, with the warrant and agreement from the 
Safety Monitoring Committee (SMC). 
1.5. 
Benefit-Risk Assessment  
1.5.1. 
Benefit-Risk Assessment for BGB-10188 Monotherapy in the Treatment of 
B-Cell Malignancies  
In B-cell malignancies, PI3K pathway activity is significantly elevated and is driven by altered 
B-cell receptor signaling together with other co-stimulatory signals present in lymphoid tissues, 
such as chemokines and cytokines.  PI3Kδ functions to integrate and transduce these signals 
from the microenvironment, thus promoting malignant B-cell proliferation, growth, survival, 
adhesion, and homing, making it an attractive drug target for B-cell malignancies.  BGB-10188 
has been shown to impede PI3Kδ activity and to inhibit lymphoma cancer cell growth and 
survival in nonclinical studies.  BGB-10188 is a potent, selective, orally active PI3Kδ inhibitor.  
In toxicity studies in rats and dogs, BGB-10188 related effects included hypersensitivity, 
hepatotoxicity, myeloid hyperplasia, lymphoid depletion, and cardiovascular event.  It is possible 
that subjects participating in the current protocol could experience events similar to those that 
occurred in animals.  These types of effects are readily monitored clinically and will be followed 
via frequent assessments of subject symptoms and laboratory parameters in the current study. 
Limited clinical safety data indicated that BGB-10188 appears to be well tolerated in patients 
with B-cell malignancies (Section 1.2.4).   
As of 05 February 2024, 34 patients had received BGB-10188 monotherapy at doses of 
60 mg/day (n = 5), 120 mg/day (n = 5), 240 mg/day (n = 8), 360 mg/day (n = 6), and 540 mg/day 
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(n = 10). Twenty-one patients were enrolled in Australia and 13 patients in China.  Two DLT 
events have been observed: one patient in BGB-10188 360 mg monotherapy cohort had Grade 3 
hepatic function abnormal lasting > 7 days, and another patient in BGB-10188 540 mg 
monotherapy cohort experienced Grade 3 hypertriglyceridemia. A total of 28 patients (82.4%) 
experienced adverse events assessed as related to BGB-10188. The most commonly (≥ 15%) 
occurring events by PT were Diarrhoea (9 patients, 26.5%) and Anaemia and Neutrophil count 
decreased (6 patients each, 17.6%).  Nine patients (26.5%) were identified as having 
treatment-related adverse events ≥ Grade 3 in severity.  No adverse events leading to treatment 
discontinuation or fatal adverse events were reported. 
PI3Kδ inhibitors, such as idelalisib and copanlisib, have been approved for a variety of B-cell 
malignancies (idelalisib: relapsed CLL, copanlisib: relapsed FL) in the USA and Europe.  
Idelalisib has hepatotoxicity, diarrhea or colitis, pneumonitis, infection, and intestinal perforation 
as a black box warning.  The most common adverse reactions (incidence ≥ 20%) in patients 
treated with idelalisib in the monotherapy trials are diarrhea, fatigue, nausea, cough, pyrexia, 
abdominal pain, pneumonia, and rash.  The most common adverse reactions (≥ 20%) to 
copanlisib are hyperglycemia, diarrhea, decreased general strength and energy, hypertension, 
leukopenia, neutropenia, nausea, lower respiratory tract infection, and thrombocytopenia.  The 
GLP toxicity studies demonstrated a bigger safety margin than idelalisib and copanlisib by 
comparing the exposure of NOAEL in GLP toxicity studies with the exposure of the approved or 
predicted efficacious dose in human.  In summary, BGB-10188 is a novel PI3Kδ inhibitor with 
high selectivity and has a favorable safety profile in nonclinical studies over those approved 
PI3Kδ inhibitors, and no adverse drug reactions have been identified based on limited clinical 
safety data, which are promising and warrants the continuation of testing of the compound in 
human. 
1.5.2. 
Benefit-Risk Assessment for the Combination of BGB-10188 and Zanubrutinib 
in the Treatment of B-Cell Malignancies  
In vivo studies showed that BGB-10188 induced dose-dependent antitumor effects against 
Farage DLBCL xenografts engrafted either subcutaneously or systemically in mice.  In addition, 
BGB-10188 in combination with a BTK inhibitor (zanubrutinib) showed therapeutic effects in 
TMD8 DLBCL and JEKO-1 MCL subcutaneous xenografts at doses of 10 to 30 mg/kg.  No 
specific concerns were identified in the vital functions of the central nervous system (CNS) or 
respiratory system in safety pharmacology and toxicity studies in rats and dogs (refer to the 
BGB-10188 IB).  The GLP toxicity studies demonstrated a bigger safety margin than idelalisib 
and copanlisib by comparing the exposure of NOAEL in GLP toxicity studies with the exposure 
of the approved or predicted efficacious dose in human. 
Zanubrutinib has demonstrated a very favorable toxicology and safety pharmacology profile, as 
determined by pharmacologic characteristics in the ongoing clinical studies.  Preliminary data 
show that zanubrutinib is well tolerated and has promising antitumor activity in advanced B-cell 
malignancies, including CLL, MCL, WM, hairy cell leukemia, DLBCL, FL, and MZL.  
Approximately 2772 patients have been enrolled worldwide in completed and ongoing clinical 
trials evaluating zanubrutinib and have received ≥ 1 dose of zanubrutinib.  Available data for 
zanubrutinib support a positive benefit-risk profile for the use of zanubrutinib as an 
investigational agent for treatment of R/R mature B-cell malignancies.  
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As of data cutoff date of 05 February 2024, safety data are available from 4 patients exposed to 
BGB-10188 240 mg once per day in combination with zanubrutinib 160 mg twice per day. Two 
DLTs occurred in the extended DLT window (ie, between Day 29 and Day 56) due to ALT and 
AST increased and persisted for more than 7 days in 2 patients. 
After BGB-10188 interruption, 1 patient (Patient ID 
 recovered gradually and has 
restarted BGB-10188 on a reduced dose of 120 mg once per day with zanubrutinib 160 mg twice 
per day.  After BGB-10188 interruption, Patient ID
received steroid treatment and 
raised ALT/AST recovered gradually, and patient has been reintroduced to BGB-10188 on a 
reduced dose of 120 mg once per day with zanubrutinib 160 mg twice per day.  One patient 
(25%) experienced a treatment-emergent SAE (Grade 4 Acute myeloid leukaemia, assessed by 
the investigator as not related to study drugs).  No TEAE leading to death was reported.  
Based on the experience with patients exposed to BGB-10188 240 mg once per day in 
combination with zanubrutinib 160 mg twice per day in Part B, and for reasons of development 
strategy, the Sponsor has suspended further exploration of this Part. 
1.5.3. 
Benefit-Risk Assessment for the Combination of BGB-10188 and Tislelizumab in 
the Treatment of Advanced Solid Tumors  
The results of nonclinical efficacy studies suggest that BGB-10188 could significantly inhibit the 
growth of solid tumors in combination with the PD-1 antibody.  In the CT26WT mouse colon 
cancer syngeneic model, BGB-10188 combined with anti-mouse PD-1 antibody muCh15mt 
significantly increased the TGI and TF% compared with a single agent alone at doses of 10 to 
30 mg/kg (TGI increased to 72% to 88% versus 21% to 56% in single agent groups; TF% 
increased to 54% to 71% versus 0 to 37% in single agent groups) (BGB-10188 IB).  The GLP 
toxicity studies demonstrated a bigger safety margin than idelalisib and copanlisib by comparing 
the exposure of NOAEL in GLP toxicity studies with the exposure of the approved or predicted 
efficacious dose in human.  In summary, BGB-10188 is a novel PI3Kδ inhibitor with best 
selectivity and improved safety profile shown in nonclinical studies, which is promising and 
warrants the testing of the compound in humans.  
Tislelizumab is being developed for the treatment of human malignancies in multiple organs and 
tissues as monotherapy or in combination with other therapies.  The overall safety experience 
with tislelizumab is based on experience in 2377 patients as a monotherapy and 2019 in 
combination with chemotherapy as of the data cutoff date of 27 October 2023.  The safety profile 
of tislelizumab given in combination with other anticancer medications is generally consistent 
with the safety profile of similar drug-class combinations using other agents.   
As of 05 February 2024, 43 patients have received BGB-10188 at doses of 20 mg/day (n = 5), 
40 mg/day (n = 5), 80 mg/day (n = 6), 160 mg/day (n = 11), 320 mg/day (n = 10), and 
540 mg/day (n = 7) in combination with tislelizumab 200 mg once every 3 weeks. One patient in 
this arm of the study received BGB-10188 but discontinued before receiving tislelizumab. 
Two patients experienced DLT events (Grade 3 Rash in 1 patient receiving BGB-10188 540 mg 
in combination with tislelizumab; Grade 3 Aspartate aminotransferase increased in 1 patient 
receiving BGB-10188 at a dose of 320 mg) that are assumed by the investigator to be related to 
BGB-10188. A third patient receiving BGB-10188 160 mg in combination with tislelizumab 
200 mg (Patient ID
 died due to Pneumonia and Haemorrhage intracranial, which 
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were both related to BGB-10188.  For more details about this DLT event, please refer to Section 
5.2.3.8 of the BGB-10188 Investigator’s Brochure. 
Overall, the dataset is currently small, and data are continuing to emerge in this ongoing study.  
However, to date, no significant actions related to safety were taken by the sponsor for the 
BGB-10188 study. 
Given the high unmet medical needs and limited efficacy of current standard of care in PROC 
and given the promising data in nonclinical studies and emerging efficacy/tolerable safety in 
clinical studies (Section 1.3.2), the benefit-risk assessment of the combination of BGB-10188 
with tislelizumab in PROC is considered favorable.  Part E will be conducted in order to further 
define the recommended Phase 2 dose and assess the potential benefit and safety of tislelizumab 
combined with BGB-10188 for patients with PROC.  To ensure the safety of enrolled patients, 
ongoing safety monitoring would be conducted.  Additionally lower doses of BGB-10188 (eg, 
80 mg) may be considered based on emerging clinical evidence (Section 1.4.4). 
1.6. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 
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2. 
STUDY OBJECTIVES  
2.1. 
Study Objectives  
Part A: BGB-10188 Monotherapy Dose Escalation in Patients With Relapsed/Refractory 
(R/R) Mature B-Cell Malignancies  
Primary:  
• To determine the maximum tolerated dose and the recommended dose for expansion 
(RDFE) of BGB-10188 as monotherapy  
• To assess the safety and tolerability of BGB-10188 as monotherapy  
Secondary:  
• To evaluate the preliminary antitumor activity of BGB-10188 monotherapy as 
measured by investigator-assessed overall response rate  
• To characterize the pharmacokinetic profiles of BGB-10188 as monotherapy  
Exploratory:  
• To explore relationships between BGB-10188 concentrations and corrected QTcF 
intervals 
• To characterize the pharmacodynamic profiles of BGB-10188 after a single dose and 
at steady state 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 monotherapy 
Part B: BGB-10188 + Zanubrutinib Dose Escalation in Patients With R/R Follicular 
Lymphoma, R/R Mantle Cell Lymphoma, or R/R Diffuse Large B-Cell Lymphoma  
Primary:  
• To determine the maximum tolerated dose and the RDFE of BGB-10188 in 
combination with zanubrutinib  
• To assess the safety and tolerability of BGB-10188 in combination with zanubrutinib  
Secondary:  
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed overall response rate, duration of 
response (DOR), and time to response 
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
zanubrutinib 
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Exploratory:  
• To characterize the pharmacokinetic profile of zanubrutinib when given in 
combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
zanubrutinib 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 in combination with zanubrutinib   
Part C: BGB-10188 + Zanubrutinib Dose Expansion in Patients With R/R Follicular 
Lymphoma, R/R Mantle Cell Lymphoma, or R/R Diffuse Large B-Cell 
Lymphoma  
Primary:  
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed overall response rate  
Secondary:   
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by investigator-assessed duration of response, time to 
response, and progression-free survival   
• To assess the safety and tolerability of BGB-10188 in combination with zanubrutinib  
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
zanubrutinib 
Exploratory:  
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
zanubrutinib as measured by overall survival  
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary antitumor activity of BGB-10188 in combination with zanubrutinib at the 
RDFE  
• To characterize the pharmacokinetic profile of zanubrutinib when given in 
combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
zanubrutinib at the RDFE  
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Part D: BGB-10188 + Tislelizumab Dose Escalation in Patients With Advanced Solid 
Tumors  
Primary:  
• To determine the maximum tolerated dose and the RDFE of BGB-10188 in 
combination with tislelizumab  
• To assess the safety and tolerability of BGB-10188 in combination with tislelizumab  
Secondary:   
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by investigator-assessed overall response rate, duration of 
response, disease control rate, and time to response 
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
tislelizumab 
Exploratory:  
• To assess host immunogenicity to tislelizumab in combination with BGB-10188 
• To assess the pharmacokinetics of tislelizumab in combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
tislelizumab 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary anticancer activity of BGB-10188 in combination with tislelizumab  
Part E: BGB-10188 + Tislelizumab Dose Expansion in Patients With Platinum-Resistant 
Ovarian Cancer (PROC)  
Primary:  
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab in PROC as measured by the investigator-assessed overall response rate. 
• To assess the safety and tolerability of BGB-10188 in combination with tislelizumab 
Secondary:  
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by investigator-assessed duration of response, 
progression-free survival, disease control rate, clinical benefit rate, and time to 
response 
• To evaluate the preliminary antitumor activity of BGB-10188 in combination with 
tislelizumab as measured by locally assessed carcinoma antigen-125 (CA-125) 
response rate per Gynecological Cancer Intergroup for CA-125 changes 
• To characterize the pharmacokinetic profiles of BGB-10188 in combination with 
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tislelizumab 
Exploratory:  
• To assess host immunogenicity to tislelizumab in combination with BGB-10188 
• To characterize the pharmacodynamic profiles of BGB-10188 in combination with 
tislelizumab at the recommended doses for expansion 
• To explore the relationships between biomarkers and mechanisms of resistance and 
preliminary anticancer activity of BGB-10188 in combination with tislelizumab at the 
RDFE 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, multicenter, dose escalation and dose expansion study to evaluate the 
safety and tolerability, determine the MTD and RDFE, and evaluate the preliminary antitumor 
activity of the following:  
• BGB-10188 monotherapy in patients with R/R CLL/SLL, R/R MZL, R/R FL, R/R 
MCL, or R/R DLBCL  
• BGB-10188 in combination with zanubrutinib in patients with R/R FL, R/R MCL, or 
R/R DLBCL  
• BGB-10188 in combination with tislelizumab in patients with advanced solid tumors.   
The study will be conducted in 4 parts, which are as follows: 
• Part A, a dose escalation phase to determine the MTD/RDFE of BGB-10188 
monotherapy in patients with R/R mature B-cell malignancies 
• Part B, planned as a dose escalation phase to determine the MTD/RDFE of 
BGB-10188 in combination with zanubrutinib in patients with R/R FL, R/R MCL, 
and R/R DLBCL.  
• Part C, a dose expansion phase for evaluation of BGB-10188 in combination with 
zanubrutinib at the RDFE in patients with R/R FL, R/R MCL, and R/R DLBCL 
• Part D, a dose escalation phase to determine the MTD/RDFE of BGB-10188 in 
combination with tislelizumab in patients with advanced solid tumors 
• Part E, a dose expansion phase for evaluation of BGB-10188 in combination with 
tislelizumab at the RDFEs for patients with PROC 
Part C, a dose expansion phase for evaluation of BGB-10188 in combination with zanubrutinib 
at the RDFE in patients with R/R FL, R/R MCL, and R/R DLBCL, was originally planned but 
was cancelled by the sponsor and will not be initiated. 
The study design schematic is presented in Figure 1.  More details about Part E, please see 
Figure 2.  A total of approximately 84 patients (excluding patients for China verification parts) 
are expected to be enrolled in Parts A, B, and D, the dose escalation portions of the study.  The 
sample size for China verification parts will be based on the escalation status in Part A and 
Part D. For Part E, approximately 30 to 50 patients with PROC are expected to be enrolled. 
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Figure 1: 
Study Schema 
 
Abbreviations: CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular 
lymphoma; MCL, mantle cell lymphoma; MTD, maximum tolerated dose; MZL, marginal zone lymphoma; PD, 
progressive disease; PROC, platinum-resistant ovarian cancer; RDFE, recommended dose for expansion; R/R, 
relapsed/refractory; SLL, small lymphocytic lymphoma. 
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Part C, a dose expansion phase for evaluation of BGB-10188 in combination with zanubrutinib at the RDFE in 
patients with R/R FL, R/R MCL, and R/R DLBCL, was originally planned but was cancelled by the sponsor and 
will not be intiated. 
For all study procedures, see Section 7 and Appendix 1 through Appendix 4. 
Part A is designed to determine the MTD and the RDFE of BGB-10188 as monotherapy in 
patients with R/R CLL/SLL, R/R MZL, R/R FL, R/R MCL, and R/R DLBCL.  Approximately 
5 dose levels of BGB-10188 monotherapy will be tested: 60 mg once daily, 120 mg once daily, 
240 mg once daily, 360 mg once daily, and 540 mg once daily.  Additional dose levels can be 
added if deemed appropriate.  Part B will be initiated at the latest cleared dose of monotherapy to 
escalated doses to determine the MTD/RDFE of BGB-10188 in combination with zanubrutinib 
160 mg twice daily in R/R FL, R/R MCL, and R/R DLBCL.  After a dose level of BGB-10188 is 
proven to be safe in Part A, the same dose level of BGB-10188 in combination with zanubrutinib 
could be opened. The dose levels of BGB-10188 may be adjusted per SMC’s recommendation 
according to the safety, tolerability, and PK data when combined with zanubrutinib. Additional 
dose levels could be added by the SMC based on safety, tolerability, and PK data.  When the 
dose of 120 mg once daily in Part A has been demonstrated safe, Part D, BGB-10188 dose 
escalation in combination with tislelizumab 200 mg once every 3 weeks in patients with 
advanced solid tumors, will be triggered.  In Part D, approximately 6 dose levels of BGB-10188 
will be tested: 20 mg once daily, 40 mg once daily, 80 mg once daily, 160 mg once daily, 320 
mg once daily, and 540 mg once daily.  The dose levels and schedules of BGB-10188 may be 
adjusted according to the safety and exposure results in Part A, and additional dose levels could 
be further explored. 
Dose expansion of BGB-10188 in combination with tislelizumab (Part E) will be explored after 
the RDFE of BGB-10188 in combination with tislelizumab (Part D) has been determined. In 
Part E, patients with PROC that have progressed on/after prior anticancer treatment and 
checkpoint inhibitor naïve will be randomized at a 2:1 ratio in an open-label setting to either 
BGB‑10188 160 mg once daily (approximately 20 patients, final patients number may change) or 
320 mg once daily (approximately 10 patients, final patients number may change) in 
combination with tislelizumab (200 mg once every 3 weeks).  
Part C, a dose expansion phase for evaluation of BGB-10188 in combination with zanubrutinib 
at the RDFE in patients with R/R FL, R/R MCL, and R/R DLBCL, was originally planned but 
was cancelled by the sponsor and will not be initiated. 
In Parts A and B, a cycle is defined as 28 days in length.  In Part D, a cycle is defined as 21 days 
in length except for Cycle 1, which is 28 days in length, due to the DLT assessment period.  In 
Part E, a cycle is defined as 21 days in length. 
BGB-10188 will be administered orally, once daily until unequivocal progression, unacceptable 
toxicity, death, withdrawal of consent, lost to follow-up, end of study, investigator’s decision, or 
the study is terminated by sponsor, whichever comes first.  Patients with disease progression in 
Part A can receive the cleared dose of BGB-10188 in combination with zanubrutinib at the 
investigator’s discretion based on the local guidance and zanubrutinib prescribing information 
that the patients can benefit from treatment in combination with zanubrutinib (see Section 7.6.1).   
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Zanubrutinib 160 mg will be administered twice daily until disease progression, unacceptable 
toxicity, death, withdrawal of consent, lost to follow-up, end of study, investigator’s decision, or 
the study is terminated by sponsor, whichever comes first.   
Tislelizumab 200 mg will be administered intravenously on C1D8 and Day 1 of each subsequent 
cycle in Part D and on Day 1 of each cycle in Part E until disease progression, unacceptable 
toxicity, death, withdrawal of consent, lost to follow-up, end of study, investigator’s decision, or 
the study is terminated by sponsor whichever comes first.  The decision to continue tislelizumab 
beyond the initial investigator-assessed progression must be agreed upon with the medical 
monitor and documented in the study records. 
A Bayesian model-based dose escalation approach will be used for dose escalation and MTD 
determination of BGB-10188 monotherapy.  Modified 3 + 3 design and dose escalation criteria 
will be used for combination therapy with zanubrutinib 160 mg twice daily.  A Bayesian 
model-based dose escalation approach will be used for dose escalation and MTD determination 
of the combination therapy with tislelizumab. 
Dose Verification in Chinese Patients (Part A and Part D) 
Before enrollment of patients in China for Part B and Part E, the safety and tolerability of 
BGB-10188 as monotherapy (Part A) and in combination with tislelizumab (200 mg once every 
3 weeks) (Part D) will be assessed in Chinese patients in accordance with detailed verification 
rules described in Section 3.2.2.  The RDFE for Chinese patients will be determined according to 
the SMC recommendation based on the totality of the safety data and preliminary efficacy data 
of BGB-10188 as monotherapy and when combined with tislelizumab 200 mg.  
Dose-Limiting Toxicity 
In Parts A, B, and D, patients will be evaluated for DLTs during Cycle 1.  Patients will continue 
to be evaluated for late-onset DLTs events up to 8 weeks due to late-onset toxicities that have 
been associated with first-generation PI3Kδ inhibitors.  A DLT is a toxicity or AE defined as 
meeting at least one of the following criteria listed in Section 3.2.4 and is not due to alternative 
causes (such as underlying illness, concurrent illness, or concomitant medication).  The SMC 
will review the accumulated safety data and model results after the last patient (decided by the 
sponsor/SMC) or ≥ 3 DLT-evaluable patients of the current cohort, whichever occurs earlier, 
have completed the 28-day observation period and make a recommendation on whether or not to 
proceed to the next dose level for the next cohort.  Sponsor will make the final decision based on 
the recommendation of the SMC.  The RDFE may not be the MTD since targeted therapies can 
achieve the desired antitumor effect at doses lower than the MTD. 
If a patient does not receive treatment with ≥ 75% of the expected dose for reasons other than 
treatment-related toxicity within the DLT observation period, then an additional patient will be 
enrolled.  However, all patients that receive ≥ 1 dose of study drug will be included in the overall 
analysis of safety and tolerability. 
Study Assessments 
Assessments of disease status during the study will include symptom-directed physical 
examination; disease-related constitutional symptoms (as necessary); complete blood count 
(CBC); bone marrow examination (as necessary); gastrointestinal examination (as necessary); 
and imaging scans. 
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For patients with CLL, disease response will be determined in accordance with the 2018 iwCLL 
guidelines (Hallek et al 2018) with modification for treatment-related lymphocytosis (Cheson et 
al 2012).  For patients with NHL (including SLL, MCL, MZL, DLBCL, and FL), disease 
response will be determined in accordance with the Lugano Classification for NHL 
(Cheson et al 2014).  Patients in Parts A and B with NHL (ie, SLL, MZL, MCL, FL, or DLBCL) 
will undergo positron emission tomography (PET)/computed tomography (CT) imaging at 
baseline; a separate CT scan of diagnostic quality should be performed in addition to the PET/CT 
imaging if the PET/CT imaging is not of diagnostic quality.  If PET-avid disease is detected, then 
subsequent tumor assessments should be conducted with PET/CT-based imaging.  Patients in 
Parts A and B with NHL without PET-avid disease, as well as patients with CLL, should 
undergo tumor assessments with CT-based imaging.  For patients with B-cell malignancies, 
(Parts A and B), tumor imaging will be performed every 8 weeks for the first 24 weeks, every 12 
weeks for the next 24 weeks, and then every 16 weeks thereafter.  For patients with advanced 
solid tumors (Parts D and E), tumor imaging will be performed at Week 10 (Part D) or Week 9 
(Part E) and approximately every 9 weeks (± 7 days) thereafter, based on Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v1.1; Eisenhauer et al 2009; Appendix 17).  
Assessments will be performed until disease progression, use of alternative anticancer therapy, 
withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first.  Patients 
with disease progression in Part A can receive the cleared dose of BGB-10188 in combination 
with zanubrutinib at the investigator’s discretion based on the local guidance and zanubrutinib 
prescribing information that the patients can benefit from treatment in combination with 
zanubrutinib.  This should be discussed and approved by the sponsor.  
Blood samples for BGB-10188 PK and pharmacodynamics analyses will be collected after single 
and repeated doses at specified timepoints in Part A through Part E.  In Part A only, all patients 
will receive a single dose of BGB-10188 followed by a washout period of 7 days.   
Patients will be evaluated for AEs (all grades, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 [NCI-CTCAE v5.0]) and SAEs.  Patients 
who, at time of progression, have an ongoing AE that leads to treatment discontinuation, will be 
followed until the event resolves, the investigator assesses the event as stable, the patient is lost 
to follow-up, or the patient starts a different anticancer therapy. 
3.2. 
Details of Dose Escalation  
After completing all screening activities, eligible patients will be enrolled. 
3.2.1. 
Starting Dose and Dose Escalation Approach  
In Part A, dose escalation will occur for 5 proposed, sequentially increasing dose levels of 
BGB-10188 monotherapy.  Each dose level of BGB-10188 that is evaluated may be referred to 
as a cohort or dose level.  Dose escalation will begin with BGB-10188 at 60 mg once daily.  The 
dose escalation phase will cease once the MTD or RDFE for BGB-10188 monotherapy has been 
determined.  Dose verification in Chinese patients will be performed, starting with the dose that 
has been identified as safe or as the RDFE in Part A.  The specific dose-verification rules are 
described in Section 3.2.2. 
In Part B, the initial dose of BGB-10188 for the combination therapy evaluation will be the latest 
cleared dose of BGB-10188 monotherapy.  In Part D, dose escalation of 6 proposed dose levels 
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of BGB-10188 with tislelizumab may begin with 20 mg BGB-10188 after the dose level of 120 
mg in Part A has been determined to be safe, ie, this dose level as a monotherapy has met the 
criteria for dose escalation as described below (Section 3.2.2).  The dose escalation phases (Part 
B and Part D) will cease once the RDFE for BGB-10188 in combination with zanubrutinib or 
tislelizumab has been determined for the respective parts.  Any remaining patients will continue 
with their originally assigned dosing regimen until they meet a discontinuation criterion.  
Intrapatient dose escalation may be considered in Part A, Part B, or Part D either when the next 
higher dose has been deemed to be safe (eg, the SMC has voted to escalate to 2 doses higher of 
the initially assigned dose of such patients), or when the MTD has been identified. This must be 
discussed with and approved by the sponsor.  Dose verification in Chinese patients will be 
performed and will start with the dose regimens that have been identified as safe or as the RDFE 
in Part D.  The specific dose-verification rules are described in Section 3.2.2. 
3.2.2. 
Rules for Dose Escalation and Dose Verification  
Part A Monotherapy and Part D Combination Therapy With Tislelizumab 
A Bayesian model-based dose escalation approach will be used to assist dose escalation and 
MTD determination for BGB-10188 monotherapy in Part A and for combination therapy with 
tislelizumab in Part D.  Two statistical models will be used: A Bayesian logistic regression 
model (BLRM, Neuenschwander et al 2008) will be used to model the dose relationship with the 
early-onset DLT events that occur within the 28-day observation period; additionally, 
considering the late onset of specific DLT events from 28 days to 8 weeks and to provide 
additional protection against overdosing, a Bayesian proportional hazard (BPH) model similar to 
Tighiouart et al (2014) will be used to account for the overall toxicity level until 8 weeks.  The 
BPH models will incorporate time-to-event data and do not require that all patients in the current 
cohort complete the entire observation period before a new cohort can be recruited.  More details 
about model-based dose escalation approaches are provided in Section 9. 
A cohort in the dose escalation step is defined as a set of approximately 3 patients sequentially 
enrolled and treated at the dose level recommended for the cohort.  One or more cohorts of 
patients can be recruited for each dose level evaluated.   
Before each dose recommendation for a new cohort, the statistical models will be run based on 
all the event data and observation period (for the BPH model) collected for the current and the 
previous dose levels.  Dose escalation/de-escalation recommendation will be based on the 
estimated distribution of DLT probabilities for each candidate dose level.  The dose with 
maximum probability within the targeted range of early-onset DLT rate while controlling the 
overdosing probabilities taking into account both early- and late-onset DLT events will be 
recommended. 
At the end of the dose escalation step, the MTD recommended is the dose level with the highest 
probability that its DLT rate falls into the target toxicity interval (16% to 33%) while the 
probabilities that it falls into the overdosing interval (≥ 33%) are controlled.  Further details are 
provided in Section 9.1.  Skipping an untested dose level is generally not allowed in the 
escalation process.  The dose recommendation by the models is non-binding.  The SMC, which 
includes investigators, the medical monitor, and study team members from Pharmacovigilance/ 
Drug Safety, Clinical Pharmacology, and Biostatistics with other members as appropriate, will 
review the accumulated safety data and model result after the last patient (decided by 
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sponsor/SMC) or ≥ 3 patients of the current cohort, whichever occurs earlier, have completed the 
28-day observation period and make the recommendation on the dose level for the next cohort 
based on the totality of data as described in the study assessment section.  Sponsor will make the 
final decision based on the recommendation of the SMC (refer to the SMC charter for more 
details).  
Part B Combination Therapy With Zanubrutinib 
For the BGB-10188 dose escalation in combination with zanubrutinib in Part B, dose escalation 
will occur in accordance with the following modified 3 + 3 dose escalation rules. 
A minimum of 3 patients will be initially enrolled per dose level. 
• If none of the first 3 evaluable patients enrolled in a given dose level experience a DLT, 
dose escalation may proceed. 
• If 1 of the first 3 evaluable patients enrolled in a given dose level experiences a DLT, 
additional patients (for a minimum of 6 evaluable patients) will be enrolled in that cohort.  
o If less than one-third of evaluable patients in a given dose level experiences a DLT 
(eg, DLTs in fewer than 2 of 6 patients), escalation will proceed to the next higher 
dose level. 
o If a DLT is observed in ≥ one-third or more of patients (eg, 2 or more in 6 patients or 
less), the MTD will have been exceeded and dose escalation will be stopped. 
• Additional patients (for a minimum of 6 evaluable patients) will be assessed for DLTs at 
the preceding dose level (if a minimum of 6 evaluable patients had not already been 
assessed at that dose level). 
o If the MTD is exceeded at a given dose level, the next highest dose level at which less 
than one-third of evaluable patients in a given cohort experiences a DLT (eg, DLTs in 
fewer than 2 of 6 patients) will be declared the MTD. 
o If less than one-third of evaluable patients (eg, DLTs in fewer than 2 of 6 patients) at 
the highest dose level experience a DLT, this dose level will be declared the 
maximum administered dose. 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), 
will be reviewed by the SMC.  On the basis of a review of safety data and available preliminary 
PK data, dose escalation may be halted or modified as deemed appropriate. 
Based on the safety data of the patients exposed to BGB-10188 240 mg once per day in 
combination with zanubrutinib 160 mg twice per day in Part B, the SMC recommended that 
recruitment in Part B combination therapy be placed on hold. The Sponsor decided to suspend 
development of this Part. 
Dose Verification in Chinese Patients (Part A and Part D) 
Based on the safety results of Part A and Part D conducted in Australia, the safety and PK 
characteristics of the BGB-10188 dose levels that are identified as safe as monotherapy and 
when combined with tislelizumab 200 mg once every 3 weeks will be assessed in Chinese 
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patients with B-cell malignancies and advanced malignant solid tumors.  Other doses may be 
further explored based on the safety results and necessity. 
A dose verification study in China will occur in Part A and Part D.  DLT will be assessed among 
evaluable patients within Cycle 1 and within a prolonged window for some events.  The SMC 
will review the accumulated data after the last patient (decided by the sponsor/SMC) or 
≥ 3 patients of the current cohort, whichever occurs earlier, have completed the 28-day 
observation period.  The SMC will make a recommendation on whether or not to proceed to the 
next dose level for the next cohort.  Approximately 3 to 6 patients will be enrolled in each cohort 
to assess DLT in Chinese patients with BGB-10188 monotherapy; these patients will be started 
at the dose that most recently identified by the SMC as safe in Part A in Australia and with 
BGB-10188 starting at the dose most recently identified by the SMC as safe when combined 
with tislelizumab 200 mg once every 3 weeks in Part D in Australia.  The SMC will recommend 
the next dose for subsequent patients.  The general dose recommendation rules will follow the 
modified 3 + 3 design as in Part B. 
By the time of initiating the China sites, if the RDFE has been identified in Australia sites for 
Part A and Part D, the China sites will enroll 3 to 6 patients with a starting dose at the RDFE 
level to confirm the safety, tolerability, PK, and pharmacodynamic profile in Chinese patients.  
The general dose-confirmation rules are as follows: 
• If no DLT is observed during the DLT assessment window in the first 3 patients in this 
cohort (0/3), the current dose may be confirmed as the MTD. 
• If 1 DLT is observed in the first 3 patients in this cohort (1/3), 3 additional patients will 
be enrolled for a total of 6 patients.  If no additional patients experience DLT(s) (1/6), the 
current dose will be confirmed as the MTD. 
• If > 1 DLT is observed in the first 3 to 6 patients during the DLT assessment window, the 
MTD is considered exceeded, and the dose will be de-escalated to the preceding lower 
level and tested repeatedly following the abovementioned dose-confirmation rules.  
If needed, a decision to proceed to other dose levels could be made by the SMC along with the 
sponsors and investigators.  
3.2.3. 
Assessment of Dose-Limiting Toxicity  
For initial dose-finding recommendations, AEs will be assessed per the DLT criteria below 
(Section 3.2.4) during the 28-day DLT assessment window, which starts with the first day of 
study drug administration on C1D1. 
Patients will be considered evaluable for DLTs if they: 1) received ≥ 75% of each scheduled 
study drug administration during the DLT assessment window, and/or 2) experienced a DLT. 
Patients will be considered not evaluable for DLTs, if they: 1) were withdrawn from the study 
before completion of the DLT assessment window and did not experience a DLT, and 2) did not 
receive ≥ 75% of each scheduled study drug administration during the DLT assessment window 
and did not experience a DLT.  Patients who are not DLT-evaluable must be replaced. 
Clinically important or persistent AEs that are not part of the DLT criteria (Section 3.2.4) may 
also be considered a DLT following review by the SMC.  For Part A, AEs that occur in the PK 
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washout period (from C1D-7 to C1D-1) will be reviewed by the SMC to decide whether the AEs 
may be considered DLTs.  Additionally, any clinically significant AEs that occur after the DLT 
assessment window (eg, late imAE) for a given dose level, may be considered regarding 
subsequent dose escalation decisions.  In such cases where patients have been safely dosed at the 
next dose level, additional dose escalation criteria (eg, increased minimum number of patients or 
expanded DLT assessment window) for subsequent dose levels will be considered by the SMC. 
Any patient who experiences a DLT may be withdrawn from treatment. 
3.2.4. 
Dose-Limiting Toxicity Definition  
All toxicities or AEs will be graded according to the NCI-CTCAE v5.0.  
DLT is defined as an AE that meets one of the following criteria: 
• Event occurs within 4 weeks (28 days) after start of study drug administration on C1D1, 
is related to the investigational agent, and is not due to alternative causes (eg, underlying 
disease, concurrent disease, or concomitant treatment): 
a. Hematologic toxicity: 
o Grade 4 neutropenia lasting > 7 days  
o ≥ Grade 3 febrile neutropenia 
o ≥ Grade 3 thrombocytopenia with Grade ≥ 2 bleeding  
o Grade 4 thrombocytopenia lasting > 7 days  
b. Nonhematologic toxicity  
o ≥ Grade 3 event persistent for more than 7 days   
o Any Grade of intracranial hemorrhage 
c. Any toxicity that does not meet the abovementioned DLT criteria but which leads to 
discontinuation or dosing interruption of > 7 days of BGB-10188 or zanubrutinib 
prior to Day 28 is considered a DLT. 
• Event occurs within a prolonged window up to 8 weeks (56 days) after starting 
BGB-10188 administration, is related to the investigational agent, and is not due to 
alternative causes (eg, underlying disease, concurrent disease, or concomitant 
treatment): 
o ≥ Grade 3 events of skin reaction, pneumonitis, colitis, diarrhea  
o Any Grade of ALT/AST increase lasting > 7 days  
Note: For Part D only, the following AEs will not be considered DLTs: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors) 
• Grade 3 infusion-related AE that is transient (resolved within 6 hours of onset) 
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3.2.5. 
Recommended Dose For Expansion Determination  
The RDFE may not be higher than the MTD (or maximum administered dose if the MTD is not 
reached) but may be lower.  The SMC will review all available applicable data and make a 
recommendation as to the RDFE, with the choice ultimately made by the sponsor.  The RDFE 
for Part A (BGB-10188 monotherapy), Part B (BGB-10188 + zanubrutinib), and Part D 
(BGB-10188 + tislelizumab) will be determined from safety, tolerability, PK, and any other 
relevant and available data that is obtained from the dose escalation phase.  Once the RDFE is 
determined, that dose will then be evaluated in the dose expansion phases. 
3.3. 
Details of Dose Expansion  
The dose expansion phase, Part E (BGB-10188 + tislelizumab), will begin once the RDFE has 
been determined from Part D.  Patients will be enrolled in each cohort in parallel.  Each cohort 
will be evaluated independently for study endpoints and may be closed due to lack of 
preliminary anticancer activity or other reasons.  In Part E, dose expansion will include patients 
with PROC in 2 arms, where 2 dose levels of BGB-10188 will be explored. Part C, a dose 
expansion phase for evaluation of BGB-10188 in combination with zanubrutinib at the RDFE in 
patients with R/R FL, R/R MCL, and R/R DLBCL, was originally planned but was cancelled by 
the sponsor and will not be initiated. 
3.3.1. 
Study Design of Part E  
Part E is an open-label, randomized, multicenter, dose expansion phase to evaluate the safety and 
preliminary efficacy of BGB-10188 combined with tislelizumab in patients with PROC.  
Approximately 30 to 50 patients with PROC that have progressed on/after prior anticancer 
treatment, and CPI-naïve will be randomized at a 2:1 ratio to receive either BGB‑10188 (160 mg 
once daily) plus tislelizumab (200 mg once every 3 weeks) or BGB‑10188 (320 mg once daily) 
plus tislelizumab (200 mg once every 3 weeks) until disease progression, intolerance, or patient 
withdrawal for other reasons. 
• Arm 1: BGB-10188 160 mg orally once daily + tislelizumab 200 mg intravenously once 
every 3 weeks 
• Arm 2: BGB-10188 320 mg orally once daily + tislelizumab 200 mg intravenously once 
every 3 weeks 
Ongoing safety and efficacy monitoring will be conducted.  Safety and efficacy data will be 
reviewed by the SMC after approximately 12 patients have been randomized and followed for at 
least 1 month, or after the first 10 patients are evaluable for efficacy assessment.  During the 
study, either arm that shows intolerable toxicity can be terminated, and additional lower dose(s) 
of BGB-10188 (eg, 80 mg orally once daily) may be added at any time. Study enrollment may be 
paused if there is a lack of efficacy during the interim review and may be reassumed if efficacy 
signal was observed with longer follow-up. The pause of enrollment and termination of either 
arm by the sponsor would be discussed and agreed by the SMC. 
The study schema of Part E is presented in Figure 2. 
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Figure 2: 
Study Schema of Part E  
 
Abbreviations: Bev, bevacizumab; CPI, checkpoint inhibitor; EOC, epithelial ovarian cancer; PARPi, PARP 
inhibitor; PROC, platinum-resistant ovarian cancer; Tisle, tislelizumab. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
Part A, Part B, and Part C 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments. 
2. Age ≥ 18 years on the day of signing the informed consent form (ICF; or the legal age of 
consent in the jurisdiction in which the study is taking place). 
3. Two negative pregnancy tests (≥ 1 blood test) must be obtained for female patients of 
childbearing potential prior to initiating therapy.  The first test must be performed within 
14 days prior to BGB-10188 therapy and the second test within 72 hours prior to first 
dose. 
4. Confirmed diagnosis of one of the following: 
• Part A: R/R CLL/SLL, R/R MZL, R/R FL, R/R MCL, or R/R DLBCL 
• Part B and Part C: R/R FL, R/R MCL, or R/R DLBCL 
R/R disease is defined for patients who must have either: 1) disease progression after CR or 
PR of the last line of systemic therapy, or 2) failure to achieve CR or PR to the most recent 
appropriate systemic therapy.  For the patients with CLL/SLL, the patient must experience 
relapsed or refractory disease from at least 1 cycle of systemic therapy, including BTK 
inhibitors or BCL-2 inhibitors, with or without CD20 monoclonal antibody-based 
chemotherapy, or must be intolerant to or refuse standard treatment.  For the patients with B-
cell NHLs, the patients must experience relapsed or refractory disease from at least 1 cycle of 
systemic therapy, such as immunomodulators, alkylating agents, or BTK inhibitors, with or 
without CD20 monoclonal antibody-based chemotherapy, or must be intolerant to or refuse 
standard treatment. 
5. ECOG Performance Status of 0 to 1. 
6. Patients with MZL, FL, MCL, DLBCL or SLL must have ≥ 1 bidimensionally 
measurable nodal lesion > 1.5 cm in the longest diameter or extranodal lesion that is 
> 1 cm in the longest diameter by CT scan or magnetic resonance imaging (MRI), as 
defined by the Lugano Classification. 
7. Adequate organ function, defined as the following: 
a. Absolute neutrophil count (ANC) ≥ 1 x 109/L, independent of growth factor support 
within 7 days before the first dose of study drug 
b. Platelet count ≥ 75 x 109/L, independent of IL-11, thrombopoietin, or transfusion 
within 7 days before first dose of study drug; platelet count ≥ 50 x 109/L with bone 
marrow involvement 
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c. Hemoglobin > 90 g/L, independent of transfusion within 7 days before first dose of 
study drug 
d. AST and ALT ≤ 2 x upper limit of normal (ULN) 
e. Bilirubin ≤ 1.5 x ULN (unless documented Gilbert syndrome, then up to 5 x ULN 
allowed) 
f. Creatinine clearance of ≥ 50 mL/min (as estimated by the Cockcroft-Gault equation 
or eGFR from the modification of diet in renal disease) 
g. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial 
thromboplastin time (aPTT) ≤ 1.5 x ULN 
8. Left ventricular ejection fraction > 50% as measured by echocardiogram or multigated 
acquisition scan. 
9. Life expectancy of > 4 months. 
10. Female patients of childbearing potential must practice highly effective methods of 
contraception (Appendix 7) initiated prior to first dose of study drug for the duration of 
the study and for ≥ 90 days after the last dose of BGB-10188 or zanubrutinib.   
11. Male patients are eligible if abstinent, vasectomized, or if they agree to the use of barrier 
contraception with other methods described in Appendix 7 during the study treatment 
period and for ≥ 90 days after the last dose of BGB-10188 or zanubrutinib.  Male patients 
must not donate sperm from the time of initial study drug administration, until 90 days 
after the last dose of BGB-10188 or zanubrutinib. 
Part D 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments. 
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the 
jurisdiction in which the study is taking place). 
3. Two negative pregnancy tests must be obtained (≥ 1 blood test) for female patients of 
childbearing potential prior to initiating therapy.  The first test must be performed within 
14 days prior to BGB-10188 therapy and the second test within 72 hours prior first dose. 
4. Patients with histologically or cytologically confirmed unresectable locally advanced or 
metastatic solid tumors previously treated with standard systemic therapy (including prior 
chemotherapy, radiotherapy, target therapy and immunotherapy as locally, or guidance 
approved therapy) or for which effective standard treatment is not available or not 
tolerated.  Enrollment will be limited to patients with advanced solid tumors for which 
there is clinical evidence of response to T-cell based immuno-oncology agents (eg, 
NSCLC, small cell lung cancer, head and neck squamous cell cancer, hepatocellular 
carcinoma, gastric or gastroesophageal junction carcinoma, nasopharyngeal carcinoma, 
renal cell carcinoma, cervical cancer, triple-negative breast cancer, OC, endometrial 
carcinoma, esophageal cancer, melanoma, urothelial carcinoma, or patient with 
confirmed MSI-H or dMMR solid tumor, etc).  Enrollment of tumor types beyond above 
situations requires sponsor’s approval. 
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5. Availability of archival tissue (formalin-fixed paraffin-embedded [FFPE] tumor tissue 
sample [block or approximately 10 to 15 unstained FFPE slides]) for analysis of potential 
predictors of response expression, or willingness to undergo fresh tumor biopsy.  A fresh 
tumor biopsy collected at screening is strongly recommended.  If archival samples are not 
available or not sufficient enough for explorations, a fresh tumor biopsy collected at 
screening is required.  Bone metastasis biopsy or cytological samples are not acceptable. 
6. ECOG Performance Status of 0 to 1. 
7. Patient must have ≥ 1 measurable lesion as defined by RECIST v1.1.   
8. Adequate organ function, defined as the following: 
a. ANC ≥ 1.5 x 109/L, independent of growth factor support within 7 days 
b. Platelet count ≥ 75 x 109/L, independent of thrombopoietin, IL-11 or transfusion 
within 7 days   
c. Hemoglobin > 90 g/L, without blood transfusion ≥ 7 days before sample collection 
d. Creatinine clearance of ≥ 50 mL/min (as estimated by the Cockcroft-Gault equation 
or eGFR from the modification of diet in renal disease) 
e. Serum total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert syndrome) 
f. AST and ALT ≤ 2 x ULN for patients with liver metastasis ≤ 5 x ULN 
g. INR ≤ 1.5 x ULN and aPTT ≤ 1.5 x ULN 
9. Female patients of childbearing potential must practice highly effective methods of 
contraception (Appendix 7) initiated prior to first dose of study drug for the duration of 
the study and for ≥ 90 days after the last dose of BGB-10188 or ≥ 120 days after the last 
dose of tislelizumab.   
10. Male patients are eligible if abstinent, vasectomized, or if they agree to the use of barrier 
contraception with other methods described in Appendix 7 during the study treatment 
period and for ≥ 90 days after the last dose of BGB-10188 or ≥ 120 days after the last 
dose of tislelizumab. 
11. Adequate pulmonary function, defined as the following: 
a. Without clinical symptoms of dyspnea at rest and pulse oxygen saturation > 92% 
while breathing room air, or 
b. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), carbon 
monoxide diffusion capacity (DLCO), or transfer factor for carbon monoxide of lung 
(TLCO) > 50% of predicted value, as well as FEV1/FVC > 60% as measured by 
pulmonary function test. 
Part E 
1. Patients must sign a written ICF and understand and agree to comply with the 
requirements of the study and the schedule of assessments. 
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the 
jurisdiction in which the study is taking place). 
3. Patients with histologically or cytologically confirmed epithelial OC (including fallopian, 
or primary peritoneal cancer) and must meet the following criteria: 
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• Patients must have received ≥ 1 line and ≤ 3 lines of systemic anticancer treatment.  
• Must be platinum resistant, which is defined if disease progression occurred between 
1 month (30 days) to 6 months (180 days) after the last platinum treatment (disease 
progression within 1 month [≤30 days] after last platinum treatment is not 
acceptable). 
• Patients must have a known Breast Cancer gene (BRCA) status and should have been 
treated with Poly (ADP-ribose) polymerase (PARP) inhibitors if there was BRCA 
mutation. 
Note: A line of anticancer treatment starts when there is disease progression assessed by the 
investigator per local practice (eg, imaging, biopsy, CA-125).  Maintenance treatment is not a 
new line of anticancer treatment.  A line of anticancer treatment may be constituted with 
chemotherapy, Tyrosine kinase inhibitor (TKI), PARP inhibitors, or other anticancer agents.  
4. Measurable disease as assessed by RECIST v1.1. 
5. ECOG Performance Status ≤ 1. 
6. Adequate organ function as indicated by the following laboratory values: 
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
i. ANC ≥ 1.5 x 109/L 
ii. Platelets ≥ 75 x 109/L 
iii. Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 using the Chronic 
Kidney Disease Epidemiology Collaboration equation (Appendix 12).  
c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 5 x ULN for patients 
with Gilbert syndrome). 
d. AST and ALT ≤ 2 x ULN or < 5 x ULN if hepatic metastases are present. 
7. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study and for ≥ 120 days after the last dose of 
tislelizumab.  They must also have a negative urine or serum pregnancy test result 
≤ 7 days before first dose of study drug.  See Appendix 7. 
8. Availability of archival tissue (FFPE tumor tissue sample [block or approximately 10 to 
15 unstained FFPE slides]) for analysis of potential predictors of response expression, or 
willingness to undergo fresh tumor biopsy.  A fresh tumor biopsy collected at screening 
is strongly recommended.  If archival samples are not available or not sufficient enough 
for explorations, a fresh tumor biopsy collected at screening is required.  Bone metastasis 
biopsy or cytological samples are not acceptable. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
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Part A, Part B, and Part C 
1. History of allogeneic stem-cell transplantation or chimeric antigen receptor-T-cell 
therapy. 
2. For patients with DLBCL in Part A, classified as T-cell/histiocyte-rich large B-cell 
lymphoma, high-grade B-cell lymphoma with myelocytomatosis viral oncogene homolog 
and B-cell lymphoma (BCL)-2 and/or BCL-6 rearrangements, high-grade B-cell 
lymphoma, primary mediastinal large B-cell lymphoma, Epstein-Barr virus positive 
DLBCL, and transformed DLBCL.  
3. Prior exposure to PI3K inhibitor (all patients).  For patients in Part B and Part C, prior 
exposure to BTK inhibitor and/or PI3K inhibitor. 
4. Major surgery within 4 weeks before screening. 
5. History of other active malignancies within 2 years prior to study entry, with the 
exception of (1) adequately treated in situ carcinoma of cervix; (2) localized basal cell or 
squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally 
(surgery or other modality) with curative intent. 
6. Clinically significant cardiovascular disease including the following: 
a. Myocardial infarction within 6 months before screening 
b. Unstable angina within 3 months before screening 
c. Clinically significant ventricular arrhythmia (eg, sustained ventricular tachycardia, 
ventricular fibrillation, torsade de pointes) 
d. QTcF interval (Fridericia’s correction) > 480 msec 
e. History of second-degree atrioventricular (AV) block type II or third-degree AV 
block without a permanent pacemaker in place. 
f. New York Heart Association (NYHA) class III or IV congestive heart failure 
(Appendix 8) 
7. History of severe bleeding disorders, such as hemophilia A, hemophilia B, von 
Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or 
other medical intervention. 
8. History of stroke or intracranial hemorrhage within 6 months before first dose of study 
drug. 
9. Unable to swallow capsules or having a disease significantly affecting gastrointestinal 
function such as malabsorption syndrome, resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
10. Uncontrolled systemic infection requiring parenteral intravenous anti-infective therapy. 
11. Known HIV infection, or serologic status reflecting active hepatitis B virus (HBV) or 
hepatitis C virus (HCV) infection as follows: 
a. Hepatitis B surface antigen (HBsAg) (+), or 
b. Hepatitis B core antibody (HBcAb) (+) and HBV DNA detected, or 
c. Presence of HCV antibody.  Patients with presence of HCV antibody are eligible if 
HCV RNA is undetectable. 
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12. Known hypersensitivity to compounds of similar chemical or biologic composition to 
PI3K inhibitor.  For patients in Part B and Part C, known hypersensitivity to compounds 
of similar chemical or biologic composition to BTK inhibitor. 
13. Pregnant or lactating women. 
14. Any life-threatening illness, medical condition, or organ system dysfunction, which, in 
the investigator's opinion, could compromise the patient’s safety or put the study at risk. 
15. Requires ongoing treatment with strong and moderate CYP3A inhibitors or inducers 
(Appendix 10).  If patients have been on a strong or moderate CYP3A inhibitors or 
inducers in the past, they will not be eligible if the administration was within 7 days 
before the first dose of study drug. 
16. Concurrent participation in another therapeutic clinical study. 
17. Current or history of CNS lymphoma.  
18. Histologically confirmed transformed lymphoma.  
19. Receipt of the following treatments prior to first dose of study drug: 
a. Corticosteroids (at doses > 20 mg/day prednisone equivalent) given with 
antineoplastic intent within 7 days 
b. Chemotherapy or radiotherapy within 5 half-lives or 14 days, whichever is shorter 
c. Monoclonal antibody within 5 half-lives or 14 days, whichever is shorter 
d. Investigational therapy within 5 half-lives or 14 days, whichever is shorter 
e. Chinese patent medicine with antineoplastic intent within 5 half-lives or 14 days, 
whichever is shorter 
20. Toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, ANC, 
hemoglobin, and platelets.  For ANC, hemoglobin, and platelets, please follow inclusion 
criterion #7 for Part A, Part B, and Part C). 
Part D 
1. Pleural effusion, pericardial effusion, or ascites that requires drainage procedures within 
14 days before first dose. 
2. Active leptomeningeal disease or uncontrolled brain metastasis.  Patients with a history 
of treated and asymptomatic CNS metastases at screening are eligible per the following 
criteria: 
a. Brain imaging at screening shows no evidence of interim progression. 
b. All brain metastases with supratentorial location. 
c. No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsant use at a stable dose is allowed. 
d. No stereotactic radiation or whole-brain radiation ≤ 14 days before the first dose of 
study drug(s). 
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3. Active autoimmune diseases or history of autoimmune diseases that may relapse or 
history of life-threatening toxicity related to prior immune therapy, with the following 
exceptions: 
a. Controlled type 1 diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
4. Prior exposure to PI3K inhibitor. 
5. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
the first dose of BGB-10188, with the following exceptions: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent). 
b. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal 
systemic absorption. 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen). 
6. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases, including but not limited to pulmonary fibrosis, acute lung diseases, etc.  
7. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia 
≤ 14 days before the first dose of study drug(s). 
8. Severe chronic or active infections (including but not limited to tuberculosis infection) 
requiring systemic treatment ≤ 14 days before the first dose of study drug(s). 
• Antiviral therapy is permitted for patients with hepatocellular carcinoma. 
9. Known HIV infection, or serologic status reflecting active HBV or HCV infection as 
follows: 
a. HBsAg (+), or 
b. HBcAb (+) and HBV DNA detected, or 
c. Presence of HCV antibody.  Patients with presence of HCV antibody are eligible if 
HCV RNA is undetectable. 
10. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks before 
the first dose of study drug(s) or anticipation of need for major surgical procedure during 
the course of the study. 
11. Prior immunodeficiency, allogeneic stem-cell transplantation, or organ transplantation. 
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12. Any of the following cardiovascular criteria: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before the first dose of study drug(s) 
b. Symptomatic pulmonary embolism or other clinically significant episode of 
thromboembolic disease ≤ 28 days before the first dose of study drug(s) 
c. History of acute myocardial infarction ≤ 6 months before the first dose of study 
drug(s) 
d. History of heart failure meeting NYHA Classification III or IV (Appendix 8) 
≤ 6 months before the first dose of study drug(s) 
e. Ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study 
drug(s) 
f. Cerebrovascular accident ≤ 6 months before the first dose of study drug(s) 
g. QTcF interval (Fridericia’s formula) > 480 msec 
h. Cardiac left ventricular ejection fraction ≤ 50% as measured by echocardiogram or 
multigated acquisition scan.  The same modality used at baseline must be applied for 
subsequent evaluations. 
i. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg despite antihypertension medications ≤ 28 days before the first dose of 
study drug(s) 
j. Syncope or seizure ≤ 28 days before the first dose of study drug(s) 
k. History of second-degree AV block type II or third-degree AV block without a 
permanent pacemaker in place 
13. Unable to swallow capsules or having a disease significantly affecting gastrointestinal 
function, such as malabsorption syndrome, resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
14. Chemotherapy, immunotherapy (eg, interleukin, interferon, or thymosin), hormonal 
therapy, or investigational therapy ≤ 14 days or ≥ 5 half-lives (whichever is shorter) 
before the first dose of study drug(s) 
15. Toxicities from prior therapy that have not recovered to baseline, ≤ Grade 1, or stabilized, 
except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific 
laboratory abnormalities) 
16. Live vaccine ≤ 4 weeks before the first dose of study drug(s) 
• Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
17. Known hypersensitivity to compounds of similar chemical or biologic composition to 
PI3K inhibitor or to PD-1/PD-L1 antibodies. 
18. Pregnant or lactating women. 
19. Requires ongoing treatment with strong and moderate CYP3A inhibitors or inducers 
(Appendix 10).  If patients have been on a strong or moderate CYP3A inhibitors or 
inducers in the past, they will not be eligible if the administration was within 7 days 
before the first dose of study drug. 
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20. Concurrent participation in another therapeutic clinical study. 
21. Medical condition or alcohol or drug abuse or dependence that, in the investigator’s 
opinion, will be unfavorable for the administration of study drug(s) or will affect the 
explanation of drug toxicity or AEs or are likely to result in insufficient compliance with 
study procedures. 
22. History of other active malignancies within 2 years prior to study entry, with the 
exception of: (1) adequately treated in situ carcinoma of cervix; (2) localized basal cell or 
squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally 
(surgery or other modality) with curative intent. 
Part E 
1. Prior exposure to PI3K inhibitor. 
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other antibody or drug 
specifically targeting T-cell stimulation or checkpoint pathways. 
3. COVID-19 antigen positive by a licensed test. 
4. Prior randomization in a tislelizumab study regardless of the treatment arm, until the 
primary and key secondary endpoints of the study have read out. 
5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis. 
• Patients with a history of treated and, at the time of screening, stable CNS metastases 
are eligible, provided they meet all the following: 
o Brain imaging at screening shows no evidence of interim progression, and there is 
no evidence of new brain metastases. 
o Patient clinically stable for ≥ 2 weeks. 
o Have measurable and/or evaluable disease outside the CNS. 
o No ongoing requirement for corticosteroids as therapy for CNS disease; off 
steroids 3 days before randomization; anticonvulsants at a stable dose are allowed.  
o No stereotactic radiation or whole-brain radiation ≤ 14 days before 
randomization. 
6. Active autoimmune diseases or history of autoimmune diseases that may relapse. 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type 1 diabetes 
b. Hypothyroidism (provided that it is managed with hormone replacement therapy 
only) 
c. Celiac disease controlled by diet alone 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
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7. Any malignancy ≤ 5 years before first dose of study drug except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast). 
8. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
first dose of study drug. 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen 
9. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before first dose of study drug. 
10. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence ≤ 14 days after intervention). 
11. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases including pulmonary fibrosis, or acute lung diseases.  Patients with significantly 
impaired pulmonary function or who require supplemental oxygen at baseline must 
undergo an assessment of pulmonary function at screening (see Appendix 4). 
12. Infection (including tuberculosis infection, etc) requiring systemic (oral or intravenous) 
antibacterial, antifungal, or antiviral therapy ≤ 14 days before first dose of study drug. 
Note: Antiviral therapy is permitted for patients who have chronic infection with HBV, or 
infection with HIV.  Patients receiving prophylactic antibiotics (eg, for prevention of urinary 
tract infection, chronic obstructive pulmonary disease, or for dental extraction) are eligible. 
13. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/mL (or 
≥ 2500 copies/mL) at screening. 
Note: Inactive HBsAg carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or 
< 2500 copies/mL) can be enrolled. 
14. Patients with active hepatitis C 
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody 
test followed by a negative HCV RNA test at screening are eligible. 
15. Untreated HIV infection, if known.  Patients with known HIV infection are eligible if the 
following criteria are met: 
a. Stable on antiretroviral therapy for ≥ 4 weeks before first dose of study drug 
b. Patient agrees to adhere to antiretroviral therapy per WHO guidelines 
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c. No documented multidrug resistance that would prevent effective antiretroviral 
therapy 
d. Viral load of < 400 copies per mL at screening 
e. CD4+ T-cell count ≥ 350 cells/μL at screening 
f. No history of an AIDS-defining opportunistic infection ≤ 12 months before first dose 
of study drug unless eligibility is agreed to by the medical monitor after consultation 
g. If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon 
agreement with the medical monitor 
16. Any major surgical procedure ≤ 28 days before first dose of study drug.  Patients must 
have recovered adequately from the toxicity and/or complications from the intervention 
before first dose of study drug. 
17. Prior allogeneic stem-cell transplantation or organ transplantation. 
18. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before first dose of study drug 
b. Pulmonary embolism ≤ 28 days before first dose of study drug 
c. Any history of acute myocardial infarction ≤ 6 months before first dose of study drug 
d. Any history of heart failure meeting NYHA Classification III or IV (Appendix 8) 
≤ 6 months before first dose of study drug 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before first 
dose of study drug  
f. Any history of cerebrovascular accident ≤ 6 months before first dose of study drug 
g. Uncontrolled hypertension that cannot be managed by standard antihypertension 
medications ≤ 28 days before first dose of study drug 
h. Any episode of syncope or seizure ≤ 28 days before first dose of study drug  
19. A history of severe hypersensitivity reactions to other monoclonal antibodies. 
20. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, 
etc) or any investigational therapies ≤ 14 days or ≤ 5 half-lives (whichever is shorter) 
before the first dose of study drug, or has received palliative radiation treatment or other 
local regional therapies ≤ 14 days before the first dose of study drug. 
21. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to 
baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy, and specific laboratory abnormalities). 
22. Was administered a live vaccine ≤ 28 days before first dose of study drug 
Note: Vaccines for COVID-19 are allowed except for any live vaccine that may be 
developed.  Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed.  Intranasal vaccines are live vaccines and are not allowed. 
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, will 
affect the explanation of drug toxicity or AEs, or will result in insufficient or impaired 
compliance with study conduct. 
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24. Women who are pregnant or are breastfeeding. 
25. Concurrent participation in another therapeutic clinical study. 
Note: Concurrent participation in observational or noninterventional studies is allowed.  In 
addition, patients who have completed active treatment in a clinical study and are in the 
follow-up period can be enrolled in this study. 
26. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, bariatric 
surgery procedures, or symptomatic partial or complete bowel obstruction. 
Note: Controlled partial bowel obstruction might be eligible. 
27. Family history, medical history, or ongoing condition of inflammatory bowel disease (eg, 
Crohn’s disease, ulcer colitis). 
Note: Patients with other causes of diarrhea or colitis must be resolved for at least 7 days 
before first dose of study drug 
28. Requires ongoing treatment with a strong or moderate CYP3A inhibitor or inducer (see 
Appendix 10).  If patients have been on a strong or moderate CYP3A inhibitors or 
inducers in the past, they will not be eligible if the administration was within 7 days 
before the first dose of study drug. 
29. QTcF interval (Fridericia’s correction) > 450 ms. 
Note: For any QTcF > 450 ms on initial ECG, a follow-up ECG will be performed in 
triplicate (ie, 3 separate ECGs recorded approximately 2 minutes apart).  Patients with mean 
follow-up QTcF ≤ 450 ms are eligible. 
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5. 
STUDY TREATMENT  
5.1. 
Study Treatment Preparation and Dispensation  
5.1.1. 
BGB-10188  
The full chemical name of BGB-10188 fumarate is 3-[(1S)-1-(8-amino-1-methylimidazo[1,5-
a]pyrazin-3-yl)ethyl]-5-chloro-6-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-[(propan-2-
yl)oxy]benzamide fumarate. 
BGB-10188 fumarate is a white to light yellow powder with a molecular formula of 
C30H39ClFN7O6 and a molecular weight of 648.13 Daltons.  BGB-10188 fumarate capsules are 
supplied in 20-mg and 80-mg strengths.  Size 3 hydroxypropyl methylcellulose (HPMC) 
capsules are used for the 20-mg strength. Size 0 HPMC capsule shells are used for the 80-mg 
strength.  Inactive ingredients include microcrystalline cellulose, mannitol, sodium starch 
glycolate, colloidal silicon dioxide, and magnesium stearate.  All excipients are compendial.  The 
product is supplied in high-density polyethylene (HDPE) bottles with desiccants. 
The study drug must be kept at the temperature condition specified on the label. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal.  
Please also refer to the BGB-10188 IB for other details regarding BGB-10188. 
5.1.2. 
Zanubrutinib  
Zanubrutinib 80-mg capsules will be provided in HDPE bottles.  
The study drug must be kept at the temperature condition specified on the label.   
The contents of the label will be in accordance with all applicable local regulatory requirements. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal.  
Please also refer to the zanubrutinib IB for other details regarding zanubrutinib. 
5.1.3. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, US Pharmacopeia type I), containing a total of 100 mg of antibody in 10 mL of 
isotonic solution.  Tislelizumab has been aseptically filled in single-use vials with a Flurotec-
coated butyl rubber stopper and an aluminum cap.  Each vial is packaged into a single-carton 
box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label.   
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal.  Please also refer to the tislelizumab IB for other details regarding tislelizumab. 
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5.2. 
Dosage and Administration  
5.2.1. 
BGB-10188  
BGB-10188 will be taken orally daily each morning with a glass of water (approximately 
240 mL).  Patients must be fasted for at least 2 hours before dosing and will remain fasted for 
2 hours after dosing. 
In Part A, 5 proposed dose levels will be tested: 60 mg once daily, 120 mg once daily, 240 mg 
once daily, 360 mg once daily, and 540 mg once daily.  Additional dose levels may be added if 
deemed appropriate.  In Part A only, all patients will receive a single dose of BGB-10188 
followed by a washout period of 7 days. 
In Part B, the initial oral, daily dose of BGB-10188 will start at the latest cleared dose of 
BGB-10188 monotherapy (Part A).  Approximately 3 dose levels are planned to be tested for 
Part B.  Dose levels may be changed or added as necessary based on the SMC review. 
In Part D, the initial oral daily dose of BGB-10188 will start at 20 mg once daily.  
Approximately 6 proposed dose levels will be tested: 20 mg once daily, 40 mg once daily, 80 mg 
once daily, 160 mg once daily, 320 mg once daily, and 540 mg once daily.  BGB-10188 should 
be given ≥ 30 minutes before tislelizumab infusion.  Additional dose levels may be added if 
deemed appropriate. 
In Part E, patients will be randomly assigned to receive either one of the 2 doses as starting dose: 
160 mg once daily or 320 mg once daily.  BGB-10188 will be taken orally daily each morning 
with a glass of water (approximately 240 mL).  Patients must be fasted for at least 2 hours before 
dosing and will remain fasted for 2 hours after dosing.  At Day 1 of each cycle, BGB-10188 
should be given ≥ 30 minutes before tislelizumab infusion.  Additional dose(s) of BGB-10188 
(eg, 80 mg orally once daily) may be added during the study with the warrant and agreement by 
the SMC. 
If 1 dose of BGB-10188 is missed, the patient will skip the missed dose and resume the same 
daily dose at the scheduled time on the next day.  If 2 or more doses of BGB-10188 are missed, 
the patient should take 1 daily dose immediately after realizing the missed doses; the time of day 
when this make-up dose was taken (Restart Time) will become the new scheduled dosing time 
for the following days.  Patients should continue to take the same daily dose at this new 
scheduled time on the next day. 
5.2.2. 
Zanubrutinib  
Zanubrutinib 160 mg will be administered orally twice a day.  When taken in combination with 
BGB-10188, zanubrutinib will be taken following BGB-10188 dosing. 
Zanubrutinib will be dispensed by the study center personnel to patients at scheduled study visits 
to ensure adequate drug supply for administration at home throughout the treatment phase as 
detailed in the Pharmacy Manual.  The investigator is to instruct the patient to take the study 
drug exactly as prescribed and at the same time each day of dosing.  Patients will be requested to 
bring their unused medication and all empty bottles to the center at each visit.  All dosages 
prescribed and dispensed to the patient and all dose changes, including reason for dose changes 
during the study, must be recorded on the appropriate electronic case report form (eCRF). 
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Zanubrutinib will be administered as two 80-mg capsules by mouth twice daily (160 mg twice 
daily) with or without food.  Patients will take zanubrutinib with water at approximately the 
same time every day with a minimum of 8 hours between consecutive doses.  Zanubrutinib 
capsules should not be opened, broken, or chewed at any time. 
Patients with disease progression in Part A can receive the cleared dose of BGB-10188 in 
combination with zanubrutinib at the investigator’s discretion based on the local guidance and 
zanubrutinib prescribing information, which has been approved by local authorities that the 
patients can benefit from treatment in combination with zanubrutinib.  This should be discussed 
and approved by the sponsor.  
If a dose of zanubrutinib is missed, patients will be advised to take the same dose immediately 
after realizing the missed dose and return to the next regularly scheduled dose.  However, if it is 
4 hours or less to the next scheduled dose, patients should skip the missed dose, and the make-up 
dose is not recommended.  
5.2.3. 
Tislelizumab  
Tislelizumab 200 mg will be administered on Day 8 of Cycle 1 and Day 1 of each subsequent 
cycle in Part D and Day 1 of each cycle in Part E.  In Part D, Cycle 1 is 28 days in length and all 
subsequent cycles are 21 days in length.  In Part E, a cycle is defined as 21 days in length.  
Tislelizumab will be administered by IV infusion through an IV line containing a sterile, 
nonpyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter.  Specific 
instructions for product preparation and administration are provided in the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 8 of Cycle 1 (Part D)/Day 1 of 
Cycle 1 (Part E) and Day 1 of Cycle 2, patients must be monitored for ≥ 60 minutes afterward in 
an area with resuscitation equipment and emergency agents.  From Cycle 3 onward, a 
≥ 30-minute monitoring period is required in an area with resuscitation equipment and 
emergency agents. 
The initial infusion (Cycle 1 Day 8 for Part D and Cycle 1 Day 1 for Part E) will be delivered 
over 60 minutes; if this is well tolerated, then the subsequent infusions may be administered over 
30 minutes, which is the shortest period permissible for infusion.  Tislelizumab must not be 
concurrently administered with any other drug (refer to Section 6).  
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and IRRs are provided in detail in Section 5.5, Section 8.7, and 
Appendix 9. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.3. 
Compliance and Accountability  
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or guardian.  
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The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed and used by each patient.  This information must be captured in the source document 
at each patient visit.  The investigator is responsible for study drug accountability, reconciliation, 
and record maintenance.  In accordance with all applicable regulatory requirements, the 
investigator or designated study center personnel must maintain study drug accountability 
records throughout the course of the study.  This person will document the amount of study drug 
received from the sponsor, the amount supplied, and/or administered to and returned by patients, 
if applicable. 
5.4. 
Overdose  
Any dose of BGB-10188 or zanubrutinib in excess of that specified in this protocol or of 
tislelizumab ≥ 600 mg in a 24-hour period is considered to be an overdose.  Incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF 
AEs associated with an overdose of study drug will be recorded on the AE eCRF.  Any SAEs 
associated with an overdose are required to be reported within 24 hours of awareness via SAE 
reporting process as described in Section 8.6.  There is no specific antidote for BGB-10188, 
zanubrutinib, or tislelizumab overdose.  In the event of an overdose, patients should be closely 
monitored and given appropriate supportive treatment. 
5.5. 
Dose Hold or Modification  
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule.  In the event of significant toxicities, dosing may be held and/or reduced based on the 
guidelines provided below.  Reasons for dose modifications or holds, the supportive measures 
taken, and the outcome will be documented in the patient's chart and recorded in the eCRF. 
5.5.1. 
BGB-10188  
5.5.1.1. 
Dose Escalation  
Patients on lower dose levels who have a suboptimal response, as determined by the investigator 
following disease assessment, may be allowed to increase their dose to higher dose levels that 
have subsequently been declared tolerable.  This must be approved by the sponsor.  Once the 
RDFE is identified, the dose for patients on lower doses may be increased to the RDFE at the 
investigator’s discretion using a plan approved by the SMC.  Any significant safety events that 
occur in these patients (eg, events that meet the definition of a DLT) will be reviewed by the 
SMC for evaluating the safety of the doses. 
Dose interruption of BGB-10188 will be allowed for DLT and other reasons.  Dose interruption 
because of a DLT event is allowed in DLT observation window.  Dosing of BGB-10188 can be 
withheld for up to 28 consecutive days. 
Dose reduction of BGB-10188 for the management of AEs will be allowed beyond the DLT 
observation window (28 days from C1D1 and up to 8 weeks prolonged window).  The AEs 
should be unlikely related to zanubrutinib in Part B or tislelizumab in Part D, or the relatedness is 
uncertain.  This dose reduction must be determined by the investigator following disease 
assessment and approved by the sponsor.  The dose can be reduced to the one prior cleared dose 
that is confirmed by SMC.  A total maximum of 2 dose reductions will be allowed throughout 
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the whole treatment period.  For patients with AEs not recovered or worsened from the first dose 
reduction, the patients will be strongly recommended to have dose interruption or discontinue 
from the treatment. 
Dose interruptions that lead to a drug compliance rate less than 75% of the prescribed dosage 
during the DLT assessment period, and for reasons other than DLT, will cause the patient to be 
replaced (Section 3.2.3).  After the DLT assessment period, if in the investigator’s opinion, it is 
in the patient’s best interest to restart treatment after dose interruptions > 28 days, written 
approval must be obtained from the sponsor’s medical monitor. 
For patients in Parts A and B who experience diarrhea and colitis, atypical infection such as 
pneumocystis jirovecii pneumonia (PJP), or cytomegalovirus (CMV) infection after the DLT 
window, the guidelines set forth should be followed (Table 1).  For Grade 1 to 2 rash, 
BGB-10188 treatment can be maintained but should be interrupted for Grade 3 rash while 
managing and treating rash per institutional guidelines.  For Grade 3 rash, BGB-10188 can be 
resumed at a reduced dose (-1 dose) if resolved to baseline.  For pneumonitis, BGB-10188 
treatment can be maintained for Grade 1 and should be interrupted for Grade 2; patients 
experiencing Grade 3 pneumonitis should discontinue BGB-10188. Treatment for pneumonitis 
should be manage and provided according to institutional guidelines. 
Table 1: 
Guidelines for Dose Modifications of BGB-10188 in Part A and B  
Event 
Action for BGB-10188 
Grade 1 Diarrhea  
OR 
Grade 1 Colitis 
Maintain study treatment 
Manage and initiate treatment per institutional guidelines 
Monitor approximately weekly until resolved 
Grade 2 Diarrhea 
 
Interrupt study treatment until resolved 
Manage and initiate treatment per institutional guidelines 
Resume at a reduced dose (-1 dose) if resolved to baseline 
Grade 3 Diarrhea 
OR 
Grade 2-3 Colitis 
Interrupt study treatment until resolved 
Manage and initiate treatment per institutional guidelines 
Monitor closely until resolved 
Resume at a reduced dose (-1 dose) if resolved to baseline 
For recurrent Grade 3 diarrhea or recurrent colitis of ≥ Grade 2, 
discontinue study treatment 
Grade 4 Diarrhea 
OR 
Grade 4 Colitis 
Discontinue study treatment 
Manage and initiate treatment per institutional guidelines 
Grade 1-2 Rash  
Maintain study treatment 
Manage and initiate treatment per institutional guidelines 
Grade 3 Rash  
Interrupt study treatment until resolved 
Manage and initiate treatment per institutional guidelines 
Resume at a reduced dose (-1 dose) if resolved to baseline 
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Grade 4 Rash 
Discontinue study treatment   
Manage and initiate treatment per institutional guidelines 
Pneumocystis jirovecii pneumonia  
Any grade 
Discontinue BGB-10188. 
CMV infection/reactivation 
Any grade 
Interrupt BGB-10188 upon unequivocal clinical or laboratory 
evidence of CMV infection and initiate treatment according to 
established clinical guidelines.  If the benefits of resuming 
BGB-10188 are judged to outweigh the risks, consideration 
should be given to administering prophylactic CMV therapy. 
5.5.1.2. 
Dose Expansion (Part E)  
In Part E, patients will be randomly assigned to receive either 320 or 160 mg dose levels of 
BGB-10188 as starting dose.  The treatment of BGB-10188 may be temporally withheld or 
reduced if the patient experiences a toxicity that is suspected to be related to BGB-10188.  
Treatment may resume only after the AEs have returned to baseline or ≤ Grade 1 severity or AEs 
that, in the opinion of the investigator, are not considered a safety risk to the patient.  The 
decision of treatment resumption should be applied to both BGB-10188 and tislelizumab if dose 
modification was previously applied to both study drugs.  For reasons other than drug-related 
AEs, eg, safety concerns due to the poor health condition, if deemed necessary by the 
investigators, dose modifications could be applied after discussion with medical monitor.  
Dosing of BGB-10188 can be withheld for up to 28 consecutive days to allow for resolution of 
toxicity.  If additional dose interruptions are required, the treating investigator should discuss 
with the study medical monitor.  A maximum of 2 dose reductions are permitted (Table 2).  Once 
the dose has been decreased, it should remain reduced for all subsequent administrations or 
further reduced if necessary.  There will be no dose escalations in this study. 
If the decision of study drug discontinuation is made, the decision should be applied to both 
BGB-10188 and tislelizumab.  If 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 medical monitor, the decision of resumption should be applied to both 
BGB-10188 and tislelizumab. 
Dose modification guidance for AEs that have been previously observed in subjects receiving 
BGB-10188 or are potential class-effect AEs is provided in Table 3.  Dose modification 
guidance for diarrhea/colitis is provided in Section 5.6.  Dose modification guidance for other 
AEs is provided in Table 4. 
Table 2: 
BGB-10188 Dose Reduction Levels in Part E  
Timepoint 
Dose Level 
Dose Level 
Starting dose 
160 mg 
320 mg 
First dose reduction 
120 mg 
240 mg 
Second dose reduction 
80 mg 
160 mg 
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Table 3: 
Guidelines for Dose Modifications of BGB-10188 in Part E  
Adverse Reactions 
Severity 
Dose Modification 
Hematologic Adverse Reactions 
Neutropenia 
ANC 0.5 to 1.0 x 109/L 
(Grade 3) 
Interrupt BGB-10188 until ANC resolved 
to > 1.0 x 109/L (Grade 2), then resume at 
same dose.  
ANC < 0.5 x 109/L 
(Grade 4) 
Interrupt BGB-10188 until ANC resolved 
to > 1.0 x 109/L (Grade 2), then resume at 
same dose. 
If recurrence or persistent for > 7 days, 
interrupt BGB-10188 until ANC resolved 
to > 1.0 x 109/L (Grade 2), then resume at 
next lower dose level. 
Thrombocytopenia 
Platelet count 25 to 
50 x 109/L (Grade 3) 
Interrupt BGB-10188 until platelet count 
resolved to > 50 x 109/L (Grade 2), then 
resume at same dose. 
Platelet count < 25 x 
109/L (Grade 4) or any 
grade platelet count 
decrease with bleeding 
not explained by 
alternative causes 
Interrupt BGB-10188 until platelet count 
resolved to > 50 x 109/L (Grade 2), then 
resume at same dose. 
If recurrence or persistent for > 7 days, 
interrupt BGB-10188 until platelet count 
resolved to > 50 x 109/L (Grade 2), then 
resume at next lower dose level. 
Nonhematologic Adverse Reactions 
ALT/AST elevation 
 
ALT/AST 3 to 5 x ULN 
(Grade 2) 
Maintain BGB-10188. 
If recurrence or persistent for > 14 days, 
interrupt BGB-10188 until ALT/AST 
resolved to < 3 x ULN (Grade 1), then 
resume at same dose. 
ALT/AST 5 to 20 x ULN 
(Grade 3) 
Interrupt BGB-10188 until ALT/AST 
resolved to < 3 x ULN (Grade 1), then 
resume at same dose. 
If recurrence or persistent for > 14 days, 
interrupt BGB-10188 until ALT/AST 
resolved to < 3 x ULN (Grade 1), then 
resume at next lower dose level. 
ALT/AST > 20 x ULN 
(Grade 4) 
Discontinue BGB-10188. 
Cutaneous reactions (eg, 
rash, pruritus) 
Grade 2 
Maintain BGB-10188. 
If recurrence or persistent for > 14 days, 
interrupt BGB-10188 until resolved to 
≤ Grade 1, then resume at same dose. 
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Adverse Reactions 
Severity 
Dose Modification 
Grade 3 
Interrupt BGB-10188 until resolved to 
≤ Grade 1, then resume at next lower dose 
level. 
Grade 4 
Discontinue BGB-10188. 
Pneumonitis 
Grade 1 
Interrupt BGB-10188 until resolved then 
resume at same dose. 
If recurrence, interrupt BGB-10188 until 
resolved then resume at next lower dose 
level. 
Grade 2 
Interrupt BGB-10188 until resolved then 
resume at next lower dose level. 
If recurrence or patient does not respond to 
steroid therapy, discontinue BGB-10188 
Grade 3 or 4 
Discontinue BGB-10188. 
Infections 
Grade 3 
Interrupt BGB-10188 until resolved then 
resume at next lower dose level. 
Grade 4 
Discontinue BGB-10188. 
Note: 
• 
≥ Grade 3 laboratory findings (ANC, platelet count, ALT/AST) should be frequently 
monitored (at least weekly) until resolved to ≤ Grade 1. 
• 
For patients with liver metastasis or abnormal baseline ALT/AST, please contact sponsor to 
discuss dose modifications. 
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; 
ULN, upper limit of normal. 
Table 4: 
Guidelines for Dose Modifications of BGB-10188 Regarding AEs not 
Mentioned in Table 3 in Part E  
Adverse Reactions 
Dose Modifications 
Grade 1 or Grade 2 toxicity  
Continue BGB-10188 and treat the toxicity; 
increase the monitoring frequency as clinically 
indicated. 
Grade 3 toxicity 
Step 1: Interrupt BGB-10188 up to 28 days until 
the toxicity is resolved to ≤ Grade 1. 
Step 2: Resume BGB-10188 at same dose or 
reduce 1 dose level 
Recurrent Grade 3 toxicity after 2 dose reductions 
Interrupt BGB-10188 up to 28 days until the 
toxicity is resolved to ≤ Grade 1 and resume at 
same dose, or discontinue BGB-10188. 
Grade 4 toxicity 
Discontinue BGB-10188.  
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5.5.2. 
Zanubrutinib  
In Part B (combination of BGB-10188 and zanubrutinib), patients experiencing a DLT should be 
considered for permanent treatment discontinuation following the dose escalation rule for 
BGB-10188.  However, such patients may continue to receive additional zanubrutinib if 
clinically appropriate in the judgment of the investigator and after consultation with and approval 
by the medical monitor. 
The guidelines set forth should be followed for dose interruption or modification of zanubrutinib 
for hematologic (Section 5.5.2.1) or nonhematologic (other than hypertension adequately 
controlled with oral medication or asymptomatic laboratory events; laboratory events indicating 
liver or renal dysfunction will not be considered asymptomatic laboratory events) 
(Section 5.5.2.2) toxicities after the DLT window. 
Table 5: 
Zanubrutinib Dose Reduction Levels 
Toxicity Occurrence 
Dose Level 
Zanubrutinib Dose  
First 
0 = starting dose 
Restart at 160 mg twice daily a 
Second 
-1 dose level 
Restart at 80 mg twice daily 
Third 
-2 dose level 
Restart at 80 mg once daily 
Fourth 
Discontinue zanubrutinib 
Discontinue zanubrutinib 
Abbreviations: DLT, dose-limiting toxicity. 
a During the DLT period in Cycle 1, patients are not eligible to restart at 160 mg twice daily and must reduce dose 
to the -1 dose level after the first DLT.  After the second DLT, patients must reduce dose to the -2 dose level.  
After the third DLT, patients must discontinue zanubrutinib. 
Zanubrutinib may be restarted upon resolution of toxicity and per investigator discretion if held 
for a maximum of 28 consecutive days.  If, in the investigator’s opinion, it is in the patient’s best 
interest to restart treatment after > 28 days, then written approval must be obtained from the 
sponsor’s medical monitor. 
5.5.2.1. 
Zanubrutinib Dose Reductions for Hematologic Toxicity  
Dosing will be held for individual patients under any of the following conditions, based on 
investigator assessment of study-drug relatedness: 
• Grade 4 neutropenia (lasting > 10 days)  
• Grade 4 thrombocytopenia (lasting > 10 days) 
• Grade 3 thrombocytopenia associated with significant bleeding 
• ≥ Grade 3 febrile neutropenia 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery 
of the toxicity to ≤ Grade 1 or baseline. 
If the same event reoccurs, patients will restart at 1 dose level lower upon recovery of the 
toxicity to ≤ Grade 1 or baseline.  A maximum of 2 dose reductions will be allowed.  Patients 
with ≥ Grade 3 thrombocytopenia associated with significant bleeding requiring medical 
intervention will be discussed with the medical monitor. 
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5.5.2.2. 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity  
Table 6: 
Zanubrutinib Dose Reduction Steps for Nonhematologic Toxicity 
Toxicity 
Action for Zanubrutinib 
Restart Dose 
≥ Grade 3 hemorrhage not 
considered related to study drug 
Hold until recovery to less than 
or equal to Grade 1. 
Restart at either the original 
dose or dose level (-1), at the 
discretion of the treating 
investigator. 
≥ Grade 3 hemorrhage 
considered related to study drug 
Hold until underlying condition 
has fully resolved.  
If underlying condition cannot 
be treated to full resolution, 
permanently discontinue 
zanubrutinib. 
Restart at dose level (-1). 
Any grade intracranial 
hemorrhage 
Permanently discontinue 
zanubrutinib. 
Not applicable 
AF that is symptomatic and/or 
incompletely controlled 
Hold until AF is controlled. 
Restart at either the original 
dose or dose level (-1), at the 
discretion of the treating 
investigator. 
Other ≥ Grade 3 toxicity 
considered related to study drug, 
including inadequately 
controlled HTN and/or liver or 
renal laboratory value 
abnormalities 
Hold until recovery to less than 
or equal to BL if BL is greater 
than Grade 1; hold until less 
than or equal to Grade 1 if BL is 
less than or equal to Grade 1. 
Restart at the original dose level. 
Abbreviations: AF, atrial fibrillation; BL, baseline; HTN, hypertension. 
Zanubrutinib should be withheld for any ≥ Grade 3 hemorrhage.  The drug should be 
permanently discontinued for any related ≥ Grade 3 hemorrhage with the exception of those 
where the underlying condition can be fully treated (eg, gastric ulcer resulting in gastrointestinal 
bleed) and the risk of a re-bleed is deemed acceptable.  Zanubrutinib should be permanently 
discontinued for any intracranial hemorrhage. 
For nonhematological toxicities ≥ Grade 3, other than hypertension adequately controlled with 
oral medication or asymptomatic laboratory events (laboratory events indicating liver or renal 
dysfunction will not be considered asymptomatic laboratory events) suspected to be related to 
study drug treatment, study drug will be held until recovery to ≤ Grade 1 or baseline, and then 
restarted at original dose level.  If the event recurs at ≥ Grade 3, drug will be held until recovery 
to ≤ Grade 1 or baseline and restarted at level -1.  If the event recurs at ≥ Grade 3, drug will be 
held until recovery to ≤ Grade 1 and restarted at level -2.  If the event recurs at ≥ Grade 3 at 
level -2, the patient will be discontinued from study treatment.  For patients experiencing atrial 
fibrillation that is symptomatic and/or incompletely controlled: after the atrial fibrillation is 
adequately controlled, zanubrutinib may be restarted at either the original dose or dose level -1, 
per discretion of the treating investigator.   
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For information on study drug holds based on the results of hepatitis B or hepatitis C testing, see 
Section 7.5.7. 
5.5.3. 
Tislelizumab  
There will be no dose reduction for tislelizumab in this study. 
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to tislelizumab and requires a dose to be withheld.  If the administration delay is 
≤ 10 days, the delayed drug will be administered; if the delay is > 10 days, the delayed drug will 
be omitted in this cycle, and the next cycle will be administered as planned as long as the AE 
resolves within 21 days. 
The patients should resume tislelizumab treatment as soon as possible after the AEs recover to 
baseline or Grade 1 (whichever is more severe) and within 12 weeks after the last dose of 
tislelizumab.  If the patient is unable to resume tislelizumab within 12 weeks after the last dose 
of tislelizumab, then the patient should be discontinued from treatment. 
If 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 medical 
monitor. 
Dose modifications for imAEs and IRRs are described in Appendix 9 and Section 8.7.1, 
respectively. 
5.6. 
Management Guidelines for Treatment-Related Diarrhea or Colitis 
(Part E)  
Subjects should inform the investigator immediately on any event of diarrhea.  In all incidences, 
development of diarrhea while using BGB-10188 should be evaluated urgently with close 
follow-up until improvement. 
Subjects presenting with diarrhea, a thorough history, physical examination and necessary 
laboratory testing should be performed during the initial patient examination (Table 7).  For each 
occurrence, attempts should be made to rule out other causes, such as metastatic disease or viral 
infection, which might require additional supportive care.  Diagnostic colonoscopy is 
recommended for atypical cases (eg, bloody diarrhea) or those in whom the recommended 
treatment interventions do not lead to resolution of diarrhea. 
For subjects with any-grade diarrhea, dietary modification is instructed (Table 8).  Solid foods 
can be gradually added after diarrhea is improved. 
Note: When treatment-related diarrhea is suspected, the causality judgment should be carefully 
assessed.  If there is strong evidence suggesting diarrhea is only related to tislelizumab, the 
diarrhea should be managed according to the guidance provided in Appendix 9.  In other 
situations, the dose modification guideline is provided in Table 9.  Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
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Table 7: 
Evaluation and Diagnostic Testing Recommendations for Subjects 
Presenting Diarrhea  
History and Physical Examination 
Laboratory Testing 
Physical examination, including assessment of 
fever, dizziness, abdominal pain/cramping, and 
weakness 
History of onset and duration of diarrhea 
Travel history 
Description of number of stools and stool 
composition (eg, watery, bloody, nocturnal) 
Medication profile to identify diarrheagenic 
agents 
Dietary profile to identify diarrheagenic foods 
Stool work-up 
Occult blood determination 
Culture for enteric pathogens (Salmonella, 
Escherichia coli, Campylobacter, infectious 
colitis) 
Clostridium difficile 
CBC, electrolytes, and BUN/Cr 
Consider colonoscopy in selected cases 
Source: Coutré et al 2015 
Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; Cr, creatinine.  
Table 8: 
Diet Modification Recommendations for Subjects With Diarrhea  
Diet Modifications 
Drink plenty of fluids, 8 to 12 glasses a day of oral-rehydration drinks, other clear liquids or clear broth 
to replace lost fluids and minerals. 
Eat 5 to 6 small meals each day. 
Eat low-fat, high-protein foods, such as lean meat and eggs. 
Try BRAT (bananas, rice, apple sauce, toast) diet to help lessen the number of bowel movements. 
Try crackers, gelatin, noodles, or oatmeal. 
Eat cooked instead of raw vegetables, and remove skins from fruits before eating. 
Avoid fried, fatty, greasy, or spicy foods. 
Avoid milk (if it makes the diarrhea worse), milk products (including ice cream), and acidic drinks (eg, 
tomato juice, citrus juices, fizzy soft drinks). 
Avoid foods that cause gas (eg, broccoli and cabbage) and high-fiber foods. 
Avoid caffeine, alcohol, and herbal supplements (some may cause diarrhea). 
Source: American Cancer Society 2013; National Cancer Institute 2012 
Table 9: 
Management and Dose Modification Guidance for Treatment-Related 
Diarrhea/Colitis  
Grade 1 
Maintain BGB-10188 and tislelizumab. 
Treat with antimotility agents (eg, 4 mg loperamide followed by 2 mg every 4 hours 
or after every unformed stool). 
Monitor approximately every 48 hours. 
If improved within 48 hours, continue dietary modification, and gradually add in 
solid foods; discontinue loperamide after 12-hour symptom-free interval. 
If not improved after 48 hours, treat per guidance for Grade 2.  
Grade 2 
Interrupt BGB-10188 and delay tislelizumab. 
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Complete evaluation for infection (eg, CMV, C. difficile) immediately. 
Monitor approximately every 48 hours. 
If improved to ≤ Grade 1 within 48 hours and/or infection is confirmed, resume 
BGB-10188 and tislelizumab at same dose (for infectious diarrhea/colitis, follow 
institutional standard-of-care, or consult with medical monitor if needed). 
If not improved to ≤ Grade 1 after 48 hours and infection is ruled out, start oral 
budesonide 9 mg once daily or oral steroid (eg, prednisolone 1 mg/kg daily), or 
consider IV steroids if patient is being given IV fluids.  If no improvement with oral 
steroid, switch to IV steroids.  
When diarrhea/colitis is resolved to ≤ Grade 1 after steroid treatment, taper steroids 
according to institutional standard-of-care. When taper is completed (≤ 10 mg/day 
prednisone or equivalent), resume BGB-10188 at next lower dose and resume 
tislelizumab. 
If Grade 2 reoccurs, treat per guidance for Grade 2 again. 
If Grade 2 reoccurs a third time, discontinue BGB-10188 and tislelizumab. 
Grade 3 
For the first occurrence, treat per guidance for Grade 2. 
If Grade 3 reoccurs, discontinue BGB-10188 and tislelizumab. 
Grade 4 
Discontinue BGB-10188 and tislelizumab. 
Source: Hanlon and Brander 2020; Kryvenko 2015 
Abbreviations: CMV, cytomegalovirus; IV, intravenous. 
5.7. 
Precautions  
Phototoxicity 
Because the molar extinction coefficient greater than 1000 L mol-1 cm-1 was noted in ultraviolet 
A between 320 and 347 nm, a potential phototoxicity risk in skin is considered.  Investigators 
should advise patients to take measures, such as avoid direct sunlight and use UV protection, eg, 
use of sunscreen and wearing of hats and long-sleeve garments, to minimize exposure to UV 
light for the duration of the treatments. 
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6. 
CONCOMITANT THERAPY  
6.1. 
Concomitant Therapy  
All concomitant medications taken during the study will be recorded in the eCRF with indication 
and dates of administration.  
Prophylactic measures against infection, for the prevention of bacterial or fungal infections 
and/or for the prevention of hepatitis B infection reactivation, should be used per institutional 
standards. 
6.1.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care at the discretion of the investigator for supportive care 
(eg, anti-emetics, antidiarrheals) and in a patient’s interest are allowed. 
6.1.1.1. 
Part A, Part B, and Part C  
The following treatments are allowed: 
• Blood transfusions and growth factor support per standard of care and institutional 
guidelines 
• Corticosteroids for non-lymphoma indications 
o Patients should not receive treatment with systemic corticosteroids other than 
intermittently to control or prevent infusion reactions, or for short durations 
(< 14 days) to treat non-lymphoma-related conditions (eg, to treat a flare of chronic 
obstructive pulmonary disease). 
o A short course (≤ 7 days) of systemic corticosteroid treatment for control of 
lymphoma-related symptoms is allowed prior to enrollment provided it is tapered off 
within 5 days after initiation of study treatment. 
o Chronic systemic corticosteroid use is not permitted, except for adrenal 
replacement consult the medical monitor for this situation. 
• Therapy to reduce symptoms per standard of care and institutional guidelines 
Tumor lysis syndrome has not been currently reported with zanubrutinib treatment; however, it 
remains a concern.  Patients with high tumor burden should be monitored closely and 
prophylactic measures, including allopurinol and hydration, may be instituted per institutional 
standards. 
Patients with hematologic malignancies, particularly those having received prior 
lymphodepleting chemotherapy or having prolonged corticosteroid exposure, are predisposed to 
opportunistic infections as a result of disease and treatment-related factors.  In patients with a 
high risk for opportunistic infections prophylaxis should be considered as per institutional 
standards.  Patients must receive trimethoprim-sulfamethoxazole or other established prophylaxis 
for PJP throughout the course of BGB-10188 treatment.  Prophylaxis will continue for a period 
of 2 to 6 months after BGB-10188 discontinuation.  The duration of prophylaxis should be based 
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on clinical judgment and may take into account risk factors such as concomitant corticosteroid 
treatment and prolonged neutropenia after BGB-10188 treatment ends.  Patients must 
permanently discontinue BGB-10188 upon diagnosis of PJP. 
6.1.1.2. 
Part D and Part E  
Unless noted otherwise, most concomitant medications and therapies deemed necessary and in 
keeping with local standards of medical care at the discretion of the investigator for supportive 
care (eg, anti-emetics, antidiarrheals, hematopoietic growth factors, or red blood cell/platelet 
transfusions) and in a patient’s interest are allowed.  Prophylactic drugs for PJP for patients with 
high risk should be considered. 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient within 28 days 
before the first dose of study drug(s) and 30 days after the last dose of study drug(s) will be 
recorded. 
Bisphosphonates and RANKL inhibitors are allowed for bone metastases if initiated before 
enrollment and at a stable dose.  Bisphosphonates are permitted during the study for a 
non-malignant indication. 
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 9) and be at nonimmunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration.  The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted. 
Palliative (limited-field) radiation therapy is permitted for solid tumors, but only for pain control 
or prophylaxis of bone fracture to sites of bone disease present at baseline provided the following 
criteria are met: 
• Repeat imaging demonstrates no new sites of bone metastases. 
• The lesion being considered for palliative radiation is not a target lesion for 
RECIST v1.1. 
• The case is discussed with the medical monitor, and the medical monitor agrees that the 
conditions required to receive palliative radiation are met. 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if clinically indicated per investigators’ discretion and after consultation with 
the medical monitor.  Whenever possible, these patients should have a tumor assessment of the 
lesion(s) before receiving the radiotherapy in order to rule out progression of disease. 
It is not required to withhold BGB-10188 and/or tislelizumab treatment during palliative 
radiotherapy. 
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6.1.2. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited during the study: 
• Live vaccines ≤ 28 days before first dose of study drugs and ≤ 60 days after the last dose 
of study drugs are prohibited. 
• Any concurrent systemic anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard anticancer agents, or investigational anticancer agents are 
prohibited during screening and through the End-of-Treatment (EOT) Visit. 
• BGB-10188 is CYP3A and P-gp substrates.  Co-administration with strong CYP3A 
inhibitors or inducers and grapefruit juice and Seville oranges should be avoided.  Please 
refer to Section 6.2 for more details. 
6.1.3. 
Restricted Concomitant Medications/Procedures  
The following medications are restricted during the study: 
• Immunosuppressive agents (except to treat a drug-related AE). 
• Patients should not abuse alcohol or other drugs during the study. 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be 
carefully monitored. 
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.1.1. 
• Herbal remedies for the treatment of cancer or Chinese patent medicines with approval 
from the China NMPA for use as anticancer treatment (regardless of cancer type). 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions (eg, hypericin). 
• Co-administration with moderate CYP3A inhibitors or inducers should be done with 
caution (Appendix 10). 
Opiates and other medication required for palliative management of patients are allowed.  
Patients must notify the investigator of all concurrent medications used during the study. 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
BGB-10188 and zanubrutinib are CYP3A and P-gp substrates.  Co-administration with strong 
CYP3A inhibitors or inducers (see Appendix 10 for list of common inhibitors and inducers) and 
grapefruit juice and Seville oranges should be avoided.  Co-administration with moderate 
CYP3A inhibitors or inducers should be done with caution, as they may affect the metabolism of 
BGB-10188 and zanubrutinib.  If at all possible, patients are encouraged to not use 
strong/moderate CYP3A inhibitors and inducers and consider using alternative agents.  If these 
agents will be used, follow the dose-modification table in Appendix 11 for zanubrutinib.  Please 
refer to the FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers List (FDA 2019) for a more complete list. 
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Zanubrutinib is a mild inducer of CYP3A4 and CYP2C19.  Narrow therapeutic index drugs that 
are metabolized by CYP3A4 (alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should be 
used with caution.  Since blood levels and efficacy of drugs that are substrates for CYP3A (eg, 
steroidal contraceptives) may be reduced by CYP3A inducers, if patients are using hormonal 
contraceptives, such as birth control pills or devices, a second barrier method of contraception 
(eg, condoms) is recommended to be used.  The coadministration of oral P-gp substrates with a 
narrow therapeutic index (eg, digoxin) should be used with caution as zanubrutinib may increase 
their concentrations. 
The drug-drug interaction potential between tislelizumab and other small or large therapeutic 
molecules is low, given tislelizumab is a monoclonal antibody with no effect on drug 
metabolizing enzymes or transporters. 
The medical monitor and clinical pharmacologist should be consulted for uncertain cases. 
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7. 
ENROLLMENT AND STUDY PROCEDURES  
The scheduled study assessments are provided in Appendices (from Appendix 1 to Appendix 4).  
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (which must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines. 
7.1. 
Screening Period  
Screening evaluations will be performed within 28 days prior to the first dose of study drug.  In 
Part A, the first dose of drug will occur on Day -7 of Cycle 1 for PK studies.  In Part B through 
Part E, the first dose of study drug will occur on Cycle 1 Day 1.  Patients who agree to 
participate in this study will sign the ICF prior to undergoing any screening procedure.  The 
screening period begins on the date the ICF is signed.  Screening evaluations may be repeated as 
needed within the screening period; the investigator is to assess preliminary patient eligibility 
according to the latest screening assessment results. 
Results of standard of care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to the first dose of study drugs (or window indicated) may be used for 
the purposes of screening rather than repeating the standard of care tests unless otherwise 
indicated. 
For Part E, patients suspected of having or known to have concurrent serious respiratory illness 
or who exhibit significant respiratory symptoms unrelated to underlying cancer should undergo 
pulmonary function testing during screening or whenever clinically indicated (see Appendix 4). 
Rescreening under limited conditions may be allowed after consultation with the sponsor.  For 
example, rescreening may be considered when a patient narrowly misses a laboratory criterion 
that is correctable and not due to rapidly deteriorating condition or disease progression.  
Rescreening is allowed only once. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures.  ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before first dose of study drugs.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
7.1.2. 
Demographics  
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations.  Race and 
ethnicity data are collected in accordance with ICH guidance (ICH E5 1998, ICH E17 2017) 
adopted by the European Medicines Agency (EMA) and US FDA, to understand whether 
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race/ethnicity could influence the PK, safety, and/or efficacy of the study drug.  For example, 
population PK analysis is a well-established, quantitative method that can quantify and explain 
the variability in drug concentrations among patients.  Such variability can be attributed to 
intrinsic factors (eg, body weight, age, gender, race/ethnicity), or to extrinsic factors (eg, 
concomitant medications), and can lead to clinically relevant changes in drug concentrations that 
require a change in the dose or dosing regimen.  Results from race/ethnicity and other 
demographic analyses will be incorporated into drug product labeling to provide guidance on 
safety and efficacy variations (if any) linked to certain populations (eg, race or ethnic group) as 
well as any potential dose adjustment needed for those populations.  Therefore, collecting 
race/ethnicity data in the study is essential to understand whether race/ethnicity could influence 
the PK, safety, and/or efficacy. 
7.1.3. 
Patient Numbering  
After obtaining informed consent, study site personnel access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant.  
Patients who are rescreened will be assigned a new patient number.  Screening numbers that are 
assigned to the same patient within the IRT system will be linked. 
7.2. 
Enrollment  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply.  
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined.  No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with ICH E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
7.2.1. 
Randomization (Part E)  
Study site personnel will access the IRT system to randomly assign the patient to a treatment arm 
and to assign study drug.  Study treatment must commence ≤ 2 business days after 
randomization/treatment assignment. 
7.3. 
Treatment Period  
In Parts A, B, and C, a cycle is defined as 28 days in length.  In Part D, Cycle 1 is 28 days in 
length and all subsequent cycles are 21 days in length.  In Part E, a cycle is defined as 21 days in 
length.  
BGB-10188 will be administered orally, once daily until unequivocal progression, unacceptable 
toxicity, death, withdrawal of consent, lost to follow-up, end of study, investigator’s decision, or 
the study is terminated by sponsor, whichever comes first.  The decision to receive BGB-10188 
in combination with zanubrutinib beyond progression in Part A must be agreed upon with the 
medical monitor and documented in the study records. 
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Zanubrutinib 160 mg will be administered orally, twice daily until disease progression, 
unacceptable toxicity, death, withdrawal of consent, lost to follow-up, end of study, 
investigator’s decision, or the study is terminated by sponsor, whichever comes first. 
Tislelizumab 200 mg will be administered intravenously on Day 8 of Cycle 1 and Day 1 of each 
subsequent cycle in Part D and on Day 1 of each cycle in Part E until disease progression, 
unacceptable toxicity, death, withdrawal of consent, lost to follow-up, end of study, 
investigator’s decision, or the study is terminated by sponsor, whichever comes first.  The 
decision to continue tislelizumab beyond the initial investigator-assessed progression must be 
agreed upon with the medical monitor and documented in the study records. 
BGB-10188 should be taken ≥ 30 minutes before tislelizumab infusion for patients in Part D and 
Part E. 
Refer to Section 7.6 and Section 8.7 for additional considerations regarding treatment 
continuation and withdrawal. 
7.3.1. 
Treatment Period (Part E)  
For Part E, after completing all screening activities, eligible patients will be randomized in a 2:1 
ratio to receive either BGB-10188 160 mg + tislelizumab 200 mg (Arm 1) or BGB-10188 
320 mg + tislelizumab 200 mg (Arm 2). 
Patients will receive open-label treatment with one of the following: 
• Arm 1: BGB-10188 160 mg orally once daily + Tislelizumab 200 mg intravenously once 
every 3 weeks 
• Arm 2: BGB-10188 320 mg orally once daily + Tislelizumab 200 mg intravenously once 
every 3 weeks 
Ongoing safety monitoring will be conducted for enrolled patients.  With emerging clinical 
evidence, the arm that shows intolerable toxicity could be terminated at any time by sponsor and 
upon the agreement by the SMC.  Additional dose(s) of BGB-10188 (eg, 80 mg orally once 
daily) may be added during the study. 
Administration of study drugs will continue until disease progression is assessed by the 
investigator per RECIST v1.1 (Section 7.6), unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met (whichever occurs first; see Section 7.13). 
In both arms, treatment beyond the initial investigator-assessed RECIST v1.1-defined disease 
progression is permitted provided that the patient has investigator-assessed clinical benefit and is 
tolerating study drug (Section 7.6.2).  
7.4. 
Visit Windows  
All visits must occur within ± 3 days of the scheduled date, unless otherwise noted (from 
Appendix 1 to Appendix 4).  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 before study drug 
administration unless otherwise noted.  Laboratory results should also be reviewed before study 
drug administration.  
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In Parts A, B, and C, the study visit schedule is based around 28-day cycles.  Procedures for a 
given visit may be split across the window to allow for drug resupply and completion of study 
procedures.   
In Parts D and E, the study visit schedule is based around 21-day cycles except for Part D 
Cycle 1, which is based around a 28-day schedule.  In Part D, all cycles after Cycle 1 will be 
calculated every 3 weeks starting from Cycle 1 Day 8.  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, with subsequent visits conducted according to the planned schedule 
every 3 weeks from Day 1 of Cycle 2 (Part D) or Day 1 of Cycle 1 (Part E). 
7.5. 
Safety Assessments  
7.5.1. 
Physical Examination and Vital Signs  
A complete physical examination that includes an assessment of cardiovascular, respiratory, 
abdominal, and neurological systems as well as lymph nodes/spleen, skin, oropharynx, and 
extremities will be performed at screening.  A targeted examination should be limited to systems 
of clinical relevance (ie, cardiovascular, respiratory, lymph nodes, liver, and spleen), and those 
systems associated with clinical signs/symptoms will be performed at PK washout and at each 
visit.  Vital signs (sitting blood pressure, pulse rate, and body temperature) will be performed 
after the patient has rested in the sitting position for ≥ 3 minutes at screening, at PK washout, at 
each visit during study treatment, at EOT, and at the Safety Follow-up Visit.  Weight will be 
assessed at screening and at every visit as indicated in the Schedule of Assessments.  Height 
(cm) is determined at screening only.  B-symptoms, which include unexplained weight loss 
> 10% over the previous 6 months, fever (> 38°C), and/or drenching night sweats will be 
assessed for patients in Parts A, B, and C only. 
Assessment of vital signs and a targeted physical examination on Cycle 1 Day 1 may be skipped 
if performed within the last 7 days. 
7.5.2. 
Ophthalmologic Examination (Part D)  
Because immune CPIs like tislelizumab may be associated with imAEs involving the eye, an eye 
examination, including visual acuity test, and optical coherence tomography (or equivalent 
diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of first dose of study drug may be used for the Screening 
evaluation.  Patients will undergo repeat assessments by an appropriate specialist approximately 
every 15 weeks (± 7 days) during study treatment and a final assessment < 30 days after the last 
dose of study treatment. 
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment.  For any change in 
vision, referral to an appropriate specialist will be made for further management guidance 
(see Appendix 9). 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 16) will be assessed per the Schedules of Assessment. 
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7.5.4. 
Laboratory Safety Tests  
Laboratory assessments of serum chemistry, hematology, coagulation, urinalysis, and thyroid 
function will be conducted, of which certain elements will be collected per the timepoints 
specified in Appendix 1 through Appendix 4. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Laboratory Assessments  
Chemistry, CBC, coagulation, urinalysis, serum immunoglobins, thyroid function (Part D and 
Part E), and hepatitis serologies will be performed at the timepoints specified in the Schedule of 
Assessments and may also be performed as medically necessary.  In Cycle 1, laboratory 
assessments should be performed before the first dose of study drug. 
Screening tests (including CBC, chemistry, and coagulation) performed within 72 hours before 
the first study drug administration do not need to be repeated in Cycle 1.  Results of blood tests 
taken within 72 hours may be used by the investigators to make the decision to proceed with 
dosing.  After Day 1 of Cycle 1, results are to be reviewed within 48 hours before study drug 
administration.  Screening hepatitis serologies performed within 4 weeks before the first study 
drug administration do not need to be repeated in Cycle 1. 
Urinalysis 
Urinalysis, which includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose, 
will be performed at specified timepoints in the Schedule of Assessment. 
Hematology 
Hematology assessments (which include hemoglobin, hematocrit, platelets, red blood cells, 
WBCs, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) are required to be 
performed as specified in the Schedule of Assessments. 
Chemistry 
Chemistry assessments include sodium, potassium, chloride, urea or blood urea nitrogen, 
creatinine, glucose, calcium, total protein, albumin, AST, ALT, ALP, total bilirubin, lactate 
dehydrogenase, phosphate or phosphorus, uric acid, magnesium, and bicarbonate.  For patients in 
Part D and Part E, serum amylase and serum lipase will be performed at screening and as 
clinically indicated.  
Chemistry assessments will be performed as specified per the Schedule of Assessments. 
Coagulation Profile 
The coagulation profile includes prothrombin time (which will also be reported as INR) and 
activated partial thromboplastin time.  The coagulation profile will be performed as specified in 
the Schedule of Assessments. 
Pregnancy Test 
Two negative pregnancy tests must be obtained for all women of childbearing potential before 
initiation of therapy.  The first test must be performed ≤ 14 days before BGB-10188 therapy and 
the second test ≤ 72 hours before BGB-10188 therapy.  At least 1 test should be a blood 
pregnancy test.  
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Pregnancy testing will be performed as specified in the Schedule of Assessments.  If a urine 
pregnancy test is positive, the result must be confirmed by a serum pregnancy test.  A patient 
who has a positive pregnancy test result at any time after the study drug administration will be 
immediately withdrawn from participation in the study. 
Thyroid Function Test (Part D and Part E) 
Thyroid function testing includes thyroid stimulating hormone, free triiodothyronine [T3], and 
free thyroxine [T4]. 
7.5.5. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings.  
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the study site. 
All ECGs are to be obtained prior to other assessments scheduled at that same time.  If this is not 
possible, then ECGs are to be obtained ≥ 20 minutes following the last procedure performed.  
The patient should rest in a supine position for ≥ 10 minutes in the absence of environmental 
distractions that may induce changes in heart rate (eg, television, radio, conversation, etc) before 
each ECG collection. 
At each timepoint (see Appendix 5), 3 consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine the mean QTcF interval. 
7.5.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE, v5.0 
(NCI-CTCAE 2017).  Characterization of toxicities will include severity, duration, and time to 
onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.5.7. 
Hepatitis B and C Testing  
7.5.7.1. 
Part A, Part B, Part C, and Part D  
Hepatitis B and C serologic markers and/or viral load will be tested at screening.  Hepatitis B and 
C testing must be conducted in a laboratory able to perform the test to the required sensitivity 
(< 20 IU/mL and < 15 IU/mL for hepatitis B and C, respectively).  If sites cannot conduct the 
tests with this sensitivity or the results are not reported with values, then any positive viral load 
result should lead to withholding of study treatment and initiation of antiviral treatment.  The 
hepatitis B testing includes HBsAg and HbcAb, as well as HBV DNA by polymerase chain 
reaction (PCR) if the patient is HbcAb positive (HbsAg negative).  The hepatitis C testing 
includes HCV antibody as well as HCV RNA by PCR if the patient is HCV antibody positive.  
Patients with positive HbsAg and/or detectable level of HBV DNA or detectable level of HCV 
RNA are not eligible.   
Patients who are HbcAb positive (HbsAg negative) and HBV DNA negative must undergo at 
least monthly HBV DNA screening by PCR (same for patients who are HbsAb positive who 
have not received the hepatitis B vaccine and are HbsAg negative).  These patients should be 
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considered for prophylactic antiviral treatment in consultation with a local HBV expert.  If a 
patient is being treated prophylactically with antivirals, HBV DNA screening by PCR must be 
done at least every 90 days. 
If, during monthly monitoring of HBV DNA by PCR, the value is between 20 IU/mL and 
100 IU/mL, then the HBV DNA level should be rechecked within 14 days.  Study drug should be 
held, and antiviral therapy initiated if the repeat level is between 20 IU/mL and 100 IU/mL.  If 
the HBV DNA by PCR is 100 IU/mL or higher, then study drug should be held, and antiviral 
therapy initiated or continued.  For patients whose HBV reactivation resolves, resumption of 
study drug should be discussed with, and approved by, the medical monitor and physicians with 
expertise in managing hepatitis B. 
Patients positive for HCV antibody, but negative for HCV RNA, must undergo monthly HCV 
RNA screening.  Patients with HCV RNA of 15 IU/mL or greater should stop study drug and 
antiviral therapy should be initiated.  For patients whose HCV reactivation resolves, resumption 
of study drug should be discussed with, and approved by, the medical monitor and physicians 
with expertise in managing hepatitis C.  
The medical monitor should be informed of any suspected hepatitis B or hepatitis C reactivation. 
Table 10 and Table 11 describes how the results for HBV and HCV testing at screening relate to 
study eligibility. 
Table 10: 
Hepatitis B Eligibility Criteria 
HbsAg-Positive 
HbcAb 
HBV DNA 
Eligible 
Yes 
Any 
N/A 
Not Eligible 
No 
Yes 
Detected 
Not Eligible 
No 
Yes 
Undetected 
Eligible a 
No 
No 
N/A 
Eligible b 
Abbreviations: HbcAb, hepatitis B core antibody; HbsAg, hepatitis B surface antigen; HBV, hepatitis B virus; 
N/A, not applicable. 
a Eligible if patient agrees to monthly monitoring of HBV DNA (or at least every 90 days for patients receiving 
prophylactic antiviral therapy). 
b If patient is negative for HbsAg antibody and HbcAb, do not need HBV DNA test at screening. 
Table 11: 
Hepatitis C Eligibility Criteria 
HCV Antibody 
HCV RNA  
Eligible 
Yes 
Undetected 
Eligible a 
No 
N/A 
Eligible b 
Yes 
Detected 
Not Eligible 
Abbreviations: HCV, hepatitis C virus; N/A, not applicable. 
a Eligible if patient agrees to monthly monitoring of HCV RNA. 
b If patient is negative for HCV antibody, do not need HCV RNA test at screening. 
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7.5.7.2. 
Part E  
Hepatitis B and C virus serologic markers and viral load will be tested by the local laboratory.  
HBV testing will include HbsAb, HbsAg, and HbcAb.  In addition, HBV DNA will be quantified 
in patients positive for HbsAg.  HCV testing will consist of HCV antibody plus HCV RNA in 
patients positive for HCV antibody. 
7.5.8. 
Cardiac Enzyme Monitoring (Part D and Part E) 
Although immune-mediated myocarditis is a rare complication of immune CPIs, serum creatine 
kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all tislelizumab studies to 
protect study participants and to quantify the risk of muscle inflammation.  Testing of CK-MB 
will be performed by a central and/or the local laboratory at the timepoints specified in 
Appendix 3 and Appendix 4.  If the site’s laboratory does not perform CK-MB testing, serum 
troponins (troponin I and/or T) measurements should be performed instead; if only 1 of the 
troponins is assessed per local standards, that same test should be evaluated throughout. 
If significant abnormalities are detected, the affected patients should be evaluated for possible 
myocarditis/myositis per institutional guidelines, including additional serum CK/CK-MB, serum 
troponin levels, ECG, etc.  Report all clinically significant abnormalities as an AE or SAE. 
7.5.9. 
Cytomegalovirus Monitoring  
Patients will be monitored for CMV reactivation using quantitative PCR assay for CMV DNA 
according to Appendix 1 through Appendix 4.  CMV surveillance for active disease (quantitative 
PCR or PP65 antigen) must be conducted approximately every cycle throughout the course of 
BGB-10188 treatment.  CMV viral load testing should be performed from the same specimen 
type whenever possible, and caution should be exercised when comparing CMV viral load 
results across different testing centers.  If unequivocal clinical or laboratory evidence of CMV 
infection is present, the patient must interrupt BGB-10188 treatment and undergo effective 
antiviral treatment according to established clinical guidelines.  If the benefits of resuming 
BGB-10188 are judged to outweigh the risks, consideration should be given to administering 
prophylactic CMV therapy. 
7.6. 
Tumor and Response Evaluations  
Part A, Part B, and Part C 
Response will be assessed and categorized per Lugano Classification for patients with NHL 
(including SLL, MZL, MCL, DLBCL, and FL) (Cheson et al 2014; Appendix 13).  For patients 
with CLL, disease response will be determined in accordance with the 2018 iwCLL guidelines 
(Hallek et al 2018) with modification for treatment-related lymphocytosis (Cheson et al 2012) 
(Appendix 14).  Response parameters will include CT scans and bone marrow aspirate/biopsy (in 
patients who experience a CR and who also had lymphoma bone marrow involvement at 
baseline).  For patients with gastrointestinal involvement who had an endoscopy performed 
during the screening period, a follow-up endoscopy is required to confirm CR.  In the event of a 
treatment delay, disease assessments are to continue per the Schedule of Assessments 
(Appendix 1).  
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Positron Emission Tomography/Computed Tomography 
Patients with NHL (ie, MZL, MCL, FL, or DLBCL) will undergo PET/CT imaging at baseline; a 
separate CT scan of diagnostic quality should be performed in addition to the PET/CT imaging if 
the PET/CT imaging is not of diagnostic quality.  If PET-avid disease is detected, then 
subsequent tumor assessments should be conducted with PET/CT-based imaging.  Patients with 
NHL without PET-avid disease, as well as patients with CLL/SLL, should undergo tumor 
assessments with CT-based imaging.   
CT with contrast of chest, abdomen, pelvis, and neck, will be performed at screening and while 
on study until disease progression, start of new anticancer therapy, withdrawal of consent, death, 
lost to follow-up, or end of study, whichever occurs first.  Patients with disease progression in 
Part A who received the treatment of BGB-10188 in combination of zanubrutinib will continue 
all study assessments.  Combined PET/CT may be used in lieu of a CT with contrast only if the 
CT of the combined PET/CT has been performed with diagnostic quality, adheres to the 
specified slice thickness/scan parameters, and IV contrast is administered.  Otherwise, both scans 
should be done. 
All efforts will be made to ensure that the imaging equipment, contrast agent, and person 
(investigator or radiologist) performing the evaluation are kept constant throughout a patient’s 
course on study.   
An MRI may be used in place of CT only for patients who have a contraindication to CT scans.  
If used, MRI should be performed of neck, abdomen, pelvis, and any other disease sites.  In 
addition to the MRI, a non-contrast CT of the chest should be performed.  
Bone Marrow Examination 
Bone marrow biopsy (for patients with CLL) and/or aspirate (for patients with NHL) is required 
during the screening period to assess bone marrow involvement of lymphoma or leukemia.  If a 
patient has had bone marrow examination performed within 90 days prior to Cycle 1 Day 1, a 
repeated bone marrow biopsy/aspirate is not required.   
Patients with baseline marrow involvement who meet clinical and laboratory criteria for CR or 
CR with incomplete bone marrow recovery (CRi) (CLL only) are required to have a bone 
marrow examination to confirm CR or CRi.  This should be performed within 40 days from the 
CT/MRI meeting the criteria of CR or CRi.  All the other clinical data should be collected within 
± 14 days from the CT/MRI (ie, CBC with differential and physical examination).  For patients 
with DLBCL, if a follow-up biopsy cannot be obtained, a PET scan that clearly documents 
continued disease clearance may be used in lieu of the repeated biopsy. 
Part D and Part E 
Tumor imaging will be performed within 28 days before the first dose of study drug.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and 
≤ 28 days prior to first dose may be used for the purposes of screening rather than repeating the 
standard-of-care tests.  During the study, tumor imaging will be performed at Week 10 (Part D, 
Appendix 3) or Week 9 (Part E, Appendix 4) and approximately every 9 weeks (± 7 days) 
thereafter, based on RECIST v1.1, until unequivocal progression, use of alternative anticancer 
therapy, withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first.   
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Screening assessments and each subsequent assessment of the tumor must include the CT scans 
(with oral/IV contrast, unless contraindicated) or MRI of the chest, abdomen, and pelvis.  Other 
known or suspected sites of disease must be included in the imaging assessments (neck, brain, 
etc). 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation.  The same radiographic procedure used to 
assess disease sites at screening are required to be used throughout the study (eg, the same 
contrast protocol for CT scans). 
• Imaging of the brain (preferably MRI or CT) should be performed at screening only when 
clinically indicated and followed throughout the study, if there is evidence of metastatic 
disease in these regions at screening.  Screening evaluations will be performed within 28 
days prior to the first dose 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a contrast-enhanced 
MRI (if possible) of abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a PET/CT scanner, the CT acquisition 
must be consistent with the standards of a diagnostic CT scan. 
• Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening if 
clinically indicated.  If bone metastases are present at screening and cannot be seen on 
CT or MRI scans, TC-99m or PET bone scans should be repeated when a CR is suspected 
in target lesion or when progression in bone is suspected. 
• CT scans of the neck or extremities should be performed at screening only if clinically 
indicated and followed throughout the study, if there is evidence of metastatic disease in 
these regions at screening. 
• At the investigator’s discretion, other methods of assessment of target lesion and 
nontarget lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (Appendix 17).  The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits. 
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later, after the first response or at the next scheduled assessment timepoint.   
7.6.1. 
Treatment After Disease Progression (Part A)  
Patients with disease progression in Part A can continue the treatment of BGB-10188 at the 
cleared dose in combination with zanubrutinib if the patient is receiving clinical benefit at the 
investigator’s discretion based on the local guidance and zanubrutinib prescribing information 
that has been approved by local authorities with prior approval from the medical monitor and 
additional patient consent.  This is particularly encouraged for patients with disease indications 
aligned with the zanubrutinib market authorization in the respective country.  Patients who 
receive the treatment of BGB-10188 in combination with zanubrutinib are required to complete 
all subsequent study assessments as listed in Appendix 1 before Part A reaches the end of study 
as defined in Section 7.14. 
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7.6.2. 
Treatment After Primary Progression of Disease (Part D and Part E)  
Some patients may benefit from additional immune therapies despite evidence of disease 
progression.  These patients may go on to exhibit a response at a later timepoint.  It is the 
responsibility of the investigator to determine if the patient should be considered for treatment 
beyond progression due to clinical benefit.  This decision should be considered carefully so as to 
permit patients who are likely to be benefiting to continue treatment while at the same time 
preventing prolonged exposure of a futile therapy to patients who may not be benefiting.  Any 
decisions to continue treatment beyond initial progression must be discussed with the medical 
monitor and documented in the study records.  
After the initial documentation of disease progression, a confirmation of tumor imaging will be 
performed ≥ 4 weeks after the tumor imaging that initially suggested the suspected progression.  
Patients with confirmed evidence of disease progression will discontinue from study drug, as 
specified in Section 7.13.1.  
The following criteria must be met in order to treat patients with suspected evidence of disease 
progression: 
• Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values). 
• Continuing to receive clinical benefit. 
• Stable ECOG Performance Status ≤ 1. 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention. 
• Investigators must obtain written informed consent for treatment beyond radiologic 
disease progression and inform patients that this practice is not considered standard in the 
treatment of cancer.   
• The decision to continue study drug(s) beyond initial investigator-assessed progression 
must be agreed upon with the medical monitor and documented in the study records. 
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. 
7.6.3. 
CA-125 Tumor Evaluations (Part E)  
For Part E, CA-125 will be tested in a local laboratory within 14 days before the first dose of 
study drug, at Week 9, and then every 9 weeks (±7 days) thereafter until loss of clinical benefit, 
use of alternative anticancer therapy, withdrawal of consent, death, lost to follow-up, or end of 
study, whichever occurs first.  Patients can be evaluated according to CA-125 only if they have a 
pretreatment sample that is at least twice the upper limit of the reference range and within 
2 weeks before starting the treatment.  When there is an initial CA-125 response, it is suggested 
to confirm the response after 28 days (+7 days) after the initial response. 
7.7. 
Pharmacokinetic and Antidrug Antibody Testing  
Part A, Part B, and Part C 
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Blood samples will be collected to characterize the PK profiles of specified compounds.  All 
blood sampling for PK assessment will be collected at the timepoints specified in the Schedule of 
Assessments (Appendix 5).  The actual collection date and time of each blood sample will be 
recorded.  The timing of PK samples may be altered and/or PK samples may be obtained at 
additional timepoints upon sponsor approval to ensure thorough PK monitoring. 
Shipping, storage, and handling of samples will be managed through a central laboratory.  The 
plasma concentrations of specified testing articles will be tested using validated assays.  Full 
details on sample collection, processing, storage, and shipment will be provided in the laboratory 
manual. 
BGB-10188 PK Characterization 
Serial plasma samples for BGB-10188 PK assessment will be collected during the PK washout 
period (only for Part A) and/or treatment Cycle 1 for all patients enrolled in dose escalation 
phases (see the full details in Appendix 5).  
Sparse plasma samples for BGB-10188 PK assessment will be collected for the patients in 
expansion cohorts (see the full details in Appendix 5). 
The sampling schedules for the combination escalation cohorts in Part B are subject to 
modification based on the preliminary data from the monotherapy escalation phase in Part A.  
Zanubrutinib PK Characterization 
For the zanubrutinib PK assessment, serial plasma samples will be collected from all patients in 
the combination escalation cohorts (Appendix 5).  
Part D and Part E 
Blood samples will be collected to characterize the PK profile and evaluate the antidrug antibody 
(ADA) for specified compounds.  All blood sampling (plasma or serum) for PK assessment and 
ADA testing will be collected at the timepoints specified in the Schedule of Assessments 
(Appendix 5, Appendix 6).  The actual collection date and time of each blood sample will be 
recorded.  The timing of PK and ADA samples may be altered and/or PK and ADA samples may 
be obtained at additional timepoints upon sponsor approval to ensure thorough PK and ADA 
monitoring. 
Shipping, storage, and handling of samples will be managed through a central laboratory.  The 
plasma or serum concentrations of specified testing articles will be tested using validated assays.  
Full details on sample collection, processing, storage, and shipment will be provided in the 
laboratory manual. 
BGB-10188 PK Characterization 
Serial plasma samples for BGB-10188 PK assessment will be collected during treatment 
Cycles 1 and 2 from all patients enrolled in dose escalation phases in Part D, and approximately 
5 patients (approximately 2 to 3 patients in each dose level) who were treated beyond C2D1 in 
Part E (see the full details in Appendix 5).  
Sparse plasma samples for BGB-10188 PK assessment will be collected from the patients in 
Part E (see the full details in Appendix 5). 
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Blood will be collected to characterize the PK of BGB-10188 using a validated liquid 
chromatography-tandem mass spectrometry method.  
Blood sampling for PK will be collected at the timepoints specified in the Schedule of 
Assessments (see Appendix 3 and Appendix 4).  The samples will be sent to the sponsor or 
designee for storage and/or analysis. 
Refer to the laboratory manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples to the central laboratory. 
The sampling schedules for Part D and Part E are subject to modification based on the 
preliminary data from Part A. 
Tislelizumab ADA and PK Characterization 
In Part D and Part E, sparse blood samples will be collected at specified cycles for all patients in 
order to evaluate anti-tislelizumab-antibody and paired tislelizumab PK (see Appendix 6).  
Tislelizumab may elicit an immune response.  Patients with signs of any potential immune 
response to tislelizumab will be closely monitored.  Validated screening and confirmatory assays 
will be employed to detect ADAs at multiple timepoints throughout the study (see Appendix 6).  
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy 
(Koren et al 2008; Rosenberg and Worobec 2004a; Rosenberg and Worobec 2004b) to 
characterize ADA responses to tislelizumab in support of the clinical development program.  
This tiered strategy will include an assessment of whether ADA responses correlate with relevant 
clinical endpoints.  Implementation of ADA characterization assays will depend on the safety 
profile and clinical immunogenicity data. 
The following assessments will be performed at a central laboratory: 
• ADA assays: serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay 
• PK assay: serum samples will be assayed for tislelizumab concentration with the use of a 
validated immunoassay 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK and ADA 
assays will be managed through a central laboratory.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
7.8. 
Pharmacodynamics  
Part A, Part B, and Part C  
For patients enrolled in Part A and Part B, and the first 5 patients in Part C, phospho-AKT 
expression in blood samples will be determined and used as a direct pharmacodynamic 
biomarker for PI3Kδ inhibition.  Blood immune cells will also be assessed to monitor 
pharmacodynamic changes after treatment with BGB-10188 monotherapy or in combination 
with zanubrutinib.  Blood samples will be collected as stated in Appendix 5.  The timing of 
pharmacodynamic samples may be altered upon sponsor approval to ensure sample collection at 
most relevant timepoints for pharmacodynamics study.  Full details regarding sample collection, 
processing, storage, and shipment will be provided in the laboratory manual. 
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Part D and Part E  
For patients enrolled in Part D and approximately 5 patients (approximately 2 to 3 patients in 
each dose level) in Part E, phospho-AKT expression in blood samples will be determined and 
used as a direct pharmacodynamic biomarker for PI3Kδ inhibition.  Blood immune cells will also 
be assessed to monitor pharmacodynamic changes after treatment with BGB-10188 monotherapy 
or in combination with tislelizumab.  Blood samples will be collected as stated in Appendix 5.  
The timing of pharmacodynamic samples may be altered upon sponsor approval to ensure 
sample collection at the most relevant timepoints for pharmacodynamics study.  Full details on 
sample collection, processing, storage, and shipment will be provided in the laboratory manual. 
7.9. 
Biomarkers  
Tissue and blood samples for biomarker assessment will be collected as stated in Appendix 1 
through Appendix 4.  Shipping, storage, and handling of blood, archival tumor, fresh tumor, and 
leftover tumor tissue for the assessment of biomarkers will be managed through a central 
laboratory.  Refer to the laboratory manual for details of sample handling. 
Part A, Part B, and Part C 
If available, either an FFPE block with tumor tissue (preferred) or 10 to 15 unstained slides 
should be sent to the central laboratory for analysis of potential predictors of response including 
assessment of PI3Kδ expression, Ki67 index, TP53 mutation status, presence of immune cells in 
the tumor microenvironment, genetic profiling, etc.  If archival samples are not available then an 
optional, fresh tumor biopsy, to be collected at screening, will be requested.  At the sites in 
mainland China, tissue will be obtained to assess PI3Kδ expression, Ki67 index, TP53 mutation 
status, presence of immune cells in the tumor microenvironment, and gene-mutation/expression 
profiling.  Baseline tissue samples collected during screening will be shipped to a central 
laboratory for biomarker testing after local regulatory approval.  This may occur after the start of 
study treatment if necessary. 
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.  Tumor tissue should be of good quality based on total and viable tumor 
content.  Bone metastasis biopsy or cytological (fine-needle aspiration, brushing, cell pellets 
from pleural effusion, and lavage) samples are not acceptable.  Enrollment of a patient who 
cannot provide sufficient tumor tissue or biopsy may be permitted on a case-by-case basis after 
discussion with the medical monitor and in consultation with the sponsor. 
To explore resistance mechanisms, optional biopsies will be taken at accessible tumor sites from 
the patients who have confirmed disease progression during the study.  Written patient consent is 
required for fresh tumor biopsies. 
Blood samples will be collected at screening, time of first response, and time of disease 
progression.  Blood-based biomarker analysis such as immune profiling, DNA and/or circulating 
tumor DNA sequencing, gene-expression profile, circulating free DNA assessment and cytokines 
profiling, plasma protein, etc, will be performed to explore their association with response, 
resistance, and prognosis.  At the sites in mainland China, blood samples will be collected for 
immune profiling, DNA and/or circulating tumor DNA sequencing, gene-expression profiling, 
circulating free DNA assessment, and cytokine profiling. 
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For patients in Part A who have CLL/SLL, optional peripheral blood samples will be collected at 
the local laboratory at screening to assess risk factors, including status of TP53 mutation, IGHV 
mutation, 11q deletion, 13q deletion, and 17p deletion.  
Part D and Part E 
Tumor tissue must be sent to the central laboratory for analysis of potential predictors of 
response, including assessment of PI3Kδ and PD-L1 expression, TP53 mutation status, presence 
of immune cells in the tumor microenvironment genetic profiling, etc.  A fresh tumor biopsy 
collected at screening is strongly recommended.  If a fresh tumor biopsy is not available, an 
archival tissue sample (either an FFPE block with tumor tissue [preferred] or 10 to 15 unstained 
slides) is required.  It is recommended that the archival tissue sample is collected within 2 years 
before screening.  An optional biopsy after approximately 3 to 5 weeks of treatment is also 
strongly recommended for biomarker analysis to explore the relationships between biomarkers 
and preliminary anticancer activity of BGB-10188 in combination with tislelizumab.  If feasible, 
any follow-up biopsy should ideally be taken from the same tumor lesion as the baseline biopsy 
to minimize the variance of tumor microenvironments due to the nature of different tissues 
(Oliver et al 2018; Kirkwood et al 2018).  At the sites in mainland China, tissue will be obtained 
to assess PI3Kδ expression, PD-L1 expression, TP53 mutation status, presence of immune cells 
in the tumor microenvironment, and gene-mutation/expression profiling.  Baseline tissue samples 
collected during the screening will be shipped to a central laboratory for biomarker testing after 
local regulatory approval.  This may occur after the start of study treatment if necessary. 
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.  Tumor tissue should be of good quality based on total and viable tumor 
content.  Bone metastasis biopsy or cytological (fine-needle aspiration, brushing, cell pellets 
from pleural effusion, and lavage) samples are not acceptable.  Enrollment of a patient who 
cannot provide sufficient tumor tissue or biopsy may be permitted on a case-by-case basis after 
discussion with the medical monitor and in consultation with the sponsor.  
To explore the resistance mechanism, optional biopsies will also be taken at accessible tumor 
sites from the patients who have confirmed disease progression during the study.  If feasible, any 
follow-up biopsy should ideally be taken from the same tumor lesion as the baseline biopsy.  
Written patient consent is required for fresh tumor biopsies.  
Blood samples will be collected at screening, C2D1, time of first response, and time of disease 
progression.  Blood-based biomarker analysis such as DNA and/or circulating tumor DNA 
sequencing, gene-expression profile, circulating free DNA assessment, immune cell and cytokine 
profiling, plasma protein, etc, will be performed to explore their association with response, 
resistance, and prognosis.  At the sites in mainland China, blood samples will be collected for 
immune profiling, DNA and/or circulating tumor DNA sequencing, gene expression profiling, 
circulating free DNA assessment, and cytokine profiling. 
7.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/targeted physical examination; ECOG Performance Status; AE 
review; concomitant medication and procedure reviews; radiographic assessments; physical 
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examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments.  The date and reason for the unscheduled visit 
must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
7.11. 
End-of-Treatment Visit  
The End-of-Treatment (EOT) Visit is conducted within 7 days after the investigator determines 
that the patient must permanently discontinue BGB-10188, zanubrutinib, or tislelizumab.  If 
routine laboratory tests (eg, hematology, clinical chemistry, coagulation, and urinalysis) were 
completed ≤ 7 days before the EOT Visit, these tests do not need to be repeated.  A tumor 
assessment is not required at the EOT Visit if < 6 weeks have passed since the last assessment.  
If the EOT Visit did not occur until 30 days (± 7 days) or later after the last dose of BGB-10188, 
zanubrutinib, or tislelizumab, the EOT Visit may also be used as the Safety Follow-up Visit. 
See Appendix 1 through Appendix 4 for assessments to be performed at the EOT Visit. 
7.12. 
Follow-up Periods  
7.12.1. 
Safety Follow-up Period  
Patients who permanently discontinue study drug will be asked to return to the clinic for the 
Safety Follow-up Visit, which is required to be conducted 30 days (± 7 days) after the last dose 
of study drug (whichever is the latest) unless otherwise specified or before the initiation of 
subsequent anticancer therapy, whichever occurs first.  The Safety Follow-up Visit may coincide 
with the EOT Visit (see Section 7.11) but cannot occur before the EOT Visit.  For Parts A, B, 
and C, a laboratory assessment is required only if the patient had an ongoing laboratory 
abnormality at the previous visit that the investigator considered to be related to study drug.  If 
the patient is unable to return to the clinic and no laboratory assessment is necessary, the 
investigator or his/her designee will contact the patient or guardian to collect information about 
AEs, including AEs that may have occurred or were ongoing after the patient discontinued study 
treatment. 
For Part D and Part E, in addition, telephone contact with patients should be conducted to assess 
imAEs and concomitant medications (if appropriate, ie, associated with an imAE or is a 
subsequent anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of study drug or 
before the initiation of a subsequent anticancer therapy, whichever occurs earlier.  If a patient 
reports a suspected imAE at a telephone follow-up contact, the investigator should arrange an 
unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
See Appendix 1 through Appendix 4 for assessments to be performed at the EOT/Safety Follow-
up Visit. 
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7.12.2. 
Survival Follow-up  
After discontinuation of study treatment, patients in Part E will be followed for survival and 
further anticancer therapy information via telephone calls, patient medical records, and/or clinic 
visits approximately every 3 months (± 14 days) after the EOT or Safety Follow-up Visit or as 
directed by the sponsor until death, loss to follow-up, withdrawal of consent, or study completion 
by the sponsor.   
7.12.3. 
Lost to Follow-up  
If attempts to contact the patient by telephone are unsuccessful, the following additional attempts 
should be made to obtain protocol-required follow-up information.  The patient should be 
contacted by mail in a manner that provides proof of receipt by the patient.  If unsuccessful, 
other contacts should be explored, such as referring physicians or relatives.  Attempts to contact 
should be documented in the patient’s source documents.  If a patient cannot be contacted despite 
all attempts, the patient will be considered lost to follow-up, and death information should be 
obtained through a public record search if local agencies permit. 
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 
will discontinue study treatment for reasons other than disease progression should be followed 
up for assessments of antitumor activity (Section 7.6), safety (Section 7.5), and survival 
(Section 7.12, if applicable), if possible. 
The primary reason for discontinuation from study treatment should be documented on the 
appropriate eCRF.  Patients may discontinue study treatment for reasons that include but are not 
limited to the following: 
• Disease progression 
• Adverse event 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she were to continue the study treatment 
• Use of any concurrent anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents) for the treatment of cancer 
• Patient noncompliance 
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: 
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• Patient withdrawal of consent 
• Death 
• Loss to follow-up 
• Patient completion of all study assessments  
• Noncompliance 
7.14. 
End of Study  
The end of the study is defined as the timepoint when the final data point is collected from the 
last patient in the study.  For each part of the study, the end of the part is when the last patient 
has been enrolled for 12 months in this part, or when the last patient dies, withdraws consent, 
completes all study assessments, or is lost to follow-up, whichever occurs earliest. 
The sponsor has the right to terminate this study at any time.  Reasons for terminating the study 
early include the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• There is a lack of efficacy observed in the enrolled patients, and further enrollment is 
unlikely to bring benefits to patients with disease under study. 
• Overall patient enrollment is unsatisfactory. 
• A rollover study becomes available. 
The sponsor will notify each investigator if a decision is made to terminate the study.  Should 
this be necessary, prematurely discontinued patients must be seen for an EOT/Safety Follow-up 
Visit as described in Section 7.11 and Section 7.12.1. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patients’ interests.  The investigator will 
be responsible for informing IRBs/IECs of the early termination of the study. 
The sponsor has the right to close a site at any time.  The decision will be communicated to the 
site in advance.  Reasons for closing a site include but are not limited to the following:  
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Noncompliance with GCP or applicable laws and regulations 
• Completion of study activity (ie, all patients have completed the study and all obligations 
have been fulfilled) 
At the end of the study as determined by the sponsor, any patient who is still on treatment and, in 
the opinion of the investigator, continues to benefit from study drug treatment will continue 
treatment in a company-sponsored long-term extension study or a post-trial continued access 
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program or be kept in the study for continuous access of study drugs, whichever is available in 
the country of the patient’s residence. 
For the patient who is kept in the study for continuous access of study drugs after the end of the 
part/study, no data collection (except for SAEs or adverse events of special interest [AESI] 
through paper forms) will be conducted by the sponsor. For Parts A and B, the treatment access 
would be discontinued for reasons listed in Section 7.13.1 or when the continuous access was 
provided for approximately 1 year after the end of the corresponding part. For Part E, the 
treatment access would be discontinued for reasons listed in Section 7.13.1 or when the total 
treatment duration reaches 2 years. During the continuous study drug treatment, patient visits 
should be dependent on investigator’s discretion.  
 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drug  
8.1.1. 
Risks Associated With BGB-10188  
As of the data cutoff date of 05 February 2024, important potential risks for BGB-10188 
treatment include hepatobiliary toxicity, diarrhea and colitis, rash, pneumonitis, and 
hypersensitivity. 
Hepatobiliary toxicity was observed in 7 patients (20.6%) receiving BGB-10188 monotherapy 
(Part A). Four patients (11.8%) experienced Alanine aminotransferase increased, and 3 patients 
(8.8%) experienced Aspartate aminotransferase increased. Alanine aminotransferase increased 
and Hepatic function abnormal of Grade 3 were reported in 1 patient (2.9%) each. 
For patients receiving BGB-10188 in combination with zanubrutinib (Part B), a total of 
2 patients (50%) experienced Grade 3 Hypertransaminasaemia (1 patient), Grade 3 Alanine 
aminotransferase increased (1 patient), and Grade 3 Aspartate aminotransferase increased 
(1 patient). 
For patients receiving BGB-10188 in combination with tislelizumab (Part D), 15 patients 
(34.1%) experienced Alanine aminotransferase increased, and 14 patients (31.8%) experienced 
Aspartate aminotransferase increased. Four patients (9.1%) experienced Grade 3 Aspartate 
aminotransferase increased, and 2 patients (4.5%) experienced Grade 3 Blood bilirubin 
increased. Grade 3 Abnormal hepatic function and Grade 4 Gamma-glutamyltransferase 
increased were reported in 1 patient each (2.3%).  
For patients receiving BGB-10188 in combination with tislelizumab (Part E), 1 patient (16.7%) 
experienced Grade 3 Alanine aminotransferase increased and Grade 2 Aspartate 
aminotransferase increased. 
Diarrhea and Colitis have been observed in 38.2% of patients receiving BGB-10188 
monotherapy (Part A), and 25% of patients receiving BGB-10188 in combination with 
tislelizumab (Part D and Part E). Most events were mild, and no Grade 3 or higher Diarrhea and 
Colitis were reported for patients receiving BGB-10188 monotherapy. For Part D, 1 patient each 
(3 patients total, 6.9%) experienced Grade 3 Colitis (1 patient), Enterocolitis (1 patient), and 
Immune-mediated enterocolitis (1 patient). For Part E, 1 patient (16.7%) experienced Grade 3 
Diarrhea. 
Rash has been observed in 32.4% of patients treated with BGB-10188 in monotherapy and 28% 
in combination with tislelizumab; these events were generally mild to moderate in severity. One 
(2.9%) serious Grade 3 treatment-emergent adverse event of drug eruption was reported in the 
monotherapy cohort (Part A). Grade 3 Rash was also reported in 2 patients (4.5%) in Part D 
(combination with tislelizumab). No Grade 4 or higher events have been reported. 
Pneumonitis has occurred in 8.8% of patients treated with BGB-10188 in monotherapy and 6.8% 
in combination with tislelizumab, including 1 serious adverse event of Grade 2 
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Immune-mediated lung disease in 1 patient treated with BGB-10188 in combination with 
tislelizumab.  No Grade 3 or higher events have been reported. 
As defined by the narrow scope Standardized MedDRA Query “anaphylactic reaction”, no 
events were reported in Study BGB-A317-3111-10188-101. Of note, drug hypersensitivity 
(Grade 1 and 2) was reported in 2 patients (5.9%) and Grade 1 Angioedema was reported in 
1 patient (2.9%) receiving BGB-10188 monotherapy (Part A). There were no drug 
hypersensitivity events described in combination therapy cohorts. No Grade 3 or higher events 
were reported. 
Other potential risks for BGB-10188 treatment include phototoxicity, reproductive and 
development toxicity, and drug interaction. 
8.1.1.1. 
Safety Data From Study BGB-10188-101  
As of 05 February 2024, safety data are available from 88 patients exposed to BGB-10188 
administered either as monotherapy or in combination with zanubrutinib or tislelizumab.  The 
overall safety data have remained consistent with the expected safety profile.  In total, 
31 patients reported treatment-emergent SAEs; of these, 9 (26.5%) were reported from the BGB-
10188 monotherapy cohort, 1 from the cohort receiving BGB-10188 in combination with 
zanubrutinib, and 21 (47.7%) from the cohort receiving BGB-10188 in combination with 
tislelizumab.  Treatment-related SAEs were reported in 5 patients (14.7%) in BGB-10188 
monotherapy and in 7 patients (15.9%) in BGB-10188 in combination with tislelizumab 
(200 mg). 
The only treatment-emergent SAE by PT occurring in more than 1 patient receiving BGB-10188 
monotherapy was Febrile neutropenia (2 patients, 5.9%). 
The only treatment-emergent SAE by PT to occur in patients receiving BGB-10188 in 
combination with zanubrutinib was Grade 4 Acute myeloid leukaemia, which led to hospital 
prolongation. This serious adverse event was assessed as not related to study drugs by the 
investigator. 
The most commonly (≥ 5%) occurring treatment-emergent SAEs by PT in patients receiving 
BGB-10188 in combination with tislelizumab were Alanine aminotransferase increased and 
Aspartate aminotransferase increased (4 patients each, 9.1%), followed by Pyrexia in 3 patients 
(6.8%). 
As of the data cutoff date, a total of 5 patients within the 360 mg (2 patients) and 540 mg 
(3 patients) BGB-10188 monotherapy cohorts experienced a total of 6 adverse events that led to 
treatment discontinuation. Half of adverse events by SOC were Gastrointestinal disorders, but 
they were all single occurrences by PT (Flatulence, Eructation, Rash, Stomatitis, Face oedema, 
and Pneumonia). All these events were non-serious except Pneumonia. Four patients had 
BGB-10188-related adverse events that led to treatment discontinuation (Flatulence, Eructation, 
Rash, Stomatitis, and Pneumonia), and only 1 of them experienced a ≥ Grade 3 adverse event 
(Grade 3 Pneumonia). This patient recovered after discontinuing treatment and receiving 
concomitant medication. 
As the data cutoff date, no patient receiving BGB-10188 in combination with zanubrutinib 
experienced adverse events that lead to treatment discontinuation. 
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A total of 8 patients receiving BGB-10188 in combination with tislelizumab (18.2%) 
experienced adverse events that led to discontinuation of study drug. Among them, 4 patients 
experienced adverse events that were considered as related to BGB-10188. For 2 patients 
receiving BGB-10188 160 mg in combination with tislelizumab 200 mg, 1 experienced Grade 3 
Immune-mediated enterocolitis, and another experienced Grade 5 Pneumonia and Grade 5 
Haemorrhage intracranial. For 2 patients receiving BGB-10188 320mg in combination with 
tislelizumab 200mg, 1 experienced Grade 3 decreased appetite, and another experienced Grade 3 
Alanine aminotransferase increased and Grade 3 Aspartate aminotransferase increased. 
Two patients with a DLT event were reported in the BGB-10188 monotherapy cohort, and 
3 patients with a DLT event were reported in patients receiving BGB-10188 in combination with 
tislelizumab.   
Two patients experienced TEAEs leading to death, of which 1 patient from BGB-10188 
monotherapy cohort died due to the disease under study, and another patient from BGB-10188 
160 mg in combination with tislelizumab 200 mg cohort due to Pneumonia and Haemorrhage 
intracranial and was considered as related to BGB-10188.  Refer to the BGB-10188 Investigator 
Brochure for more details on the safety of BGB-10188. 
Clinical experience with existing drugs in this therapeutic class (PI3K) suggests that patients 
may experience fatal and/or serious hepatotoxicity; diarrhea or colitis; pneumonitis; infection 
including pneumonia, CMV, and PJP; intestinal perforation; and severe cutaneous reactions.  
The most common adverse reactions (incidence ≥ 20%) for approved agents from the same class 
of drugs are presented below. 
• In patients treated with copanlisib: hyperglycemia (high blood sugar), diarrhoea, 
decreased general strength and decreased energy, hypertension (high blood pressure), 
leukopenia (low numbers of leukocytes, a type of WBC), neutropenia, nausea, lower 
respiratory tract infections, and thrombocytopenia (low numbers of blood platelets).  
Copanlisib can cause serious side effects, including infections, hyperglycemia, 
hypertension, pneumonitis, neutropenia, and skin rashes.   
• In patients treated with duvelisib: diarrhoea or colitis, neutropenia, rash, fatigue, fever, 
cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and 
anaemia (low amounts of blood haemoglobin, which is associated with low numbers of 
red blood cells).  Duvelisib has a US boxed warning due to the risk of these fatal and 
serious toxicities: infections, diarrhoea or colitis, skin reactions and pneumonitis. 
• In patients treated with idelalisib: diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and 
nausea.  Common laboratory abnormalities were neutropenia, ALT elevations, and AST 
elevations.  Idelalisib has a US boxed warning due to the risk of these fatal and serious 
toxicities: hepatotoxicity, severe diarrhea or colitis, pneumonitis, infections, and intestinal 
perforation. 
• In patients treated with linperlisib: WBC count decreased, neutropenia, platelet count 
decreased, and anaemia. 
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Patients enrolled in this study must be closely monitored for the abovementioned or other AEs, 
and delay or interruption of BGB-10188 should be considered according to Section 5.5.1 and 
Section 5.6. 
8.1.2. 
Risks Associated With Zanubrutinib  
Zanubrutinib has received approvals for the indications of MCL, WM, MZL, CLL/SLL, and FL 
in over 65 countries/regions worldwide (including all EU states).  Available data indicated that 
zanubrutinib was generally well tolerated at exposure levels resulting in complete and sustained 
BTK inhibition in patients with B-cell malignancies.  Please refer to the zanubrutinib IB and 
zanubrutinib prescribing information for a summary of safety data and guidance for the 
investigator. 
8.1.3. 
Risks Associated With Tislelizumab  
Tislelizumab has been approved in China, Macao China, Europe, US, and South Korea. 
Tislelizumab is still in clinical development for other indications worldwide.  Any 
recommendations are based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class.  Refer to the tislelizumab IB 
for more details. 
The PD-1/PD-L1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions.  Potential risks observed with anti-PD-1 therapy are presented in Section 8.7.1. 
Although most imAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Suggested evaluation and management guidelines for suspected imAEs are 
provided in Appendix 9. 
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 zanubrutinib and tislelizumab, as well as the 
nonclinical/clinical data from other drug classes, 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 allogenic stem cell or organ transplantation and 
patients who have received a live viral vaccine within 28 days before the 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 of Assessments in Appendix 1 through Appendix 4.  Clinical 
laboratory results must be reviewed prior to the start of each cycle. 
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In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study.  Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 
measurements (hematology, chemistry, etc) and other assessments.  In addition, patients will be 
closely monitored for the development of any signs or symptoms of autoimmune conditions and 
infection. 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients in Part D 
and Part E.  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 5.2.3). 
All AEs will be recorded during the study (AEs from the time of the first dose and SAEs from 
the time of signing of informed consent) and for up to 30 days after the last dose of study drug(s) 
or until the initiation of another anticancer therapy, whichever occurs first.  At the end of 
treatment, ongoing AEs considered related to study treatment will be followed until the event has 
resolved to baseline or ≤ Grade 1, the event is assessed by the investigator as stable, the patient is 
lost to follow-up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the AE. 
Immune-mediated AEs will be recorded up to 90 days after the last dose of study drug or 
initiation of a subsequent anticancer therapy, whichever occurs earlier. 
All drug-related SAEs will be recorded by the investigator 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 pre-existing condition, including an increase in 
severity, frequency, or duration, and/or has an association with a significantly worse 
outcome 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concurrent medication (overdose per se should not be reported as an AE or SAE) 
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When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results and diagnostics reports) relative to 
the AE or SAE.  The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF.  However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor.  In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will 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 v5.0 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 IB for BGB-10188, zanubrutinib, or tislelizumab 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 the causality assessment is one of the criteria used when 
determining regulatory reporting requirements.  The investigator may change his/her opinion of 
causality considering follow-up information, amending the SAE report accordingly. 
Two-Point Causality Assessment  
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The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.”  An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation).  A number of factors should be considered in making this assessment, 
including: 
• Temporal relationship of the AE to the administration of study treatment/study procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
• Biological plausibility 
An AE should be considered "related" to study drug if any of the following 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 as may be indicated to elucidate the nature and/or causality of the AE or SAE.  
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.  The investigator is obligated to assist.  If a patient dies during participation in 
the study or during a recognized follow-up period, the sponsor will be provided with a copy of 
any postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the timeframes outlined in Section 8.6.2. 
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8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, CBC, coagulation, or urinalysis) or other 
abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs.  This includes clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline and 
significantly worsen during the study.  The definition of clinical significance is left to the 
judgment of the investigator.  In general, these are the laboratory test abnormalities or other 
abnormal assessments that: 
• are associated with clinical signs or symptoms, or 
• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or 
• further diagnostic investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, ALP and 
bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, cholestasis) should be 
recorded on the Adverse Event eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF unless the etiology changes.  The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
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 
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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 judgment 
(eg, may jeopardize the patient or may require medical/surgical intervention to prevent 
one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (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, the specificity or severity of which is not consistent 
with those noted in the IB. 
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, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after the last dose of BGB-10188, zanubrutinib, or tislelizumab or 
until initiation of new anticancer therapy, whichever occurs first.  Immune-mediated AEs 
(serious or nonserious) should be reported until 90 days after the last dose of study drug or 
initiation of a subsequent anticancer therapy, whichever occurs earlier.  SAEs considered related 
to the study drug(s) that are brought to the attention of the investigator should be reported 
regardless of time since the last dose of treatment. 
AEs and SAEs should be recorded according to the details in Table 12.  For the follow-up period 
for AEs, see Section 8.3.4.  For the definition of TEAEs, see Section 9.5.3. 
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Table 12: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms  
Event Type 
Record New or Worsening Events That Occur During This 
Period 
Begin 
End 
SAEs (not treatment-related) 
Signing of informed 
consent 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Treatment-related SAEs 
Signing of informed 
consent 
Patient death, withdrawal of consent, or 
loss to follow-up, whichever occurs first 
AEs due to PD 
Do not record (see Section 8.6.5) 
Nonserious AEs 
First dose of study drug 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study drug 
Up to 90 days after last dose (or initiation 
of a subsequent anticancer therapy, 
whichever occurs earlier), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events and Adverse Events of Special 
Interest 
As soon as the investigator determines that an AE meets the protocol definition of an SAE or 
adverse event of special interest of BGB-10188 (see Section 8.7.2), the event must be reported 
promptly (within 24 hours of site awareness) to the sponsor or designee as described in Table 13. 
Table 13: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events and Adverse Events of Special Interest to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe 
for Making 
Follow-up 
Report  
Documentation 
Method 
Reporting 
Method 
All SAEs; 
AESI of 
BGB-10188 
(see 
Section 8.7.2) 
Within 24 hours 
of first 
knowledge of 
the SAE 
SAE Report 
Within 24 
hours of site 
awareness 
SAE Report 
Email or fax 
SAE form  
Abbreviations: AE, adverse event; AESI, adverse event of special interest; SAE, serious adverse event. 
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8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report and Adverse 
Events of Special Interest 
Once an investigator becomes aware that an SAE or AESI (see Section 8.7.2) 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 or AESI 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 timeframes. 
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 IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for BGB-10188, zanubrutinib, and tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised IB) from the sponsor, the investigator or designated responsible person is required to 
promptly notify his/her IRB or IEC as per local regulations.  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. 
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 
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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), unless the 
signs/symptoms are clinically significant. 
8.6.5. 
Disease Progression  
Progression of an underlying malignancy and related symptoms (including fatal outcomes) is not 
reported as an adverse event if it is clearly consistent with the expected pattern of progression of 
the underlying cancer.  In most cases, the expected pattern of progression in Parts A and B will 
be based on Lugano criteria (Cheson 2014), while the expected pattern of progression in Parts D 
and E will be based on RECIST v1.1 (Eisenhauer et al 2009).  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through the use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an 
adverse event during the adverse event recording period on the Adverse Event eCRF, and 
immediately reported to the sponsor if assessed as a serious adverse event. 
8.6.6. 
Death on Study  
For deaths that occur during the study safety reporting period (refer to Section 8.6.1), regardless 
of relationship to study drug(s), the primary cause of death must be recorded as a fatal serious 
adverse event on the Adverse Event eCRF and be immediately reported to the sponsor. 
Death should be considered an outcome and not a distinct event.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF.  Generally, only one such event should be reported.  If the cause of 
death is unknown or if it is a sudden death, then the death could be recorded as an adverse event 
as “unknown cause of death” or “sudden death.” 
8.6.7. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving study drugs, 
or within 90 days after the last dose of BGB-10188 and/or zanubrutinib (Parts A and B), or 
within 90 days after the last dose of BGB-10188 and/or 120 days after the last dose of 
tislelizumab (Parts D and E), 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 8 weeks following the estimated delivery date.  Any premature termination of the pregnancy 
will be reported. 
While pregnancy itself is not considered an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous should 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. 
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8.6.8. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following Reference Safety Information documents: 
• Tislelizumab IB 
• Zanubrutinib IB 
• BGB-10188 IB 
8.6.9. 
Assessing and Recording Immune-Mediated Adverse Events (Part D and Part E)  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (see Section 8.7.1.2) should be classified as imAEs and 
identified as such in the eCRF AE page until Day 90, after treatment discontinuation. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune CPIs, in Appendix 9. 
An extensive list of potential imAEs appears in Section 8.7.1.2.  All conditions similar to those 
listed should be evaluated to determine whether they are imAEs, based on a similar diagnostic 
process to those reactions that are presented in more detail in Appendix 9. 
8.6.10. 
Assessing and Recording Infusion-Related Reactions (Part D and Part E)  
The signs and symptoms of an IRR should be recorded as the adverse terms for those individual 
signs and symptoms.  In assessing whether an AE is infusion related, note that the symptoms of 
IRRs may include, but are not limited to, fever, chills/rigor, nausea, pruritus, angioedema, 
hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or 
hypertension.  Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, or cardiogenic shock. 
8.7. 
Management of Adverse Event of Special Interest (AESI) (Part D 
and Part E)  
8.7.1. 
AESI of Tislelizumab  
IRRs, severe hypersensitivity reactions, and imAEs according to the NCI-CTCAE criteria are 
outlined below. 
8.7.1.1. 
Infusion-Related Reactions and Hypersensitivity Reactions  
Patients should be closely monitored during and after study drug administration for IRRs and 
hypersensitivity reactions.  See Section 5.2.3 for the monitoring periods required.  Immediate 
access to an Intensive Care Unit (ICU) or equivalent environment and appropriate medical 
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therapy (including epinephrine, corticosteroids, antihistamines, bronchodilators, and oxygen) 
must be available to treat IRRs. 
See Table 14 for management of IRRs and hypersensitivity reactions as well as treatment 
modifications. 
8.7.1.2. 
Immune-Mediated Adverse Events  
In this study, imAEs are of special interest.  Potential imAEs are listed in Table 15 below.  All 
AEs similar to those listed in the table should be evaluated in patients receiving tislelizumab to 
determine whether the AE is immune mediated.  The investigator should exclude alternative 
explanations (eg, combination drugs, infectious disease, metabolic causes, toxins, disease 
progression, or other neoplastic causes) with appropriate diagnostic tests that may include, but 
are not limited to, serologic, immunologic, and histologic (biopsy) data (see Appendix 9).  If 
alternative causes have been ruled out and the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy, and it is consistent with an immune-mediated 
mechanism of action, the imAE indicator in the eCRF AE page should be checked. 
Recommendations for managing imAEs are detailed in Appendix 9. 
Table 14: 
Treatment Modifications 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. 
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. 
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Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Table 15: 
Examples of Immune-Mediated Adverse Events  
Body System Affected 
Events 
Skin (mild-common) 
Pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
Follicular or urticarial dermatitis; erythematous/lichenoid rash; 
Sweet syndrome 
Skin (severe-rare) 
Full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
Colitis (includes diarrhea with abdominal pain or 
endoscopic/radiographic evidence of inflammation); pancreatitis; 
hepatitis; 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 
Musculoskeletal 
Arthritis; arthralgia; myalgia; myasthenic syndrome/myasthenia 
gravis; myositis 
Blood 
Anemia; leukopenia; thrombocytopenia 
Renal 
Interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
Pericarditis; myocarditis; heart failure 
Neurologic 
Encephalitis; Guillain-Barré syndrome; meningitis; 
meningoradiculitis; meningoencephalitis; neuropathy 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
8.7.2. 
AESI of BGB-10188  
Adverse events of special interest of BGB-10188 (whether nonserious or serious) are required to 
be reported by the investigator to the sponsor immediately (ie, no more than 24 hours after 
learning of the event) following the same requirements and procedure as described in 
Section 8.6.2.1 and Section 8.6.2.2.  Adverse events of special interest of BGB-10188 for this 
study are as follows:  
• Any treatment-emergent diarrhea: 
− ≥ Grade 2 diarrhea 
− ≥ Grade 1 diarrhea lasting for more than 7 days 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed for the planned analysis and the database is locked and released.  Statistical analyses 
that support model-based dose escalation will be performed recurrently before each SMC 
meeting that decides the dose level for next group of patients or enroll more eligible patients.  
Details of the statistical analyses will be included in a separate Statistical Analysis Plan (SAP).  
Please see Section 2 for study objectives. 
9.1. 
Bayesian Model-based Dose Escalation Design  
Model-based dose escalation methods will be used for monotherapy in Part A and combination 
therapy with tislelizumab in Part D to adaptively recommend dose for new cohort and end of 
dose escalation phase and recommendation of MTD.  The model recommendation is non-binding 
and the decision of next dose and/or eventually the identification of RDFE will be made by the 
SMC based on the totality of data, given the safety of trial patients is protected.  Rule-based 
modified 3 + 3 design will be used for dose escalation for combination therapy with zanubrutinib 
in Part B.  The algorithm is provided in Section 3.2.2.  
9.1.1. 
Planned Dose/Combination Levels  
In Part A, 5 proposed dose levels of BGB-10188 monotherapy will be tested in mature B-cell 
malignancies: 60 mg once daily, 120 mg once daily, 240 mg once daily, 360 mg once daily, and 
540 mg once daily.  Additional dose levels or schedule could be added if deemed appropriate. 
In Part B, dose escalation of BGB-10188 in combination with zanubrutinib 160 mg twice daily 
will start at the latest cleared dose in Part A.  
In Part C, dose expansion of BGB-10188 in combination with zanubrutinib 160 mg twice daily 
will start at the RDFE identified from Part B. 
In Part D, when BGB-10188 monotherapy dose level 120 mg once daily has been cleared, start 
of dose escalation in combination with tislelizumab in advanced solid tumor will be triggered.  In 
combination with tislelizumab 200 mg once every 3 weeks, 6 proposed dose levels of 
BGB-10188 are planned: 20 mg once daily, 40 mg once daily, 80 mg once daily, 160 mg once 
daily, 320 mg once daily, and 540 mg once daily.  The dose levels and dosages of BGB-10188 
may be adjusted according to the safety and exposure result in Part A and additional dose levels 
may be added if deemed appropriate. 
In Part E, dose expansion of BGB-10188 in combination with tislelizumab 200 mg once every 
3 weeks will start at the RDFE identified from Part D. 
9.1.2. 
Cohort Size  
A cohort in the dose escalation step is defined as a set of patients sequentially enrolled and 
administered at the dose level recommended for the cohort.  The size of a cohort is 
approximately 3 patients.  
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9.1.3. 
Statistical Models  
A Bayesian model-based dose escalation approach will be used for dose escalation for 
monotherapy BGB-10188 in Part A and combination therapy of BGB-10188 and tislelizumab in 
Part D.  At the time of dose recommendation for new cohort, the model will estimate DLT rate of 
each dose based on data collected from all the cohorts of patients by the time, not only the 
limited data from patients only from the current cohort.  Two types of statistical models will be 
used: A Bayesian logistic regression model (BLRM, Neuenschwander et al 2008) will be used to 
model dose relationship with the early-onset DLT events that occur within the 28-day 
observation period (“early-onset"); additionally, as a further step of protection against 
overdosing considering both early and late-onset DLT events until 8 weeks, a Bayesian 
proportional hazard (BPH) model similar to Tighiouart et al (2014) will be used to account for 
the overall toxicity level until 8 weeks.  However, the BPH models do not require all the patients 
to complete the 8-week late-onset events observation period before next dose decision can be 
made.  They will use all the available data collected up to each dose decision point to estimate 
the DLT rate of both early and late-onset events up to 8 weeks for each dose/combination.  Those 
2 models will be used jointly to help recommend next dose/combination. 
9.1.3.1. 
Bayesian Logistic Regression Model  
A BLRM (Neuenschwander et al 2008) will be used to model dose relationship with the 
early-onset DLT events, up to the end of 28-day observation period.  
Part A BGB-10188 Monotherapy  
For monotherapy in Part A, a two-parameter BLRM (Neuenschwander et al 2008) will be used 
for BGB-10188 dose escalation.  All the current and previous cohorts’ data will be used to 
continuously update the model.  The model will estimate distribution of the toxicity (DLT rate) 
at each dose level, which will be classified into 3 categories: underdosing (DLT rate ≤ 0.167), 
target toxicity (DLT rate between 0.167 and 0.333), and overdosing (DLT rate ≥ 0.333), based 
on which the dose recommendation will be primarily made.  
Part D Combination Therapy With Tislelizumab  
For combination therapy in solid tumors in Part D, a similar two-parameter BLRM model will be 
used to model the dose relationship with the joint toxicity of BGB-10188 and tislelizumab 
200 mg once every 3 weeks.  The model parameters can be considered reflecting the toxicity 
induced by BGB-10188 in conjunction with a potential synergistic effect from the combination 
therapy.  Therefore, different prior settings will be adopted based on the candidate dose levels 
considered for the combination therapy.  
9.1.3.2. 
Bayesian Proportional Hazard Model  
BPH models in the same spirit of Tighiouart et al (2014) will be used to further take into account 
the late-onset DLT events within the 8-week observation period as a gate keeping criterion for 
dose escalation and MTD recommendation.  
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Part A BGB-10188 Monotherapy 
The BPH method models patients’ DLT hazard over time based on the BGB-10188 doses they 
received from C1D1.  In order to incorporate all DLT events in the model, including those that 
occurred within the first 28 days and the events that occurred after 28 days but within 8 weeks, a 
three-parameter BPH model will be used, which assumes different baseline hazards for the first 
28 days and for the remaining period until 8 weeks.  
For patients with a DLT observed within 8 weeks, actual time to the onset of the DLT will be 
used and considered an event.  For patients without a DLT observed, time to the end of the 
observation period or 8-weeks whichever is earlier will be used and considered censored.  
Part D Combination Therapy With Tislelizumab 
The BPH model for BGB-10188 dose escalation combination with tislelizumab at 200 mg once 
every 3 weeks will be similar to the monotherapy dose escalation in Part A, except that different 
prior range of MTD will be adopted to consider potentially different toxicity profile induced by 
BGB-10188 in conjunction with a possible synergistic effect from the combination therapy with 
tislelizumab.   
9.1.4. 
Next Dose Recommendation Rules  
For both Part A and Part D, next dose recommendation from the models will be a 
dose/combination that  
• has the highest posterior probability falling into the target toxicity interval (DLT rate 
between 0.167 and 0.333) based on BLRM, and  
• has a posterior probability in the overdosing interval (DLT rate ≥ 0.333) not exceeding 
0.25 threshold based on BLRM, and 
• satisfies the overdosing protection criterion based on BPH model, ie, with a posterior 
probability in the overdosing interval (overall DLT rate ≥ 0.333) not exceeding a 
0.5 threshold; in other words, the estimated posterior median overall DLT rate including 
the potential late-onset events of the recommended dose cannot exceed 0.333. 
A dose can be recommended for next cohort only when the dose satisfies both BLRM and BPH 
models’ criteria. 
Dose escalation will be indicated if the dose satisfying the above criteria is higher than the 
current dose.  In general, dose skipping for a dose escalation is not allowed.  Dose de-escalation 
will be indicated if the dose satisfying the above criteria is a dose lower than the current dose.  
The dose recommendation is non-binding by the 2 models and will be made along with other 
related available information.  The SMC will make the recommendation on the dose level for the 
next cohort. 
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9.1.5. 
Escalation Phase Stopping and MTD Recommendation Rules  
For both Part A and Part D, the models will recommend an end of dose escalation when one of 
the following criteria is met:  
• The next dose recommended has been tested on ≥ two previous cohorts and the 
probability that the DLT rate for this dose falls into the target toxicity interval (between 
16.7% and 33.3%) is greater than 50%, or 
• The next dose recommended has been used in the 2 immediately previous cohorts, or 
• The next dose recommended has been used in 3 previous cohorts, or 
• No dose can be recommended, or 
• The maximal allowable sample size is reached.  
When the dose escalation is stopped due to any of above reasons, the MTD is the dose level with 
the highest probability that its DLT rate falls into the target toxicity interval while the probability 
that it falls into the overdosing interval is controlled as described in Section 9.1.4.  The RDFE 
may be determined based on the totality of safety, PK, efficacy, and/or any other relevant data as 
well as the MTD recommended by the BLRM and BPH models. 
9.2. 
Study Endpoints  
Part A: BGB-10188 Monotherapy  
Primary Endpoint  
• The RDFE of BGB-10188 monotherapy in hematologic malignancies.  
• The incidence and severity according to NCI-CTCAE v5.0 of TEAEs, SAEs, and AEs 
leading to discontinuation of BGB-10188 
Secondary Endpoints  
• ORR by disease type defined as the proportion of patients achieving  
o CR, complete response with incomplete marrow recovery, PR, or partial response 
with lymphocytosis for CLL as per the 2018 iwCLL guidelines (Hallek et al 2018) 
with modification for treatment-related lymphocytosis (Cheson et al 2012) 
o PR or better for MCL, MZL, FL, and SLL as per the Lugano Classification for NHL 
(Cheson et al 2014)  
• PK characteristics of BGB-10188 including plasma concentrations of BGB-10188 as a 
function of time and PK parameters for single (first) dose and multiple doses  
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Exploratory Endpoints  
• Correlation between BGB-10188 concentrations and corrected QT intervals 
• Pharmacodynamic biomarkers (eg, phospho-AKT level in normal or malignant B cells) 
will be assessed after single (first) dose and multiple doses of BGB-10188  
• Identification of mutations or signatures associated with resistance and other biomarkers 
(eg, proportion and absolute number of Treg cells in peripheral blood or in tumor tissue, 
mutation profile, PI3K expression level, etc) will be correlated with efficacy of 
BGB-10188 monotherapy in the evaluated disease types. 
Part B: BGB-10188 + Zanubrutinib Dose Escalation  
Primary Endpoint  
• The RDFE of BGB-10188 in combination with zanubrutinib in hematologic 
malignancies.  
• The incidence and severity according to NCI-CTCAE v5.0 of TEAEs, SAEs, and AEs 
leading to discontinuation of BGB-10188 in combination with zanubrutinib 
Secondary Endpoints  
• Secondary antitumor endpoints as determined by investigator per the Lugano 
Classification for NHL (Cheson et al 2014) are as follows:  
o ORR defined by disease type as the proportion of patients achieving partial response 
or better for MCL, FL, and DLBCL  
o DOR defined as the time from the first response documentation to the date that 
progression is documented after treatment initiation or death, whichever occurs first. 
o TTR defined as the time from treatment initiation to the first documentation of 
response. 
• PK characteristics of BGB-10188 including plasma concentrations as a function of time 
and PK parameters for single (first) dose and multiple doses  
Exploratory Endpoints  
• Identification of mutations or signatures associated with resistance and biomarkers (eg, 
proportion and absolute number of Treg cells in peripheral blood or in tumor tissue, 
mutation profile, PI3K expression level, etc) will be correlated with efficacy of 
BGB-10188 in combination with zanubrutinib, in the evaluated disease types. 
• Plasma concentrations and PK parameters of zanubrutinib 
• Pharmacodynamic biomarkers (eg, phospho-AKT level in normal or malignant B cells) 
will be assessed after single (first) dose and multiple doses of BGB-10188.   
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Part C: BGB-10188 + Zanubrutinib Dose Expansion  
Primary Endpoint  
• ORR by disease type defined as the proportion of patients achieving partial response or 
better for FL, MCL, and DLBCL as per the Lugano Classification for NHL (Cheson et al 
2014) 
Secondary Endpoints  
• Secondary antitumor endpoints as determined by investigator per the Lugano 
Classification for NHL (Cheson et al 2014) are as follows:  
o DOR 
o TTR 
o PFS defined as time from treatment initiation to documentation of progression or 
death due to any cause, whichever happens first 
• The incidence and severity according to NCI-CTCAE v5.0 of TEAEs, SAEs, and AEs 
leading to discontinuation of BGB-10188 + zanubrutinib 
• PK characteristics of BGB-10188 including plasma concentrations as a function of time 
and PK parameters for single (first) dose and multiple doses  
Exploratory Endpoints  
• OS defined as the time from treatment initiation until death. 
• Identification of mutations or signatures associated with resistance and biomarkers (eg, 
proportion and absolute number of Treg cells in peripheral blood or in tumor tissue, 
mutation profile, PI3K expression level, etc) will be correlated with efficacy of 
BGB-10188 in combination with zanubrutinib, in the evaluated disease types. 
• Plasma concentrations and PK parameters of zanubrutinib 
• Pharmacodynamic biomarkers (eg, phospho-AKT level in normal or malignant B cells) 
will be assessed after single (first) dose and multiple doses of BGB-10188.  
Part D: BGB-10188 + Tislelizumab Dose Escalation  
Primary Endpoints  
• The RDFE of BGB-10188 in combination with tislelizumab in advanced solid tumors 
• The incidence and severity according to NCI-CTCAE v5.0 of TEAEs, SAEs, and AEs 
leading to discontinuation of BGB-10188 in combination with tislelizumab 
Secondary Endpoints  
• ORR, DOR, DCR, and TTR as assessed using RECIST v1.1 
• PK characteristics of BGB-10188 in combination with tislelizumab including plasma 
concentrations of BGB-10188 as a function of time and PK parameters for single (first) 
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dose and multiple doses  
Exploratory Endpoints  
• Immunogenic responses to tislelizumab, evaluated through the detection of ADA  
• Pharmacodynamic biomarkers (eg, phospho-AKT level in B cells or T cells, change of 
immune cell profiling) will be assessed after single (first) dose and multiple doses of 
BGB-10188 in combination with tislelizumab.  
• Identification of mutations or signatures associated with resistance and other biomarkers 
(eg, proportion and absolute number of Treg cells in peripheral blood or in tumor tissue, 
mutation profile, PI3K and/or PD-L1 expression level, etc) will be correlated with the 
preliminary anticancer activity of BGB-10188 in combination with tislelizumab in 
patients with advanced solid tumors. 
Part E: BGB-10188 + Tislelizumab Dose Expansion  
Primary Endpoints  
• ORR as assessed using RECIST v1.1 per investigator 
• The incidence and severity according to NCI-CTCAE v5.0 of TEAEs, SAEs, and AEs 
leading to discontinuation of BGB-10188 in combination with tislelizumab 
Secondary Endpoints  
• DOR, PFS, DCR, clinical benefit rate, and TTR as assessed using RECIST v1.1 
• Locally assessed CA-125 response rate per Gynecological Cancer Intergroup 
(Appendix 20)  
• PK characteristics of BGB-10188 in combination with tislelizumab including plasma 
concentrations of BGB-10188 as a function of time and PK parameters for single (first) 
dose and multiple doses  
Exploratory Endpoints  
• Immunogenic responses to tislelizumab, evaluated through the detection of ADAs  
• Pharmacodynamic biomarkers (eg, phospho-AKT level in B cells or T cells, change of 
immune cell profiling) will be assessed after single (first) dose and multiple doses of 
BGB-10188 in combination with tislelizumab 
• Identification of mutations or signatures associated with resistance and other biomarkers 
(eg, proportion and absolute number of Treg cells in peripheral blood or in tumor tissue, 
mutation profile, PI3K and/or PD-L1 expression level, etc) will be correlated with the 
preliminary anticancer activity of BGB-10188 in combination with tislelizumab in 
patients with PROC 
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9.3. 
Statistical Analysis  
Data will be listed and summarized according to the sponsor-agreed reporting standards, where 
applicable, by study part and further by indication and dose level if specified.  All analyses will 
be conducted in appropriate analysis sets as specified below. 
9.3.1. 
Analysis Sets  
9.3.1.1. 
Part A, Part B, and Part C  
• DLT-Evaluable set is defined as all patients who received ≥ 75% of the scheduled dose of 
each study treatment during the first 28-day treatment cycle.  Additionally, patients who 
had a DLT event during the corresponding DLT observation window despite having 
received < 75% of the scheduled dose will also be considered evaluable. 
• Safety Analysis Set is defined as all patients who received at least one medication of 
BGB-10188 and/or zanubrutinib (for combination therapy part).  This will be the primary 
analysis set used for safety analyses.  
• Efficacy Analysis Set is defined in the same way as the Safety Analysis Set and will be 
the primary analysis set used for efficacy analyses. 
• PK Analysis Set is defined as all patients who had ≥ 1 postdose plasma concentration and 
no important protocol deviation affecting PK. 
9.3.1.2. 
Part D  
• DLT-Evaluable Set is defined as all patients who received ≥ 75% of the scheduled dose 
of BGB-10188, ≥ 75% of the scheduled dose of tislelizumab during the first 28-day 
treatment cycle.  Additionally, patients who had a DLT event during the corresponding 
DLT observation window despite having received < 75% of scheduled dose of 
tislelizumab or < 75% of the scheduled dose of BGB-10188 will also be considered 
evaluable. 
• Safety Analysis Set is defined as all patients who received at least one medication of 
BGB-10188 and/or tislelizumab.  This will be the primary analysis set used for safety 
analyses.  
• The Efficacy Analysis Set is defined in the same way as the Safety Analysis Set and will 
be the primary analysis set used for efficacy analyses. 
• The PK Analysis Set is defined as all patients who had ≥ 1 postdose plasma concentration 
and no important protocol deviation affecting PK. 
9.3.1.3. 
Part E  
• The Safety Analysis Set is defined as all patients who received at least one medication of 
BGB-10188 and/or tislelizumab.  Patients are analyzed according to the treatment they 
actually received.  This will be the primary analysis set used for safety analyses.  
• The Efficacy Analysis Set follows the modified intent-to-treat principle and includes all 
patients who are randomized/enrolled and treated.  The patients will be analyzed 
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according to the treatment group to which they were randomized/enrolled to.  The 
Efficacy Analysis Set will be the primary analysis set used for efficacy analyses. 
• The Efficacy Evaluable Analysis Set includes all patients who received at least one dose 
of study drugs, have evaluable disease at baseline, and have at least one evaluable 
postbaseline tumor response assessment unless any clinical disease progression or death 
occurred before the first postbaseline tumor assessment.  The Efficacy Evaluable 
Analysis Set will be the sensitivity analysis set for efficacy analyses.  
• The PK Analysis Set is defined as all patients who had at least one postdose plasma 
concentration and no important protocol deviation affecting PK. 
9.3.2. 
Randomization Method (Part E)  
In Part E, patients will be randomized at a 2:1 ratio to receive either BGB‑10188 160 mg once 
daily plus tislelizumab 200 mg once every 3 weeks or BGB‑10188 320 mg once daily plus 
tislelizumab 200 mg once every 3 weeks.  The randomization will be performed centrally using 
the IRT system on or immediately prior to Cycle 1 Day 1. 
9.3.3. 
Patient Disposition  
The number of patients enrolled, treated, and discontinued from study drug or study will be 
summarized.  The primary reason for study drug discontinuation will be summarized according 
to the categories recorded 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. 
9.3.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized descriptively.  Continuous 
variables include but not limited to age, weight, vital signs, time since initial disease diagnosis, 
etc; categorical variables include but not limited to sex, age group, disease stage, ECOG, prior 
line of therapy, etc. 
9.3.5. 
Disease History  
The number (percentage) of patients reporting a history of disease and characteristic will be 
summarized descriptively.  Disease characteristics include but not limited to time since first 
diagnosis of disease to study entry, time from most recent relapse or refractory to study entry, 
disease subtype, etc. 
9.3.6. 
Prior and Concomitant Medications  
Prior and concomitant medications will be assigned a preferred name using the World Health 
Organization Drug Dictionary drug codes.  Prior and concomitant medications will be further 
coded to the appropriate Anatomical Therapeutic Chemical (ATC) class indicating therapeutic 
classification.  Prior and concomitant medications will be summarized and listed by preferred 
name and therapeutic class.  Prior medications will be defined as medications that started before 
the day of first dose of study drug.  Concomitant medications will be defined as medications that 
1) started before the first dose of study drug and were continuing at the time of the first dose of 
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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. 
9.3.7. 
Medical History  
Medical history will be mapped to a SOC and a PT using the MedDRA of the version currently 
in effect at BeiGene at the time of database lock.  The number (percentage) of patients reporting 
a history of any medical condition, as recorded on the CRF, will be summarized by SOC and PT. 
9.4. Efficacy Analyses  
Efficacy assessments will use the applicable criteria to assess related efficacy endpoints 
(Appendix 13, Appendix 14, and Appendix 17).  Analyses will be conducted by study part 
(where applicable) and indication based on the Efficacy Analysis Set.  
9.4.1. 
Part A, Part B, and Part C  
Overall Response Rate (ORR) 
ORR will be estimated as crude proportion of patients achieving PR with lymphocytosis or better 
for CLL patients by investigator; and PR or better for MCL, MZL, FL, DLBCL, and SLL 
patients by investigator.  Two-sided Clopper-Pearson 95% CI of ORR will be constructed to 
assess the precision of the point estimate of ORR. 
Best overall response is defined as the best response recorded from the start of treatment to the 
end of the best response determination period.  The proportion for each response category (CR, 
PR, stable disease, and disease progression) will be presented.  Patients with no postbaseline 
response assessment (due to any reason) will be considered as non-responders for best overall 
response. 
Progression-free Survival (PFS) 
PFS is defined as time from treatment initiation to documentation of progression or death due to 
any cause, whichever happens first assessed by investigator.  The median and other quartiles of 
PFS will be estimated by the Kaplan-Meier method.  The 2-sided 95% CIs of median and other 
quartiles will be constructed using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982).  Event-free rates at selected timepoints for PFS will be 
estimated using the Kaplan-Meier method with their 2 sided 95% CIs based on the Greenwood 
formula (Kalbfleisch and Prentice 1980). 
More details including the censoring rules will be provided in the SAP. 
Duration of Response (DOR) 
DOR is defined as the time from the first determination of an objective response to the date that 
progression is documented after treatment initiation assessed by investigator or death, whichever 
occurs first.  DOR will be analyzed using the same methods as PFS, but only for patients who 
have achieved an overall response of at least PR.  The distribution of DOR will be summarized 
by the Kaplan-Meier method. 
Overall Survival (OS) 
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OS is defined as the time from treatment initiation until death.  OS will be analyzed using the 
similar methods employed for the PFS analysis except for the censoring rules.   
Time to Response (TTR)  
TTR is defined as the time from treatment initiation to the first documentation of response 
assessed by investigator.  TTR will be summarized only for responders by descriptive statistics. 
Other Efficacy Analyses 
Exploratory endpoints, including but not limited to correlation of clinical response to 
BGB-10188 or in combination with zanubrutinib and biomarker characteristics (eg, presence of 
Treg cells in peripheral blood or in tumor tissue, mutation profile, PI3K expression, etc), will be 
explored.  
9.4.2. 
Part D  
Overall Response Rate (ORR) 
ORR is defined as the proportion of patients achieving PR or better assessed by the investigator 
using RECIST v1.1 and will be analyzed the same way as in Section 9.4.1. 
Duration of Response (DOR) 
DOR is defined as the time from the first determination of an objective response per RECIST 
v1.1 until the first documentation of progression assessed by investigator or death, whichever 
comes first, and will be analyzed the same way as in Section 9.4.1. 
Disease Control Rate (DCR)  
DCR is defined as the proportion of patients with best overall response, as defined in RECIST 
v1.1, of a CR, PR, and stable disease assessed by investigator.  This will be summarized 
similarly as ORR.  Two-sided Clopper-Pearson 95% CI of DCR will be constructed.  
Time to Response (TTR)  
TTR is defined as the time from treatment initiation to the first documentation of response 
assessed by investigator.  TTR will be analyzed the same way as in Section 9.4.1. 
Other Efficacy Analyses  
Exploratory endpoints, including but not limited to correlation of clinical response to 
BGB-10188 in combination with tislelizumab and biomarker characteristics (eg, presence of 
Treg cells in peripheral blood or in tumor tissue, tumor mutation profile, tumor 
microenvironment, etc), will be explored. 
9.4.3. 
Part E  
Overall Response Rate (ORR) 
ORR is defined as the proportion of patients achieving PR or better assessed by the investigator 
using RECIST v1.1 and will be analyzed the same way as in Section 9.4.1. 
CA-125 Response Rate 
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CA-125 response rate is defined as the proportion of patients achieving a CA-125 response 
according to the Gynecological Cancer Intergroup criteria.  A response has occurred if there is at 
least a 50% reduction in CA-125 levels from baseline.  Patients can be evaluated according to 
CA-125 only if they have a pretreatment sample that is at least twice the upper limit of normal 
and within 2 weeks prior to starting treatment.  Two-sided Clopper-Pearson 95% CI of CA-125 
rate will be constructed to assess the precision of the point estimate. 
Duration of Response (DOR) 
DOR is defined as the time from the first determination of an objective response per 
RECIST v1.1 until the first documentation of progression assessed by the investigator or death, 
whichever comes first, and will be analyzed the same way as in Section 9.4.1. 
Progression-free Survival (PFS) 
PFS is defined as the time from treatment initiation to the date of the first documentation of 
disease progression assessed by the investigator using RECIST v1.1 or death, whichever occurs 
first. The median and other quartiles of PFS will be estimated by the Kaplan-Meier method.  The 
2-sided 95% CIs of median and other quartiles will be constructed using the Brookmeyer and 
Crowley method (Brookmeyer and Crowley 1982).  Event-free rates at selected timepoints for 
PFS will be estimated using the Kaplan-Meier method with their 2 sided 95% CIs based on the 
Greenwood formula (Kalbfleisch and Prentice 1980). 
More details including the censoring rules will be provided in the SAP. 
Disease Control Rate (DCR)  
DCR is defined as the proportion of patients with best overall response, as defined in 
RECIST v1.1, of a CR, PR, or stable disease assessed by the investigator.  This will be 
summarized similarly as ORR.  Two-sided Clopper-Pearson 95% CI of DCR will be constructed.  
Clinical Benefit Rate 
Clinical benefit rate is defined as the proportion of patients with best overall response, as defined 
in RECIST v1.1, of a CR, PR, or at least 24 weeks of stable disease assessed by the investigator.  
This will be summarized similarly as ORR.  Two-sided Clopper-Pearson 95% CI of DCR will be 
constructed. 
Time to Response (TTR) 
TTR is defined as the time from treatment initiation to the first documentation of response 
assessed by the investigator.  TTR will be analyzed the same way as in Section 9.4.1. 
Other Efficacy Analyses 
Exploratory endpoints, including, but not limited to, correlation of clinical response to 
BGB-10188 in combination with tislelizumab and biomarker characteristics (eg, presence of 
Treg cells in peripheral blood or in tumor tissue, tumor mutation profile, tumor 
microenvironment, etc), will be explored. 
9.5. 
 Safety Analyses  
The safety analyses will be conducted by study part, indication, dose level, and overall, as 
appropriate based on the Safety Analysis Set.  
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9.5.1. 
Extent of Exposure  
Extent of exposure to the study drugs will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity (mg/day), and relative dose intensity. 
The number (percentage) of patients requiring dose interruption and dose delay/reduction will be 
summarized.  The frequency of the dose interruption/delay/reduction and the cycle in which the 
first dose interruption/delay/reduction occurred will be summarized descriptively.   
9.5.2. 
Dose-Limiting Toxicities  
DLT events will be summarized by dose level and study part in the dose escalation phase. 
9.5.3. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA.  AEs will be coded to MedDRA lower level term, PT, and primary SOC. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation (the last one for combination therapies) or initiation of a new anticancer therapy, 
whichever occurs first.  Worsening of an event to Grade 5 TEAE beyond Day 30 after the last 
dose of study drugs is also considered a TEAE (if it is prior to the start of a new anticancer 
therapy).  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.   
For Part D and Part E, imAEs will be identified from all AEs that had an onset date or worsening 
in severity from baseline (pretreatment) on or after the first dose of study drug and up to 90 days 
from the last dose of study drug or initiation of a subsequent anticancer therapy, whichever 
occurs earlier. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT.  A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v5.0 within an SOC and PT, even if the patient experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of patients with TEAEs will also be 
summarized by relationship to the study drug.  Treatment-related AEs include those events 
considered by the investigator to be related to treatment or with missing assessment of the causal 
relationship.   
SAEs, deaths, TEAE with ≥ Grade 3, imAE (for Part D and Part E), treatment-related TEAEs, 
and TEAEs that led to treatment discontinuation and/or dose modification, dose interruption, or 
dose delay will be summarized.  
9.5.4. 
Laboratory Analyses  
CBC, serum chemistry, coagulation, and urinalysis values will be evaluated for each laboratory 
parameter.  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.  Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, maximum for continuous variables; n [%] for categorical variables) for 
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laboratory parameters and their changes from baseline will be calculated.  Laboratory values will 
be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 or iwCLL (2018) will be 
summarized by NCI-CTCAE grade or iwCLL grade accordingly.  In the summary of laboratory 
parameters by grade, parameters with grading in both high and low directions (eg, calcium, 
glucose, magnesium, potassium, sodium) will be summarized separately. 
9.5.5. 
Vital Signs Analyses  
Descriptive statistics for vital sign parameters (eg, systolic and diastolic BP, heart rate, 
temperature) and changes from baseline will be presented by visit.  
9.5.6. 
Ophthalmologic Examination (Part D)  
Ophthalmologic examination results will be listed by patient. 
9.6. 
Pharmacokinetic Analyses  
For the PK evaluation of BGB-10188 and zanubrutinib, plasma concentration-time data of each 
patient will be tabulated and graphically presented on linear semi-logarithmic scales.  PK 
parameters will be determined using a standard noncompartmental method.  A listing of patients 
excluded from the analysis set and individual data points excluded from the analysis will be 
provided.  The PK parameters will be summarized with descriptive statistics (N, arithmetic 
mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of 
variation (CV) % associated to the geometric mean).  
PK parameters will include, but are not limited to, the following as allowed by data: 
Cmax (μg/mL)  
Observed maximum plasma concentration during a sample interval  
Cτ (μg/mL)  
Observed trough concentration at steady state 
Tmax (hr)  
Observed time to maximum plasma concentration during a sampling 
interval  
t½ (h)  
Terminal elimination half-life, determined from the quotient 0.693/λz  
AUC(0-t) (μg·h/mL)  
Area under the plasma concentration-time curve from time zero to the last 
measurable timepoint calculated by log-linear trapezoidal summation  
AUC(0-τ) (μg·h/mL)  
Area under the plasma concentration-time curve from time zero to dosing 
interval (tau) postdose at steady state; calculated by log-linear trapezoidal 
summation  
AUC(0-inf)(μg·h/mL) 
Area under the plasma concentration-time curve from time zero to 
infinity after single dose; calculated by log-linear trapezoidal summation  
CL/F (L/hr)  
Apparent clearance after oral administration  
Ro  
Observed accumulation ratio determined by AUC(0-τ),ss /AUC(0-24), Day 1 
The BGB-10188, zanubrutinib and tislelizumab PK concentration data collected sparsely at 
predose and postdose (around time to the maximum observed plasma concentration [Tmax]) will 
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be tabulated and summarized by visit/cycle.  Descriptive statistics will include means, standard 
deviations, medians, and ranges as appropriate. 
Population PK analyses may be conducted as appropriate, and the results of such analysis may be 
reported separately from the clinical study report. 
9.7. 
Other Analyses  
9.7.1. 
Related PK Analyses  
If data permits, correlation between BGB-10188 concentration and corrected QTcF intervals will 
be assessed to analyze the cardiovascular impact of BGB-10188. 
9.7.2. 
Immunogenicity Analyses  
Samples to assess anti-tislelizumab-antibodies will be collected only in patients who receive 
study drug(s) and at sites that are able to adequately perform sampling, handling, and processing 
as outlined in the laboratory manual. 
The ADA results will be summarized using descriptive statistics by the number and percentage 
of patients who develop detectable ADAs.  The incidence of positive ADAs and neutralizing 
ADAs will be reported for evaluable patients.  The effect of immunogenicity on PK, efficacy, 
and safety may be evaluated if data allow. 
9.8. 
Determination of Sample Size  
For the dose escalation phase of the study, the number of dose levels examined, the dose 
escalation cohort size, and the emerging toxicities of the therapy will determine the sample size.  
A cohort of approximately 3 patients in the dose escalation step will be enrolled and 
administered at the dose level recommended for the cohort.  
Approximately 5 dose levels will be tested for the dose escalation path of BGB-10188 
monotherapy in Part A.  A total of approximately 30 patients are expected to be enrolled for the 
BGB-10188 monotherapy dose escalation.  The doses of BGB-10188 for the combination 
therapy in Part B with zanubrutinib 160 mg twice daily will be the latest cleared dose in Part A 
and subsequent higher dose levels from monotherapy dose escalation.  Therefore, a total of 
approximately 18 patients are expected to be enrolled for the combination therapy dose 
escalation.  
Approximately 6 dose levels of BGB-10188 will be tested for combination therapy dose 
escalation with tislelizumab 200 mg once every 3 weeks in Part D.  A total of approximately 
36 patients are expected to be enrolled.  
The total sample size in Part A, Part B, and Part D is expected to be approximately 84, excluding 
patients for the China verification parts. Part C was planned to have approximately 20 patients 
but will not be initiated. Part E is expected to have approximately 30 to 50 patients.  In Part E, 
patients will be randomized at a 2:1 ratio to receive either BGB‑10188 160 mg once daily plus 
tislelizumab 200 mg once every 3 weeks or BGB‑10188 320 mg once daily plus tislelizumab 200 
mg once every 3 weeks.  No formal hypothesis testing will be performed in the efficacy 
evaluation.  Table 16 shows the two-sided 95% CI for ORR with 10/20/30 patients for different 
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observed response rates based on the Clopper-Pearson method.  The sample size for China 
verification parts will be based on the escalation status in Part A and Part D. 
Table 16: 
Two-Sided 95% Confidence Interval for ORR With 10/20/30 Patients 
Number of Observed 
Responders/Number of 
Patients 
ORR Estimates  
95% CI of ORR  
1/10 
10%  
(0.3%, 44.5%) 
2/10 
20%  
(2.5%, 55.6%) 
3/10 
30%  
(6.7%, 65.2%) 
4/10 
40%  
(12.2%, 73.8%) 
2/20 
10%  
(1.2%, 31.7%)  
4/20 
20%  
(5.7%, 43.7%)  
6/20 
30%  
(11.9%, 54.3%)  
8/20 
40%  
(19.1%, 63.9%)  
3/30 
10%  
(2.1%, 26.5%)  
6/30 
20%  
(7.7%, 38.6%)  
9/30 
30%  
(14.7%, 49.4%)  
12/30 
40%  
(22.7%, 59.4%)  
Abbreviations: ORR, overall response rate. 
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Safety Monitoring Committee  
An SMC will be established and include both the sponsor (including the medical monitor and 
study team members from Pharmacovigilance/Drug Safety, Clinical Pharmacology, and 
Biostatistics with other members as appropriate) and investigators.  The SMC will review all 
available safety, efficacy, PK, and exploratory data and make recommendations on dose 
escalation, dose modification, and dose selection throughout the study.  The SMC may also be 
called upon by the sponsor on an ad hoc basis where applicable to the conduct of the study.  A 
separate charter will outline the details for the composition and responsibility of the SMC. 
Part A and Part D (Dose Verification in China) 
For the patients in China who receive BGB-10188 as monotherapy or in combination with 
tislelizumab in the dose-verification study, the SMC will review all the safety data (including 
AEs and laboratory assessments) and recommend the RDFE before patients join Part B and Part 
E. 
Part E 
An SMC meeting will be scheduled once approximately 12 patients have been randomized and 
have completed at least 1 month of follow-up, or after the first 10 patients are evaluable for 
efficacy assessment.  The SMC will review all available safety and efficacy data and make 
recommendations on whether the study should continue.  Ad hoc meetings can be requested by 
the SMC if any specific safety concern arises. 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented.  Such records include but are not limited to the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals.  In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation 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 any 
time during or after completion of this clinical study.  If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately.  The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit.  Regulatory agencies may also conduct a regulatory inspection 
of this study.  Such audits/inspections can occur at any time during or after completion of the 
study.  If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines.  
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs.  The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product.  Dispensation records will document quantities received from 
BeiGene’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, patient initials, and the initials of the 
person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene’ requirements specified in the 
Pharmacy Manual.  At appropriate times during the conduct of the study or at the end of the 
study, the study site will dispose of and/or destroy all unused study drug supplies following drug 
inventory reconciliation by the monitor.  These including empty containers, according to these 
procedures.  If the site cannot meet BeiGene’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will 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 ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted to the IRB/IEC by the principal investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  In addition, all patient recruitment 
materials must be approved by the IRB/IEC. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC.  Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments.  In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC.  Investigators may receive written 
investigational new drug safety reports or other safety-related communications from the sponsor.  
Investigators are responsible for ensuring that such reports are reviewed and processed in 
accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor.  All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements.  Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in sponsor medical 
monitor or contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and the patients must read, understand, and sign each revised 
ICF confirming their willingness to remain in the study. 
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13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The final IRB/IEC-approved ICFs must be provided 
to the sponsor for health authority submission purposes according to local requirements. 
The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate.  The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study.  For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative.  All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality  
The investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH GCP Guideline, as implemented locally.  Such 
laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study.  
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to the sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
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• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part of 
this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex life, 
sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives.  
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) designated 
by the sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws.  If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of the US FDA, the China NMPA, and all other national and local health 
authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter.  This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor.  The investigator further agrees 
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to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
13.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of 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 BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor.  
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Collection  
Data required by the protocol will be entered into an EDC system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The investigator or designee must provide e-signature in the 
EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
14.1.2. 
Data Management/Coding  
At the end of the study, all final patient data, both eCRF and external data (eg, laboratory data), 
that were collected according to the protocol will be stored by BeiGene or will be properly stored 
or handled in accordance with applicable laws and regulations. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file that includes all database modifications) will be 
followed to support accurate data collection.  Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation.  The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained.  Checking the 
eCRFs for completeness and clarity and cross-checking with source documents is required to 
monitor the progress of the study.  Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
AEs will be coded using MedDRA.  Concomitant medications will be coded using the WHO 
Drug Dictionary.  Concomitant diseases/medical history will be coded using MedDRA. 
14.2. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into ≥ 1 the following categories: 1) investigator’s study file, and/or 2) patient 
clinical source documents. 
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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC- and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports, consultant letters, 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 ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required.  Furthermore, the investigator must 
ensure 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 10 years or as allowed by IRB/IEC. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that the documents can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
14.3. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  Investigators assert that they will apply 
due diligence to avoid protocol deviations. 
The investigator is to document and explain any deviations from the approved protocol.  The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
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14.4. 
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 (sponsor), 
regardless of the outcome of the study.  The data generated in this clinical study are the exclusive 
property of the sponsor and are confidential.  For multicenter studies, 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 2016). 
After conclusion of the study and without prior written approval from BeiGene, investigators in 
this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of BeiGene in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for ≥ 2 years. 
• No such communication, presentation, or publication will include BeiGene’s confidential 
information. 
• Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsor prior to submission.  This allows the sponsors to 
protect proprietary information, provide comments based on information from other 
studies that may not yet be available to the investigator, and ensure scientific and clinical 
accuracy.  The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this trial will be presented in the investigator’s 
clinical study agreement. 
14.5. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
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• Review of study records for completeness 
• Return of treatment codes to the sponsor 
• Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for reasons including 
but not limited to safety or ethical issues or severe noncompliance.  If the sponsor determines 
that such action is needed, the sponsor will discuss this with the investigator (including the 
reasons for taking such action) at that time.  When feasible, the sponsor will provide advance 
notification to the investigator of the impending action prior to it taking effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons, and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action.  If 
required by applicable regulations, the investigator must inform the IEC/IRB promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor.  In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study. 
Financial compensation to the investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
14.6. 
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, are the sole property of the sponsor and are hereby 
assigned to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or study 
center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a patient 
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• Study results that may be published as described in Section 14.4 
If a written contract for the conduct of the study, which includes provisions inconsistent with this 
statement, is executed, that contract’s provisions shall apply rather than this statement. 
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15. 
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APPENDIX 1. PART A AND PART B SCHEDULE OF ASSESSMENTS  
Screening a 
-35 to -8 
(Part A) 
 
-28 to -1  
(Part B) 
 
Treatment Period (1 Cycle = 28 Days) 
EOT c 
Safety 
Follow-up d 
PK 
Washout b 
-7 to -1 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Day 
-7 
1 
8 
15 
22 
1 
15 
1 
≤ 7 Days 
After 
Stopping 
Treatment 
30 Days 
After Last 
Dose 
Window (Day) 
 
 
- 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
Informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
Medical history/baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
B-symptoms f 
x 
 
x 
 
 
 
x 
x 
x 
x 
 
Complete physical examination 
and weight (height at Screening 
only) g 
x 
 
 
 
 
 
 
 
 
 
 
Targeted PE g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Echocardiogram or multigated 
acquisition scan 
x 
 
 
 
 
 
 
 
 
 
 
12-lead ECG h 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
BGB-10188 administration  
 
x 
Once daily 
 
 
Zanubrutinib administration 
 
 
Twice daily (only for Part B and patients with disease progression in Part A) 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events/serious adverse 
events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tumor imaging i 
x 
 
Every 8 weeks for the first 24 weeks, every 12 weeks for the next 24 weeks, and 
then every 16 weeks (± 7 days) 
x 
 
Bone marrow aspiration or 
biopsy j 
x 
 
At time of CR 
 
 
Endoscopy k 
x 
 
At time of CR 
 
 
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Screening a 
-35 to -8 
(Part A) 
 
-28 to -1  
(Part B) 
 
Treatment Period (1 Cycle = 28 Days) 
EOT c 
Safety 
Follow-up d 
PK 
Washout b 
-7 to -1 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Day 
-7 
1 
8 
15 
22 
1 
15 
1 
≤ 7 Days 
After 
Stopping 
Treatment 
30 Days 
After Last 
Dose 
Window (Day) 
 
 
- 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
Laboratory Tests l 
 
 
 
 
Hematology  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Clinical chemistry  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Coagulation 
x 
 
x 
 
 
 
x 
 
x 
x 
 
Pregnancy test m 
x 
 
x 
 
 
 
x 
 
x 
 
x 
Viral serologies n 
x 
 
As clinically needed 
 
 
Cytomegalovirus monitoring 
x 
 
x 
 
 
 
x 
 
x 
 
x 
Urinalysis o 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
 
Quantitative serum 
immunoglobulins (IgG, IgM, 
IgA) 
x 
 
 
 
 
 
x 
 
x 
 
 
β2-Microglobulin 
x 
 
 
 
 
 
x 
 
x 
 
 
PK/pharmacodynamics 
blood sampling  
 
See Appendix 5 
 
 
Biomarker blood  
x 
 
To be collected at time of first response and time of disease progression p 
 
 
Archival or fresh tumor tissue q  
x 
 
Optional biopsy at time of relapse 
 
 
Abbreviations: CT, computed tomography; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EOT, End of Treatment; FFPE, formalin-fixed 
paraffin-embedded; FL, follicular lymphoma; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C 
virus; Ig, immunoglobulin; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; PE, physical examination; PET, positron emission tomography; PK, 
pharmacokinetics; SLL, small lymphocytic lymphoma 
Note: Assessments scheduled on study drug administration days should be performed prior to dosing, unless otherwise specified. 
a. Screening period is from 28 days prior to first dose of study drug, during which all criteria should be strictly assessed.  In Part A, the first dose of study drug 
will be on Day -7.  In Part B, the first dose of study drug will be on Cycle 1 Day 1. 
b. For Part A only, the first dose of BGB-10188 will occur on Day -7, followed by a PK washout period. 
c. EOT is defined as end of treatment of zanubrutinib or BGB-10188, whichever is later.  The EOT Visit will be conducted within 7 days after treatment 
discontinuation.  If routine laboratory tests (eg, hematology, clinical chemistry, coagulation, and urinalysis) were completed ≤ 7 days before the EOT Visit, 
these tests do not need to be repeated.  A tumor assessment is not required at the EOT Visit if < 6 weeks have passed since the last assessment.  If the EOT 
Visit did not occur until 30 days (± 7 days) or later after the last dose of study drug, the EOT Visit may also be used as the Safety Follow-up Visit. 
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d. The safety follow-up should be conducted within 30 days (± 7 days) after the last dose of zanubrutinib or BGB-10188, whichever is later, or before the start of 
a new anticancer treatment, whichever occurs first.  Investigators should also collect the information about new antitumor therapy.  If the interval between 
EOT Visit and Safety Follow-up Visit is < 7 days, the EOT Visit can be delayed and combined with the safety follow-up visit.  If EOT visit and safety 
follow-up visit are combined, then the site should ensure that all assessments for both visits are done, as some assessments are not common between the visits.  
e. This must occur before any study-specific procedures are conducted and may be obtained before the 28-day screening window.  Consent must be obtained 
using the current version of the form approved by the Independent Ethics Committee/Institutional Review Board. 
f. Unexplained weight loss > 10% over previous 6 months, fever (> 38°C), and drenching night sweats. 
g. Physical examination includes assessments of cardiovascular, respiratory, abdominal, and neurological systems as well as lymph nodes/spleen, skin, 
oropharynx, and extremities (as detailed in Section 7.5.1).  Targeted physical examination should be limited to systems of clinical relevance (ie, cardiovascular, 
respiratory, lymph nodes, liver, and spleen), and those systems associated with clinical signs/symptoms and should be performed at every visit including Day -
7.  Weight will be assessed at screening and at every visit.  
h. All ECGs are to be obtained prior to other assessments scheduled at that same time.  If this is not possible, then ECGs are to be obtained ≥ 20 minutes 
following the last procedure performed.  The 12-lead ECG will be done in triplicate (2 minutes apart).  The calculated QTcF average of 3 ECGs must be 
≤ 480 msec for eligibility.  Patients should be in a supine position and resting for ≥ 10 minutes before obtaining the ECGs.  
i. Patients in Part A or Part B with non-Hodgkin lymphoma (ie, SLL, MZL, MCL, FL, or DLBCL) will undergo PET/CT imaging at baseline; a separate CT scan 
of diagnostic quality should be performed in addition to the PET/CT imaging if the PET/CT imaging is not of diagnostic quality.  If PET-avid disease is 
detected, then subsequent tumor assessments should be conducted with PET/CT-based imaging.  Patients in Part A or Part B with non-Hodgkin lymphoma 
without PET-avid disease, as well as patients with CLL, should undergo tumor assessments with CT-based imaging.  
j. Bone marrow biopsy and/or aspirate is required during screening to assess bone marrow involvement of lymphoma.  If a patient has had bone marrow 
examination performed within 90 days prior to first dose of study drug, a repeated bone marrow biopsy/aspirate is not required.  Repeat bone marrow biopsy 
and aspirate are required if imaging results demonstrate a CR in patients with bone marrow involvement of lymphoma at baseline.  For patients with DLBCL, 
if a follow-up biopsy cannot be obtained, a PET scan that clearly documents continued disease clearance may be used in lieu of the repeated biopsy.  More 
details about bone marrow examination refer to Section 7.6. 
k. For patients with MCL, endoscopy may be performed at Screening for patients with gastrointestinal involvement of their disease.  Patients who had an 
endoscopy performed during the screening period, which confirmed gastrointestinal involvement of MCL, will require an endoscopy to confirm CR.  If a 
follow-up biopsy cannot be obtained, a PET scan that clearly documents continued disease clearance maybe used in lieu of the repeated biopsy. 
l. Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Section 7.5.4. 
m. Two negative pregnancy tests (including ≥ 1 blood test) must be obtained before initiating therapy.  The first test must be performed within 14 days before 
BGB-10188 therapy and the second test must be ≤ 72 hours before BGB-10188 therapy.  Pregnancy tests must be continued every cycle for ≥ 90 days after the 
last dose of zanubrutinib and/or BGB-10188.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  A patient who has a 
positive pregnancy test result at any time after the study drug administration will be immediately withdrawn from participation in the study. 
n. Hepatitis B serology includes HBsAg and HBcAb.  Patients negative for HBV antibody do not need HBV DNA test by PCR at screening.  Patients who are 
HBsAg negative, HBcAb positive, and HBV DNA negative will undergo viral load measurement (HBV DNA by PCR) monthly.  If a patient is being treated 
prophylactically with antivirals, HBV DNA screening by PCR must be done at least every 90 days.  Hepatitis C serology includes HCV antibody.  Patients 
negative for HCV antibody do not need HCV RNA test by PCR at screening.  Patients who are HCV antibody positive, but negative for HCV RNA, will 
undergo viral load testing (HCV RNA by PCR) monthly.  Hepatitis B and hepatitis C testing must be conducted in a laboratory able to perform the tests to the 
required sensitivity (< 20 IU/mL and < 15 IU/mL for hepatitis B and C, respectively). If sites cannot conduct the tests with this sensitivity or the results are not 
reported with values, then any positive viral load result should lead to withholding of study treatment and initiation of antiviral treatment.  The medical 
monitor should be informed of any suspected hepatitis B or hepatitis C reactivation. 
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o. Perform urine dipstick, as well as urine microscopy if dipstick is abnormal.  If the urine protein is ≥ 2+ in urinalysis or per clinical discretion, collect 24-hour 
urine sample.  
p. For all patients, blood samples will be collected at screening, time of first response, and time of disease progression to assess blood-based biomarkers and their 
association with response, resistance, and prognosis.  
q. If available, archival tumor tissues (FFPE blocks or approximately 10 to 15 unstained slides) will be requested and sent to the central laboratory for analysis of 
biomarkers potentially associated with clinical responses.  In the absence of archival tumor tissues, an optional, fresh biopsy of a tumor lesion at baseline will 
be requested.  Baseline tissue samples collected during screening will be shipped to a central laboratory for biomarker testing after local regulatory approval.  
This may occur after the start of study treatment if necessary.  A biopsy at disease progression is optional to explore mechanisms of resistance.  Written 
informed consent is required prior to fresh tumor biopsies. 
 
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APPENDIX 2. PART C SCHEDULE OF ASSESSMENTS  
 
Screening a 
-28 to -1 
Treatment Period (1 Cycle = 28 Days) 
EOT b 
Safety 
Follow-up c 
Survival 
Follow-up d 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Day 
 
1 
2 e 
15 
1 
15 
1 
≤ 7 Days After 
Stopping 
Treatment 
30 Days 
After Last 
Dose 
Every 
3 Months 
Window (Day) 
 
- 
- 
± 3 
± 3 
± 3 
± 3 
± 7 
± 14 
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history/baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
B-symptoms g 
x 
x 
 
 
x 
 
x 
x 
 
 
Complete physical 
examination and weight  
(height at Screening 
only) h 
x 
 
 
 
 
 
 
 
 
 
Targeted PEh 
 
x 
 
 
x 
 
x 
x 
x 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
 
x 
x 
x 
 
Echocardiogram or 
multigated acquisition 
scan 
x 
 
 
 
 
 
 
 
 
 
12-lead ECG i 
x 
x 
 
 
x 
 
x 
x 
 
 
BGB-10188 
administration  
 
Once daily 
 
 
 
Zanubrutinib 
administration 
 
Twice daily 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events/serious 
adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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Screening a 
-28 to -1 
Treatment Period (1 Cycle = 28 Days) 
EOT b 
Safety 
Follow-up c 
Survival 
Follow-up d 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Day 
 
1 
2 e 
15 
1 
15 
1 
≤ 7 Days After 
Stopping 
Treatment 
30 Days 
After Last 
Dose 
Every 
3 Months 
Window (Day) 
 
- 
- 
± 3 
± 3 
± 3 
± 3 
± 7 
± 14 
Tumor imaging j 
x 
Every 8 weeks for the first 24 weeks, every 12 weeks for the next 
24 weeks, and then every 16 weeks (± 7 days) 
x 
 
 
Bone marrow aspiration 
or biopsy k 
x 
x k 
 
 
 
Endoscopy l 
x 
At time of CR 
 
 
 
Laboratory Tests 
 
 
 
 
 
 
Hematology  
x 
x 
 
 
x 
 
x 
x 
 
 
Clinical chemistry  
x 
x 
 
x 
x 
x 
x 
x 
 
 
Coagulation 
x 
x 
 
 
x 
 
x 
x 
 
 
Pregnancy test m 
x 
x 
 
 
x 
 
x 
 
x 
 
Viral serologies n 
x 
 
 
 
 
 
 
 
 
 
Cytomegalovirus 
monitoring 
x 
x 
 
 
x 
 
x 
 
x 
 
Urinalysis o 
x 
x 
 
 
x 
 
x 
x 
 
 
Quantitative serum 
immunoglobulins  
(IgG, IgM, IgA) 
x 
 
 
 
x 
 
x 
 
 
 
β2-Microglobulin 
x 
 
 
 
x 
 
x 
 
 
 
PK/pharmacodynamics 
blood sampling  
 
See Appendix 5 
 
 
 
Biomarker blood p 
x 
To be collected at time of first response and time of disease progression p 
 
 
 
Archival or fresh tumor 
tissue q 
x 
Optional biopsy at time of relapse 
 
 
 
Survival status 
 
 
 
 
x 
Abbreviations: CT, computed tomography; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EOT, End-of-Treatment; FFPE, formalin-fixed 
paraffin-embedded; FL, follicular lymphoma; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C 
virus; Ig, immunoglobulin; MCL, mantle cell lymphoma; PE, physical examination; PET, positron emission tomography; PK, pharmacokinetics; QTcF, QT 
interval corrected with Fridericia’s formula 
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Note: Assessments scheduled on study drug administration days should be performed prior to dosing, unless otherwise specified. 
a. Screening period is from 28 days prior to first dose of study drug, during which all criteria should be strictly assessed.  In Part C, the first dose of study drug 
will be on Cycle 1 Day 1. 
b. EOT is defined as end of treatment of zanubrutinib or BGB-10188, whichever is later.  The EOT Visit will be conducted within 7 days after treatment 
discontinuation.  If routine laboratory tests (eg, hematology, clinical chemistry, coagulation, and urinalysis) were completed ≤ 7 days before the EOT Visit, 
these tests do not need to be repeated.  A tumor assessment is not required at the EOT Visit if < 6 weeks have passed since the last assessment.  If the EOT 
Visit did not occur until 30 days (± 7 days) or later after the last dose of study drug, the EOT Visit may also be used as the Safety Follow-up Visit. 
c. The safety follow-up should be conducted within 30 days (± 7 days) after the last dose of zanubrutinib or BGB-10188, whichever is later, or before the start of 
a new anticancer treatment, whichever occurs first.  Investigators should also collect the information about new antitumor therapy.  If the interval between 
EOT visit and safety follow-up visit is less than 7 days, the EOT visit can be delayed and combined with the safety follow-up visit.  If EOT visit and safety 
follow-up visit are combined, then site should ensure that all assessments for both visits are done as some assessments are not common between the visits. 
d. All patients will be followed for survival and further anticancer therapy information after discontinuation of study treatment via telephone calls, patient 
medical records, and/or clinic visits until death, loss to follow-up, withdrawal of consent, or study completion by the sponsor.  
e. Cycle 1 Day 2 visit is only for the first 5 patients in Part C. 
f. This must occur before any study-specific procedures are conducted and may be obtained before the 28-day screening window.  Consent must be obtained 
using the current version of the form approved by the Independent Ethics Committee/Institutional Review Board. 
g. Unexplained weight loss > 10% over previous 6 months, fever (> 38°C), and drenching night sweats. 
h. Physical examination includes assessments of cardiovascular, respiratory, abdominal, and neurological systems as well as lymph nodes/spleen, skin, 
oropharynx, and extremities.  Targeted physical examination should be limited to systems of clinical relevance (ie, cardiovascular, respiratory, lymph nodes, 
liver, and spleen), and those systems associated with clinical signs/symptoms.  Weight will be assessed at screening and at every visit.  
i. All ECGs are to be obtained prior to other assessments scheduled at that same time.  If this is not possible, then ECGs are to be obtained ≥ 20 minutes 
following the last procedure performed.  The 12-lead ECG will be done in triplicate (2 minutes apart).  The calculated QTcF average of 3 ECGs must be 
≤ 480 msec for eligibility.  Patients should be in a supine position and resting for ≥ 10 minutes before obtaining the ECGs.  
j. Patients with non-Hodgkin lymphoma (ie, MCL, FL, or DLBCL) will undergo PET/CT imaging at baseline; a separate CT scan of diagnostic quality should be 
performed in addition to the PET/CT imaging if the PET/CT imaging is not of diagnostic quality.  If PET-avid disease is detected, then subsequent tumor 
assessments should be conducted with PET/CT-based imaging.  Patients with non-Hodgkin lymphoma without PET-avid disease should undergo tumor 
assessments with CT-based imaging. 
k. Bone marrow biopsy and/or aspirate is required during screening to assess bone marrow involvement of lymphoma.  If a patient has had bone marrow 
examination performed within 90 days prior to first dose of study drug, a repeated bone marrow biopsy/aspirate is not required.  Repeat bone marrow biopsy 
and aspirate are required if imaging results demonstrate a CR in patients with bone marrow involvement of lymphoma at baseline.   
l. For patients with MCL, endoscopy may be performed at Screening for patients with gastrointestinal involvement of their disease.  Patients who had an 
endoscopy performed during the screening period, which confirmed gastrointestinal involvement of MCL, will require an endoscopy to confirm CR.  If a 
follow-up biopsy cannot be obtained, a PET scan that clearly documents continued disease clearance maybe used in lieu of the repeated biopsy. 
m. Two negative pregnancy tests (including ≥ 1 blood test) must be obtained before initiating therapy.  The first test must be performed within 14 days before 
BGB-10188 therapy and the second test ≤ 72 hours before BGB-10188 therapy.  Pregnancy tests must be continued every cycle for ≥ 90 days after the last 
dose of zanubrutinib and BGB-10188.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  A patient who has a positive 
pregnancy test result at any time after the study drug administration will be immediately withdrawn from participation in the study. 
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n. Hepatitis B serology includes HBsAg and HBcAb.  Patients negative for HBV antibody do not need HBV DNA test by PCR at screening.  Patients who are 
HBsAg negative, HBcAb positive and HBV DNA negative will undergo viral load measurement (HBV DNA by PCR) monthly.  If a patient is being treated 
prophylactically with antivirals, HBV DNA screening by PCR must be done at least every 90 days.  Hepatitis C serology includes HCV antibody. Patients 
negative for HCV antibody do not need HCV RNA test by PCR at screening.  Patients who are HCV antibody positive, but negative for HCV RNA, will 
undergo viral load testing (HCV RNA by PCR) monthly.  Hepatitis B and hepatitis C testing must be conducted in a laboratory able to perform the tests to the 
required sensitivity (< 20 IU/mL and <15 IU/mL for hepatitis B and C, respectively).  The medical monitor should be informed of any suspected hepatitis B or 
hepatitis C reactivation. 
o. Perform urine dipstick, as well as urine microscopy if dipstick is abnormal.  If the urine protein is ≥ 2+ in urinalysis or per clinical discretion, collect 24-hour 
urine sample. 
p. For all patients, blood samples will be collected at screening, time of first response, and time of disease progression to assess blood-based biomarker and their 
association with response, resistance, and prognosis.  
q. If available, archival tumor tissues (FFPE blocks or approximately 10 to 15 unstained slides) will be requested and sent to the central laboratory for analysis of 
biomarkers potentially associated with clinical responses.  In the absence of archival tumor tissues, an optional, fresh biopsy of a tumor lesion at baseline will 
be requested.  Baseline tissue samples collected during screening will be shipped to a central laboratory for biomarker testing after local regulatory approval.  
This may occur after the start of study treatment if necessary.  A biopsy at disease progression is optional to explore mechanisms of resistance.  Written 
informed consent is required prior to fresh tumor biopsies
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APPENDIX 3. PART D SCHEDULE OF ASSESSMENTS  
Screening a 
Treatment Period 
Safety Follow-up c 
Cycle 1 
(28 Days) 
Cycle 2 
(21 Days) 
Cycle 3 
(21 Days) 
≥ Cycle 4 
(Every 
21 Days) 
EOT 
Visit b 
Visit Day 
-28 to -1 
1 
8 
15 
22 
1 
8 
(Phone 
Call) p 
15 
1 
8   
(Phone 
Call) p 
1 
0 to 
7 Days 
+ 30 
Days 
(Visit) 
+ 60 
Days 
(Phone 
Call)  
+ 90 
Days 
(Phone 
Call) 
Visit Window 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
± 7 
± 14 
± 14 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical historyd 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/height/weighte 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
Physical examinationf 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
Echocardiogram or multigated 
acquisition scan 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead triplicate ECGg 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Eye examination, visual acuity test, 
and optical coherence tomography 
(or equivalent diagnostic test)h 
x 
 
 
Cycle 4 
then 
every 
15 weeks 
(± 7 days
) 
xh 
xh 
 
 
Adverse eventsi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior and concomitant procedures 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematologyj 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
xb 
x 
 
 
Clinical chemistryj 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
xb 
x 
 
 
Coagulation parametersj 
x 
x 
 
 
 
x 
 
 
As clinically indicated 
xb 
x 
 
 
Urinalysisj 
x 
x 
 
 
 
x 
 
 
x 
 
x 
xb 
x 
 
 
CK and CK-MBk 
x 
x 
xk 
x 
x 
xk 
x 
xk 
 
xk 
xb 
x 
 
 
Pregnancy testl 
xl 
xl 
xl 
 
 
xl 
 
 
xl 
 
xl 
x 
x 
 
 
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Screening a 
Treatment Period 
Safety Follow-up c 
Cycle 1 
(28 Days) 
Cycle 2 
(21 Days) 
Cycle 3 
(21 Days) 
≥ Cycle 4 
(Every 
21 Days) 
EOT 
Visit b 
Visit Day 
-28 to -1 
1 
8 
15 
22 
1 
8 
(Phone 
Call) p 
15 
1 
8   
(Phone 
Call) p 
1 
0 to 
7 Days 
+ 30 
Days 
(Visit) 
+ 60 
Days 
(Phone 
Call)  
+ 90 
Days 
(Phone 
Call) 
Visit Window 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
± 7 
± 14 
± 14 
Thyroid functionm 
xm 
 
 
 
 
xm 
 
 
 
Even 
Cyclesn 
 
x 
 
 
Cytomegalovirus monitoring 
x 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 
 
 
HBV/HCV testsn 
x 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function testso 
x 
As clinically indicated 
 
 
 
Biomarkers blood 
x 
At C2D1, time of first response, and at time of confirmed disease progression 
 
 
 
Pharmacokinetics/pharmacodynamic
s blood sampling 
 
Appendix 5  
 
 
 
 
Tumor assessmentq 
x 
Week 10 and every 9 weeks (± 7 days) thereafter 
xb 
 
 
 
Archival or fresh tumor tissuer 
x 
After about 3 to 5 weeks of treatment and at time of confirmed disease progression  
 
 
 
BGB-10188s 
 
Daily 
 
 
 
 
Tislelizumab administrationt 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
 
 
Anti-tislelizumab antibodies 
 
See Appendix 6 
 
Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CT, computed tomography; DLCO, carbon monoxide 
diffusion capacity; EOT, End of Treatment (Visit); FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HBcAb, hepatitis B core antibody; 
HbsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; imAE, immune-mediated adverse event; NCI-CTCAE, National Cancer 
Institute Common Terminology Criteria for Adverse Events; SAE, serious adverse event; T3, triiodothyronine; T4, thyroxine; TLCO, transfer factor for carbon 
monoxide of lung. 
a. Written informed consent is required before performing any study-specific procedure.  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drug(s) may be used for screening assessments rather than repeating such 
tests unless otherwise indicated.  
b. The EOT Visit is conducted ≤ 7 days after the investigator determines that the patient must permanently discontinue BGB-10188.  If routine laboratory tests 
(eg, hematology, clinical chemistry, coagulation, and urinalysis) were completed ≤ 7 days before the EOT Visit, these tests do not need to be repeated.  A 
tumor assessment is not required at the EOT Visit if < 6 weeks have passed since the last assessment.  If the EOT Visit did not occur until 30 days (± 7 days) 
or later after the last dose of study drug, the EOT Visit may also be used as the Safety Follow-up Visit.  If EOT visit and safety follow-up visit are combined 
then site should ensure that all assessments for both visits are done as some assessments are not common between the visits. 
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c. Patients who permanently discontinue BGB-10188 will be asked to return to the clinic for the Safety Follow-up Visit, which is required to be conducted 
30 days (± 7 days) after the last dose of BGB-10188 (whichever is the latest), unless otherwise specified or before the initiation of subsequent anticancer 
therapy, whichever occurs first.  The Safety Follow-up Visit may coincide with the EOT Visit but cannot occur before the EOT Visit.  
Telephone contacts with patients should be conducted to assess imAEs and concomitant medications (if appropriate, ie, associated with an imAE or is a 
subsequent anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of study drug or the initiation of a subsequent anticancer therapy, whichever 
occurs earlier.  If patients report a suspected imAE at a telephone follow-up contact, the investigator should arrange an unscheduled visit if further assessment 
is indicated.   
d. Includes age or year of birth, gender, and self-reported race/ethnicity. 
e. Height assessment is required only at screening.  Vital signs include measurements of temperature (°C), pulse rate, and blood pressure (systolic and diastolic) 
while the patient is in a seated position after resting for 10 minutes.  If coinciding with study drug infusions, the patient’s vital signs are required to be 
recorded within 60 minutes before, during, and 30 minutes after the first infusion of study drug(s).  For subsequent infusions, vital signs will be collected 
within 60 minutes before infusion of each study drug(s), and if clinically indicated, during and 30 minutes after each study drug(s) infusion.  Weight will be 
assessed at screening and at every visit.  
f. Complete physical examination is required at screening while subsequent visits entail limited, symptom-directed physical examinations (as detailed in 
Section 7.5.1).  In addition, investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled 
study visit during study treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
g. The triplicate ECG recordings will be performed at the timepoints specified in the table and when clinically indicated.  All ECGs are to be obtained prior to 
other assessments scheduled at that same time.  If this is not possible, then ECGs are to be obtained ≥ 20 minutes following the last procedure performed.  
The patient should rest in supine position for ≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate (eg, television, 
radio, conversation, etc) before each ECG collection. 
h. Eye examination, visual acuity test, and optical coherence tomography (OCT; or equivalent diagnostic test for retinal examination) captured as standard of 
care prior to obtaining written informed consent and within 28 days of first dose of study drug may be used rather than repeating tests.  Eye examination, 
including visual acuity test and optical coherence tomography (or equivalent diagnostic test), will be assessed by an appropriate specialist at the Screening 
Visit.  Patients treated with tislelizumab will undergo repeat assessments approximately every 15 weeks (± 7 days).  
i. The AEs and laboratory abnormalities will be graded per NCI-CTCAE Version 5.0.  All AEs will also be evaluated for seriousness.  After the informed 
consent form has been signed, but before the administration of study drug(s), only SAEs should be reported to the sponsor.  After initiation of study drug(s), 
all AEs and SAEs, regardless of relationship to study drug(s), will be reported until either 30 days after last dose of study drug(s) or the initiation of 
subsequent anticancer therapy, whichever occurs first.  imAEs (serious or nonserious) should be reported until 90 days after the last dose of study drug or 
initiation of a subsequent anticancer therapy, whichever occurs earlier.  
j. Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Section 7.5.4.  If clinical 
chemistry, hematology, and coagulation at screening are not performed within 72 hours before the first study drug administration, these tests should be 
repeated and reviewed before study drug administration.  After Day 1 of Cycle 1, results are to be performed and reviewed within 48 hours before study drug 
administration.  Hematology and clinical chemistry will be performed weekly for the first 2 cycles and then on Day 1 only of each subsequent cycle.  
Coagulation test will be conducted on Day 1 of the first 2 cycles and as clinically indicated at subsequent cycles.  Urinalysis test will be conducted on Day 1 
of every cycle.  If the urine protein ≥ 2+ in urinalysis or per clinical discretion, collect 24-hour urine sample.  Refer to Section 7.5.4 for additional information 
regarding clinical assessment and management of clinical laboratory abnormalities. 
k. CK and CK-MB levels will be evaluated at the timepoints specified within the table and when clinically indicated.  If CK-MB fractionation is not available, 
troponin I and/or troponin T should be tested instead. 
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l. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
≤ 14 days before the first dose of study drug(s).  A negative urine pregnancy test must be completed and recorded ≤ 72 hours before the administration of 
study drug(s) at each cycle.  On Cycle 1 Day 8, a negative urine pregnancy test also must be completed and recorded ≤ 72 hours before the administration of 
tislelizumab.  A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
m. Analysis of free T3, free T4, and thyroid stimulating hormone will be performed by a central laboratory and/or the local study site laboratory. 
n. Hepatitis B serology includes HbsAg and HbcAb.  Patients negative for HBV antibody do not need HBV DNA test by PCR at screening.  Patients who are 
HbsAg negative, HbcAb positive and HBV DNA negative will undergo viral load measurement (HBV DNA by PCR) monthly.  If a patient is being treated 
prophylactically with antivirals, HBV DNA screening by PCR must be done at least every 90 days.  Hepatitis C serology includes HCV antibody.  Patients 
negative for HCV antibody do not need HCV RNA test by PCR at screening.  Patients who are HCV antibody positive, but negative for HCV RNA, will 
undergo viral load testing (HCV RNA by PCR) monthly.  Hepatitis B and hepatitis C testing must be conducted in a laboratory able to perform the tests to the 
required sensitivity (< 20 IU/mL and <15 IU/mL for hepatitis B and C, respectively). If sites cannot conduct the tests with this sensitivity or the results are not 
reported with values, then any positive viral load result should lead to withholding of study treatment and initiation of antiviral treatment.  The medical 
monitor should be informed of any suspected hepatitis B or hepatitis C reactivation. 
o. The pulmonary function tests including the measurements of FEV1, FVC, DLCO or TLCO, and so on, will be performed ≤ 4 weeks before the first dose of 
study drug(s).   
p. Cycle 3 Day 8 visit may be a telephone visit.  The investigator should arrange an unscheduled visit if further assessment is indicated.  
q. Tumor imaging will be performed ≤ 28 days before the first dose of study drug(s).  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drug(s) may be used for the purposes of screening rather than repeating the 
standard-of-care tests.  During the study, tumor imaging will be performed, based on RECIST Version 1.1, at screening and Week 10 then every 9 weeks 
(±7 days) thereafter until loss of clinical benefit, use of alternative anticancer therapy, withdrawal of consent, death, lost to follow-up, or end of study, 
whichever occurs first.  Tumor assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI, with preference for CT, of 
the chest, abdomen, and pelvis.  All measurable and evaluable lesions should be assessed and documented at the Screening Visit and reassessed at each 
subsequent tumor evaluation.  The same radiographic procedure used to assess disease sites at screening must be used throughout the study (eg, the same 
contrast protocol for CT scans). 
r. Archival or fresh tumor tissue: A fresh tumor biopsy collected at screening is strongly recommended for analysis of biomarkers potentially associated with 
clinical responses.  If a fresh tumor biopsy is not available, an archival tissue sample (either an FFPE block with tumor tissue [preferred] or 10 to 15 unstained 
slides) is required. It is recommended that the archival tissue sample is collected within 2 years before screening.  Baseline tissue samples collected during 
screening will be shipped to a central laboratory for biomarker testing after local regulatory approval.  This may occur after the start of study treatment if 
necessary.  An optional biopsy after approximately 3 to 5 weeks of treatment is also strongly recommended for biomarker analysis.  Optional biopsies will 
also be taken at accessible tumor sites from the patients who have confirmed disease progression during the study for mechanisms of resistance.  If feasible, 
any follow-up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
s. BGB-10188 will be administered orally daily at the dose designated by predefined dose levels during the 28-day cycle of Cycle 1 and then each 21-day cycle 
of Cycle 2 and beyond.  Patients will receive study drug until they are no longer considered to be achieving clinical benefit, unacceptable toxicity, or 
withdrawal of informed consent. 
t. Tislelizumab will be given intravenously on Day 8 of Cycle 1 and Day 1 of each subsequent 21-day cycle (once every 3 weeks) (see Section 5.2.3 for details).  
Note: Tislelizumab must not be concurrently infused with any other drug.  Tislelizumab should be infused ≥ 30 minutes after BGB-10188 administration.  
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APPENDIX 4. PART E SCHEDULE OF ASSESSMENTS  
 
Screening a 
Treatment Period 
EOT 
Visit b 
Safety Follow-up c 
Survival Follow-up d 
(Every 3 Months) 
± 14 Days 
Cycle 1 and Cycle 2 
(21 Days) 
Cycle 3 and 
Beyond 
(21 days) 
Visit Day 
-28 to -1 
1 
8 
15 
1 
0 to 
7 Days 
+ 30 
Days 
(Visit) 
+ 60 
Days 
(Phone 
Call) 
+ 90 
Days 
(Phone 
Call) 
Visit Window 
 
± 3 
(C2D1 
Only) 
± 3 
± 3 
± 3 
 
± 7 
± 14 
± 14 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
Demographics/medical historye 
x 
 
 
 
 
 
 
 
 
 
Vital signs/height/weightf 
x 
x 
 
 
x 
x 
x 
 
 
 
Physical examinationg 
x 
x 
 
 
x 
x 
x 
 
 
 
ECOG Performance Status 
x 
x 
 
 
x 
x 
x 
 
 
 
12-lead triplicate ECGh 
x 
 
 
 
 
 
 
 
 
 
Adverse eventsi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Prior and concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Prior and concomitant procedures 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Hematologyj 
x 
x 
x 
x 
x 
xb 
x 
 
 
 
Clinical chemistryj 
x 
x 
x 
x 
x 
xb 
x 
 
 
 
Coagulation parametersj 
x 
x 
 
 
As 
clinically 
indicated 
xb 
x 
 
 
 
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Screening a 
Treatment Period 
EOT 
Visit b 
Safety Follow-up c 
Survival Follow-up d 
(Every 3 Months) 
± 14 Days 
Cycle 1 and Cycle 2 
(21 Days) 
Cycle 3 and 
Beyond 
(21 days) 
Visit Day 
-28 to -1 
1 
8 
15 
1 
0 to 
7 Days 
+ 30 
Days 
(Visit) 
+ 60 
Days 
(Phone 
Call) 
+ 90 
Days 
(Phone 
Call) 
Visit Window 
 
± 3 
(C2D1 
Only) 
± 3 
± 3 
± 3 
 
± 7 
± 14 
± 14 
 
Urinalysisj 
x 
x 
 
 
As 
clinically 
indicated 
xb 
x 
 
 
 
CK and CK-MBk 
x 
x 
x 
x 
xl 
xb 
x 
 
 
 
Pregnancy testl 
x 
x 
 
 
x 
x 
x 
 
 
 
Thyroid functionm 
x 
x 
(C2D1 
only) 
 
 
Every even 
cycle 
 
x 
 
 
 
Cytomegalovirus monitoring 
x 
x 
 
 
x 
 
x 
 
 
 
HBV/HCV testsn 
x 
 
 
 
 
 
 
 
 
 
Pulmonary function testso 
As clinically indicated 
 
 
 
 
Biomarkers blood 
x 
At C2D1, time of first response, and at time of 
confirmed disease progression 
 
 
 
 
Pharmacokinetics/ 
pharmacodynamics 
blood sampling 
 
See Appendix 5 
 
 
 
 
 
Tumor assessmentp 
x 
Week 9 and every 9 weeks (± 7 days) 
thereafter 
xb 
 
 
 
 
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Screening a 
Treatment Period 
EOT 
Visit b 
Safety Follow-up c 
Survival Follow-up d 
(Every 3 Months) 
± 14 Days 
Cycle 1 and Cycle 2 
(21 Days) 
Cycle 3 and 
Beyond 
(21 days) 
Visit Day 
-28 to -1 
1 
8 
15 
1 
0 to 
7 Days 
+ 30 
Days 
(Visit) 
+ 60 
Days 
(Phone 
Call) 
+ 90 
Days 
(Phone 
Call) 
Visit Window 
 
± 3 
(C2D1 
Only) 
± 3 
± 3 
± 3 
 
± 7 
± 14 
± 14 
 
CA-125q 
x 
(-14 to -1) 
Week 9 and every 9 weeks (± 7 days) 
thereafter 
xb 
 
 
 
 
Archival or fresh tumor tissuer 
x 
After about 3 to 5 weeks of treatment and at time 
of confirmed disease progression 
 
 
 
 
BGB-10188 administrations 
 
Daily 
 
 
 
 
 
Tislelizumab administrationt 
 
x 
 
 
x 
 
 
 
 
 
Anti-tislelizumab antibodies  
 
See Appendix 6 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
x 
Abbreviations: AE, adverse event; CA-125, carcinoma antigen-125; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CT, computed 
tomography; DLCO, carbon monoxide diffusion capacity; EOT, End of Treatment (Visit); FEV1, forced expiratory volume in 1 second; FVC, forced vital 
capacity; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C 
virus; imAE, immune-mediated adverse event; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; SAE, serious adverse 
event; T3, triiodothyronine; T4, thyroxine; TLCO, transfer factor for carbon monoxide of lung. 
a. Written informed consent is required before performing any study-specific procedure.  Results of standard-of-care tests or examinations performed before 
informed consent which have been obtained ≤ 28 days before the first dose of study drug(s) may be used for screening assessments rather than repeating such 
tests unless otherwise indicated.  
b. The EOT Visit is conducted ≤ 7 days after the investigator determines that the patient must permanently discontinue BGB-10188 and tislelizumab.  If routine 
laboratory tests (eg, hematology, clinical chemistry, coagulation, and urinalysis) were completed ≤ 7 days before the EOT Visit, these tests do not need to be 
repeated.  A tumor assessment (including CA-125 tumor assessment) is not required at the EOT Visit if < 6 weeks have passed since the last assessment.  
Patients who discontinue study treatment before disease progression will need to undergo tumor assessments as outlined in Section 7.6.  If the EOT Visit did 
not occur until 30 days (± 7 days) or later after the last dose of study drug, the EOT Visit may also be used as the Safety Follow-up Visit.  If EOT visit and 
safety follow-up visit are combined then site should ensure that all assessments for both visits are done as some assessments are not common between the 
visits. 
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c. Patients who permanently discontinue BGB-10188 will be asked to return to the clinic for the Safety Follow-up Visit, which is required to be conducted 
30 days (± 7 days) after the last dose of BGB-10188 or tislelizumab (whichever is later) unless otherwise specified or before the initiation of subsequent 
anticancer therapy, whichever occurs first.  The Safety Follow-up Visit may coincide with the EOT Visit but cannot occur before the EOT Visit.  Telephone 
contacts with patients should be conducted to assess imAEs and concomitant medications (if appropriate, ie, associated with an imAE or is a subsequent 
anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of study drug or the initiation of a subsequent anticancer therapy, whichever occurs 
earlier. If patients report a suspected imAE at a telephone follow-up contact, the investigator should arrange an unscheduled visit if further assessment is 
indicated.  
d. Survival follow-up information will be collected via telephone calls, email or other communication; patient medical records; and/or clinic visits 
approximately every 3 months after the EOT/Safety Follow-up Visit or directed by the sponsor until death, loss to follow-up, withdrawal of consent, or study 
termination by sponsor.  Only new anticancer treatment will be collected at Survival Follow-up Visits.   
e. Includes age or year of birth, gender, and self-reported race/ethnicity. History of treatment for the primary diagnosis, including prior medication, loco-
regional treatment(s), and surgical treatment(s).  Pre-existing AEs at baseline should be recorded as medical history. 
f. Height assessment is required only at screening.  Vital signs include measurements of temperature (°C), pulse rate, and blood pressure (systolic and diastolic) 
while the patient is in a seated position after resting for 10 minutes.  If coinciding with study drug infusions, the patient’s vital signs are required to be 
recorded within 60 minutes before, during, and 30 minutes after the first infusion of study drug(s).  For subsequent infusions, vital signs will be collected 
within 60 minutes before infusion of each study drug(s), and if clinically indicated, during and 30 minutes after each study drug(s) infusion.  Weight will be 
assessed at screening and at every visit. 
g. Complete physical examination is required at screening while subsequent visits entail limited, symptom-directed physical examinations (as detailed in 
Section 7.5.1).  In addition, investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled 
study visit during study treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance. 
h. The triplicate ECG recordings will be performed at the timepoints specified in the table and when clinically indicated.  All ECGs are to be obtained prior to 
other assessments scheduled at that same time.  If this is not possible, then ECGs are to be obtained ≥ 20 minutes following the last procedure performed.  
The patient should rest in supine position for ≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate (eg, television, 
radio, conversation, etc) before each ECG collection. 
i. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0.  All AEs will also be evaluated for seriousness.  After the informed consent form 
has been signed, but before the administration of study drug(s), only SAEs should be reported to the sponsor.  After initiation of study drug(s), all AEs and 
SAEs, regardless of relationship to study drug(s), will be reported until either 30 days after last dose of study drug(s) or the initiation of subsequent anticancer 
therapy, whichever occurs first.  imAEs (serious or nonserious) should be reported until 90 days after the last dose of study drug or initiation of a subsequent 
anticancer therapy, whichever occurs earlier. 
j. Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Section 7.5.4.  If clinical 
chemistry, hematology, and coagulation at Screening are not performed within 72 hours before the first study drug administration, these tests should be 
repeated and reviewed before study drug administration.  After Day 1 of Cycle 1, results are to be performed and reviewed within 48 hours before study drug 
administration.  Hematology and clinical chemistry will be performed weekly for the first 2 cycles and then on Day 1 only of each subsequent cycle.  
Coagulation test will be conducted on Day 1 of the first 2 cycles and as clinically indicated at subsequent cycles.  Urinalysis test will be conducted on Day 1 
of every cycle.  If the urine protein ≥ 2+ in urinalysis or per clinical discretion, collect 24-hour urine sample. Refer to Section 7.5.4 for additional information 
regarding clinical assessment and management of clinical laboratory abnormalities. 
k. CK and CK-MB levels will be evaluated at the timepoints specified within the table and when clinically indicated.  If CK-MB fractionation is not available, 
troponin I and/or troponin T should be tested instead. 
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10 April 2024 
 
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l. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
≤ 14 days before the first dose of study drug(s).  A negative urine pregnancy test must be completed and recorded ≤ 72 hours before the administration of 
study drug(s) at each cycle.  A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
m. Analysis of free T3, free T4, and thyroid stimulating hormone will be performed by a central laboratory and/or the local study site laboratory. 
n. Testing at screening will consist of HBsAg, HBsAb, HBcAb, and HCV antibody.  Patients negative for HBV antibody do not need HBV DNA test by PCR at 
screening.  Patients who are HBsAg negative, HBcAb positive and HBV DNA negative will undergo viral load measurement (HBV DNA by PCR) monthly.  
If a patient is being treated prophylactically with antivirals, HBV DNA screening by PCR must be done at least every 90 days.  Patients negative for HCV 
antibody do not need HCV RNA test by PCR at screening.  Patients who are HCV antibody positive, but negative for HCV RNA, will undergo viral load 
testing (HCV RNA by PCR) monthly.  The medical monitor should be informed of any suspected hepatitis B or hepatitis C reactivation.   
o. Patients suspected or known to have serious/severe respiratory conditions or who exhibit significant respiratory symptoms unrelated to the underlying cancer 
or who have a history of thoracic radiotherapy will undergo pulmonary function testing during screening or whenever clinically indicated. The pulmonary 
function tests including the measurements of FEV1, FVC, DLCO or TLCO, and so on, will be performed ≤ 4 weeks before the first dose of study drug(s).   
p. Tumor imaging will be performed ≤ 28 days before the first dose of study drug(s).  Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drug(s) may be used for the purposes of screening rather than repeating the 
standard-of-care tests.  During the study, tumor imaging will be performed, based on RECIST Version 1.1, at screening, Week 9, and then every 9 weeks 
(±7 days) thereafter until loss of clinical benefit, use of alternative anticancer therapy, withdrawal of consent, death, lost to follow-up, or end of study, 
whichever occurs first.  Tumor assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI, with preference for CT, of 
the chest, abdomen, and pelvis.  All measurable and evaluable lesions should be assessed and documented at the Screening Visit and reassessed at each 
subsequent tumor evaluation.  The same radiographic procedure used to assess disease sites at screening must be used throughout the study (eg, the same 
contrast protocol for CT scans). 
q. Patients will have CA-125 tested in local laboratory within 14 days before the first dose of study drug, at Week 9, and then every 9 weeks (±7 days) thereafter 
until loss of clinical benefit, use of alternative anticancer therapy, withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first.  
Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the upper limit of the reference range and within 2 
weeks before starting the treatment. When there is initial CA-125 response, it is suggested to confirm the response after 28 days (+7 days) after the initial 
response. 
r. Archival or fresh tumor tissue: A fresh tumor biopsy collected at screening is strongly recommended for analysis of biomarkers potentially associated with 
clinical responses.  If a fresh tumor biopsy is not available, an archival tissue sample (either an FFPE block with tumor tissue [preferred] or 10 to 15 unstained 
slides) is required.  It is recommended that the archival tissue sample is collected within 2 years before screening. Baseline tissue samples collected during 
screening will be shipped to a central laboratory for biomarker testing after local regulatory approval.  This may occur after the start of study treatment if 
necessary.  An optional biopsy after approximately 3 to 5 weeks of treatment is also strongly recommended for biomarker analysis.  Optional biopsies will 
also be taken at accessible tumor sites from the patients who have confirmed disease progression during the study for mechanisms of resistance.  If feasible, 
any follow-up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy.  
s. BGB-10188 will be administered orally daily at the dose designated by predefined dose levels. 
t. Tislelizumab will be given intravenously on Day 1 of each 21-day cycle (once every 3 weeks) (see Section 5.2.3 for details).  Note: Tislelizumab must not be 
concurrently infused with any other drug.  Tislelizumab should be infused ≥ 30 minutes after BGB-10188 administration.  
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APPENDIX 5. SCHEDULE OF PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS  
Part A 
BGB-10188 Monotherapy Dose Escalation  
Time 
PK Washout (D-7 to D1) a and C1D15 
Sample 
Predose 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
12 b h 
24 d h 
48 h 
72 h 
168 h 
 
Window Allowed 
-30 min 
±10 
min 
±10 
min 
±10 
min 
±15 
min 
±15 
min 
±20 
min 
±30 
min 
±1 h 
±1 h 
±1 h 
±1 h 
±1 h 
All  
Patients 
BGB-10188 - PK 
(PK washout) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BGB-10188 - PK 
(C1D15) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Mealtime 
Collect the mealtime within 6 hours postdose 
 
 
 
 
 
 
BGB-10188 
pharmacodynamic 
(PK washout and 
C1D15) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
ECG c 
Triplicate per point 
(PK washout and 
C1D15) 
X 
(within - 
30 min) 
 
 
X 
(within 
- 30 
min) 
 
X 
(within 
- 30 
min) 
 
 
 
 
 
 
 
Abbreviation: PK, pharmacokinetics. 
Notes: The triplicate ECGs for each patient should be obtained from the same machine whenever possible.  
It is important that PK and pharmacodynamic sampling occurs as close as possible to the scheduled time.  To achieve this, other assessments at the same time can 
be advanced or delayed so that there is sufficient time to complete the blood sampling.  Thus, the sequence at a particular timepoint is as follows: 1) scheduled 
ECG; 2) vital sign measurements; 3) PK/pharmacodynamic blood samples (to be performed at the precise protocol scheduled time); and 4) any other scheduled 
or unscheduled measurements at that timepoint. 
a. Applies to all dose levels. 
b. Sampling at 12 hours is optional. 
c. ECG tests at 2 hours and 4 hours should be paired with related PK sampling. 
d. 24-hour samples should be collected prior to next dosing. 
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Part B 
BGB-10188 + Zanubrutinib Dose Escalation  
Time 
C1D1 and C1D15 
Sample 
Predose 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
12 a h 
24 b h 
 
Window Allowed 
-30 min 
±10 min 
±10 min 
±10 min 
±15 min 
±15 min 
±20 min 
±30 min 
±1 h 
±1 h 
All  
Patients 
BGB-10188--PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BGB-10188--
pharmacodynamic 
X 
 
 
X 
 
 
 
 
 
 
Zanubrutinib--PK  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviation: PK, pharmacokinetics. 
It is important that PK and pharmacodynamic sampling occurs as close as possible to the scheduled time.  To achieve this, other assessments at the same time can 
be advanced or delayed so that there is sufficient time to complete the blood sampling. 
a. Sampling at 12 hours is optional. 
b. 24-hour samples should be collected prior to next dosing. 
 
Part C 
BGB-10188 + Zanubrutinib Dose Expansion  
Time 
C1D1 and C2D1 
Day 1 of Cycles 5, 7, 
10, and 13 
Sample 
Predose 
0.5 h 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
12 a h 
24 b h 
Predose 
2 h 
 
Window Allowed 
-30 min 
±10 
min 
±10 
min 
±10 
min 
±15 
min 
±15 
min 
±20 
min 
±30 
min 
±1 h 
±1 h 
-30 min 
±10 min 
First Patients  
in Each 
Cohort 
BGB-10188 - PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BGB-10188 - 
pharmacodynamic 
X 
 
 
X 
 
 
 
 
 
 
 
 
Zanubrutinib - PK 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Remaining  
Patients 
BGB-10188 - PK 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Abbreviation: PK, pharmacokinetics. 
It is important that PK and pharmacodynamic sampling occurs as close as possible to the scheduled time.  To achieve this, other assessments at the same time can 
be advanced or delayed so that there is sufficient time to complete the blood sampling. 
a. Sampling at 12 hours is optional. 
b. 24-hour samples should be collected prior to next dosing. 
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Part D 
BGB-10188 + Tislelizumab Dose Escalation  
Time 
C1D1 and C2D1 
Sample 
Predose 
0.5 h 
1 h 
2 h 
4 h 
6 h 
8 h 
12 a h 
24 b h 
 
Window Allowed 
-30 min 
±10 min 
±10 min 
±10 min 
±15 min 
±20 min 
±30 min 
±1 h 
±1 h 
All  
patients 
BGB-10188 - PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BGB-10188 - 
pharmacodynamic 
X 
 
 
X 
 
 
 
 
 
Mealtime 
Collect the mealtime within 6 hours after dosing 
 
 
 
Abbreviation: PK, pharmacokinetics. 
It is important that PK and pharmacodynamic sampling occurs as close as possible to the scheduled time.  To achieve this, other assessments at the same can be 
advanced or delayed so that there is sufficient time to complete the blood sampling. 
a. Sampling at 12 hours is optional. 
b. 24-hour sample should be collected prior to next dosing.  
Part E 
BGB-10188 + Tislelizumab Dose Expansion  
Time 
C1D1 and C2D1 
Day 1 of 
Cycles 5 
and 9 
Sample 
Predose 
0.5 h 
1 h 
2 h 
4 h 
4 to 6 h 
6 h 
8 h 
24 a h 
Predose 
 
Window Allowed 
-30 min 
±10 min 
±10 min 
±10 min 
±15 min 
 
±20 min 
±30 min 
±1 h 
-30 min 
Approximately 
5 Patients 
 
BGB-10188 - PK 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
BGB-10188 - 
pharmacodynamic 
X 
 
 
X 
 
 
 
 
 
 
Remaining 
Patients 
BGB-10188 - PK 
X 
 
 
X 
 
X 
 
 
 
X 
Abbreviation: PK, pharmacokinetics. 
It is important that PK and pharmacodynamic sampling occurs as close as possible to the scheduled time.  To achieve this, other assessments at the same time can 
be advanced or delayed so that there is sufficient time to complete the blood sampling. 
a. 24-hour sample should be collected prior to next dosing.  
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APPENDIX 6. PART D AND PART E SCHEDULE OF PK/ADA ASSESSMENTS  
Part D 
BGB-10188 + Tislelizumab Dose Escalation  
Time 
Cycle 1 Day 8 
Cycle 2 
Day 1 
Cycle 5 Day 1 
Cycle 9 
Day 1 
Cycle 17 
Day 1 
EOT/Safety 
Follow-up Visit 
 
Pre-
infusion 
0 h Post-
infusion 
Pre-
infusion 
Pre-
infusion 
0 h Post-
infusion 
Pre-
infusion 
Pre-
infusion 
 
Window Allowed 
-1 h 
+30 min 
-1 h 
-1 h 
+30 min 
-1 h 
-1 h 
 
Tislelizumab - PK Serum 
Sample a 
X 
X 
X 
X 
X 
X 
X 
X 
Tislelizumab - ADA Serum 
Sample b 
X 
 
X 
X 
 
X 
X 
X 
Abbreviations: ADA, antidrug antibody; EOT, end of treatment; IEC, Independent Ethics Committee; IRB, Institutional Review Board; PK, pharmacokinetics. 
a. Should a patient taking tislelizumab present with any Grade 3 or above immune-mediated adverse event, an additional blood PK samples may be taken to 
determine the serum concentration of tislelizumab.  These tests are required when it is allowed by local regulations/IRBs/IECs. 
b. All samples should be drawn at the same time as blood collection for predose PK samples.  These tests are required when it is allowed by local 
regulations/IRBs/IECs.  
Part E 
BGB-10188 + Tislelizumab Dose Expansion  
Time 
Cycle 1 Day 1 
Cycle 2 
Day 1 
Cycle 5 Day 1 
Cycle 9 
Day 1 
Cycle 17 
Day 1 
EOT/Safety 
Follow-up Visit 
 
Pre-
infusion 
0 h Post-
infusion 
Pre-
infusion 
Pre-
infusion 
0 h Post-
infusion 
Pre-
infusion 
Pre-
infusion 
 
Window Allowed 
-1 h 
+30 min 
-1 h 
-1 h 
+30 min 
-1 h 
-1 h 
 
Tislelizumab - PK Serum 
Sample a 
X 
X 
X 
X 
X 
X 
X 
X 
Tislelizumab - ADA Serum 
Sample b 
X 
 
X 
X 
 
X 
X 
X 
Abbreviations: ADA, antidrug antibody; EOT, end of treatment; IEC, Independent Ethics Committee; IRB, Institutional Review Board; PK, pharmacokinetics. 
a. Should a patient taking tislelizumab present with any Grade 3 or above immune-mediated adverse event, an additional blood PK samples may be taken to 
determine the serum concentration of tislelizumab.  These tests are required when it is allowed by local regulations/IRBs/IECs. 
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b. All samples should be drawn at the same time as blood collection for predose PK samples.  These tests are required when it is allowed by local 
regulations/IRBs/IECs. 
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APPENDIX 7. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” 
“NO CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control 
(Clinical Trials Facilitation Group 2014).  These methods include the following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with the inhibition of ovulation 
o Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
o Oral, injectable, implantable 
o Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
o Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has 
been a medical assessment confirming surgical success 
o A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment).  NOTE: Total sexual 
abstinence should only be used as a contraceptive method if it is in line with the 
patients’ usual and preferred lifestyle.  Periodic abstinence (eg, calendar, ovulation, 
sympto-thermal, post-ovulation methods), declaration of abstinence for the duration 
of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
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Definitions of “Women of Childbearing Potential” and “Women of No Childbearing Potential” 
In this protocol, “women of childbearing potential” are defined as 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: 
o ≥ 55 years of age with no spontaneous menses for ≥ 12 months, OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If an follicle-stimulating hormone measurement is required to confirm postmenopausal state, 
concomitant use of hormonal contraception or hormonal replacement therapy should be 
excluded. 
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APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure 
at rest.  If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin 1994. 
Original source: Criteria Committee, New York Heart Association, Inc.  Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
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APPENDIX 9. INFUSION-RELATED REACTIONS, 
HYPERSENSITIVITY REACTIONS AND IMMUNE-
MEDIATED ADVERSE EVENTS: EVALUATION AND 
MANAGEMENT  
Management of Infusion-Related Reactions and Hypersensitivity Reactions 
Management and treatment modifications for symptoms of infusion-related reactions associated 
with study drug(s) administration are provided in the table below. 
If a hypersensitivity reaction occurs, the patient must be managed according to the best available 
medical practice, as described in the guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) (Soar et al 
2008).  Patients should be instructed to report any delayed reactions to the investigator 
immediately. 
Treatment Modifications for Symptoms of Infusion-Related or Hypersensitivity Reactions 
Associated with Study Drug(s) Administration 
NCI-CTCAE Grade 
Treatment Modification for Study Drug(s) 
Grade 1 - Mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Closely monitor 
for worsening signs or symptoms.  Medical 
management as needed. 
Subsequent infusions should be given after 
appropriate premedication and at the reduced 
infusion rate. 
Grade 2 - Moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, corticosteroids, and/or intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion.  Infusion may be resumed at 50% 
of previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity.  
Closely monitor for worsening signs or 
symptoms.  Appropriate 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 
observation or clinical management. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – Life-Threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviation: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. 
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If the infusion rate of study drug(s) has been decreased by 50% or suspended due to an 
infusion-related reaction, this decreased rate must be maintained for all subsequent infusions and 
be administered 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. 
For the prophylaxis of mild events (eg, nasal congestion or flu-like symptoms), a dose of 25 mg 
indomethacin or a comparable dose of nonsteroidal anti-inflammatory drugs (eg, 600 mg 
ibuprofen or 500 mg naproxen sodium) may be administered 2 hours before and 8 hours after the 
start of each dose of study drugs(s) infusion.  Alternative treatments for fever (eg, paracetamol) 
may be given to patients at the discretion of the investigator. 
National Cancer Institute Common Terminology Criteria for Adverse Events (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), an antipyretic (eg, paracetamol), and if considered indicated, oral or 
intravenous glucocorticoids, epinephrine, bronchodilators, and oxygen.  In subsequent cycles, the 
patient should receive oral premedication with an antihistamine (eg, diphenhydramine) and an 
antipyretic (eg, paracetamol), and should be closely monitored for clinical signs and symptoms 
of an infusion reaction. 
NCI-CTCAE Grade 3 or 4 Infusion Reaction: Proper medical management should be 
instituted immediately, as indicated per type and severity of the reaction.  This includes, but is 
not limited to, oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, 
bronchodilators, and oxygen. 
In the event of a systemic anaphylactic/anaphylactoid reaction the infusion must be stopped 
immediately, and the patient discontinued from study treatment.  Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes following administration 
of the drug/antigen and are characterized by respiratory distress; laryngeal edema; and/or intense 
bronchospasm; and often followed by vascular collapse or shock without antecedent respiratory 
difficulty; cutaneous manifestations such as pruritus and urticaria (with or without edema); and 
gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea. 
The patient will be administered epinephrine injection and dexamethasone infusion if severe 
hypersensitivity reaction is observed.  The patient should be closely monitored, and intensive 
care unit should be alerted for possible transfer as indicated. 
Evaluation of Immune-Mediated Adverse Events 
The recommendations below for the diagnosis and management of any immune-mediated 
adverse events are intended as guidance.  This document should be used in conjunction with 
expert clinical judgment (by specialist physicians experienced in the treatment of cancer using 
immunological agents), and individual institutional guidelines or policies. 
The recommendations for diagnostic evaluation and management of immune-mediated adverse 
events are based on European Society for Medical Oncology and American Society of Clinical 
Oncology guidelines (Haanen et al 2017, Brahmer et al 2018).  For any adverse events not 
included in the tables below, refer to the American Society of Clinical Oncology Clinical 
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Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation and 
management of immune-mediated toxicities. 
Criteria used to diagnose immune-mediated adverse events 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 immune-
mediated adverse event diagnosis: 
• What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
• How did the patient respond to withdrawal 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 immune-
mediated adverse event field associated with the adverse event in the electronic case report form 
should be checked.  If further diagnostic evaluations change the assessment, the electronic case 
report form should be updated accordingly. 
Recommended Diagnostic Tests in the Management of 
Possible Immune-Mediated Adverse Events 
Immune-Mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  
Perform pituitary and whole-brain MRI in patients with headache, visual 
disturbance, unexplained fatigue, asthenia, weight loss, and unexplained 
constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is 
detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or 
signs, such as an upper respiratory infection, new cough, shortness of 
breath, or hypoxia should be assessed by high-resolution CT.  Consider 
pulmonary function test including DLCO.  
Radiographic appearance is often nonspecific.  Depending on the location 
of the abnormality, bronchoscopy, and bronchoalveolar lavage or lung 
biopsy may be considered.  Consult with a respiratory medicine physician 
for cases of uncertain cause.  
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all 
CNS symptoms; review alcohol history and other medications.  Conduct a 
diabetic screen, and assess blood B12/folate, HIV status, TFTs, and 
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Recommended Diagnostic Tests in the Management of 
Possible Immune-Mediated Adverse Events 
Immune-Mediated 
Toxicity 
Diagnostic Evaluation Guideline 
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 Grades 3 and 4; every 2 to 3 days if 
Grade 2, until recovering).  Review medications (eg, statins, antibiotics) 
and alcohol history.  Perform liver screen including Hepatitis A/B/C 
serology, Hepatitis E PCR and assess anti-ANA/SMA/LKM/SLA/LP/LCI, 
iron studies.  Consider imaging, eg, ultrasound scan for metastases or 
thromboembolism.  Consult with a hepatologist and consider liver biopsy.  
Renal Toxicity 
Review hydration status and medication history.  Test and culture urine.  
Consider renal ultrasound scan, protein assessment (dipstick/24-hour urine 
collection), or phase-contrast microscopy.  Refer to nephrology for further 
management assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider 
dermatology referral for skin biopsy. 
Joint or Muscle 
Inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to 
exclude metastatic disease.  Perform autoimmune serology and refer to 
rheumatology for further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, 
CRP, troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, carbon monoxide diffusion capacity; ESR, 
erythrocyte sedimentation rate; FBC, full blood count; INR, international normalized ratio; LCI, liver cytosolic 
antigen; LFT, liver function test; LKM, liver kidney microsomal antibody; LP, liver pancreas antigen; MRA, 
magnetic resonance angiogram; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, thyroxine; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; UEC, urea, electrolytes, and creatinine. 
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Management of Immune-Mediated Adverse Events 
Immune-mediated adverse events can escalate quickly.  Study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention as appropriate is required.  
Immune-mediated adverse events should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further specialist 
advice, and contact the study medical monitor. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade after restart of study drug should permanently discontinue 
treatment. 
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be considered 
if there is evidence of a clinical response to study treatment, after consultation with the study 
medical monitor.  For France only: Tislelizumab must be permanently discontinued for any onset 
of Grade 4 or recurrent Grade 3 immune-mediated adverse events. 
Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  Equivalent 
dosages of other corticosteroids can be substituted.  For steroid-refractory immune-mediated 
adverse events, consider use of steroid-sparing agents (eg, mycophenolate mofetil).  Consider 
prophylactic antibiotics for opportunistic infections if the patient is receiving long-term 
immunosuppressive therapy. 
Management of Immune-Mediated Adverse Events 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Thyroid Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if 
hypothyroid, until TSH/T4 
levels return to normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  
In cases with systemic 
symptoms: withhold study 
treatment, treat with a beta 
blocker and consider oral 
prednisolone 0.5 mg/kg/day 
for thyroid pain.  Taper 
corticosteroids over 2 to 
4 weeks.  Monitor thyroid 
function regarding the need 
for hormone replacement. 
Continue study 
treatment or 
withhold treatment 
in cases with 
systemic 
symptoms. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
3-4 
Severe symptoms, 
hospitalization 
required 
Refer patient to an 
endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5 to 1.6 µg/kg/day 
(for the elderly or those with 
co-morbidities, the suggested 
starting dose is 0.5 
µg/kg/day).  Add oral 
prednisolone 0.5 mg/kg/day 
for thyroid pain.  Thyrotoxic 
patients require treatment with 
a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grades 0 and 1. 
For France only: 
For Grade 3: Hold 
study treatment; 
resume when 
resolved/improved 
to Grades 0 and 1. 
For recurrent Grade 
3: Discontinue 
study treatment. 
For Grade 4: 
Discontinue study 
treatment 
Hypophysitis 
1-2 
Mild to moderate 
symptoms 
Refer patient to an 
endocrinologist for hormone 
replacement.  Add oral 
prednisolone 0.5 to 
1 mg/kg/day for patients with 
pituitary inflammation.  Taper 
corticosteroids over 
≥ 1 month.  If there is no 
improvement in 48 hours, treat 
as Grades 3 and 4.  Taper 
corticosteroids over 
≥ 1 month. 
Continue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
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 ≥ 1 month.  
Maintain hormone 
replacement according to 
endocrinology advice.  
Maintain hormone 
replacement according to 
endocrinology advice. 
Hold study 
treatment for 
patients with 
headache/visual 
disturbance due to 
pituitary 
inflammation until 
resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not 
necessary. For 
France only: For 
Grade 3: Hold 
study treatment; 
resume when 
resolved/improved 
to Grades 0 and 1. 
Discontinuation is 
usually not 
necessary. 
For recurrent Grade 
3: Discontinue 
study treatment.   
For Grade 4: 
Discontinue study 
treatment 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2 to 
3 days.  
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment 
until appearance 
improves and cause 
is determined. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
2 
Symptomatic: 
exertional 
breathlessness 
Commence antibiotics if 
infection suspected.  Add oral 
prednisolone 1 mg/kg/day if 
symptoms/appearance persist 
for 48 hours or worsen.  
Consider Pneumocystis 
infection prophylaxis.  Taper 
corticosteroids over 
≥ 6 weeks. 
Consider prophylaxis for 
adverse steroid effects: eg, 
blood glucose monitoring, 
vitamin D/calcium 
supplement. 
Hold study 
treatment.  
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and 
initiate treatment with IV 
methylprednisolone 2 to 
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 
≥ 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 to 1 mg/kg/day.  Taper 
over ≥ 4 weeks.  Obtain 
neurology consultation. 
Hold study 
treatment; resume 
when 
resolved/improved 
to Grades 0 and 1. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 
1 to 2 mg/kg/day, depending 
on symptoms.  Taper 
corticosteroids over ≥ 4 
weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response 
within 72 to 96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 4 liquid stools per 
day over baseline and 
feeling well 
Symptomatic management: 
fluids, loperamide, avoid high 
fiber/lactose diet. 
If Grade 1 persists for > 14 
days manage as a Grade 2 
event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4 
to 6 liquid stools per 
day over baseline, or 
abdominal pain, or 
blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 
0.5 mg/kg/day (non-enteric 
coated). 
Do not wait for any diagnostic 
tests to start treatment.  Taper 
steroids over 2 to 4 weeks, 
consider endoscopy if 
symptoms are recurring. 
Hold study 
treatment; resume 
when 
resolved/improved 
to baseline grade. 
3 
Severe 
symptoms: > 7 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
Initiate IV methylprednisolone 
1 to 2 mg/kg/day. 
Convert to oral prednisolone 
and taper over ≥ 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, 
Hold study 
treatment; 
retreatment may be 
considered when 
resolved/improved 
to baseline grade 
and after discussion 
with the study 
medical monitor. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
4 
Life-threatening 
symptoms 
hepatitis, NYHA grade III/IV 
CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10% to 
30% of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate 
strength cream once a day or 
potent cream twice a day) ± 
oral or topical antihistamines 
for itch.  Consider a short 
course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% 
BSA or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows 
based on clinical judgment: 
For moderate symptoms: oral 
prednisolone 0.5 to 
1 mg/kg/day for 3 days then 
taper over 2 to  4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5 to 1 
mg/kg/day; convert to oral 
prednisolone and taper over 
≥ 4 weeks. 
Hold study 
treatment. 
Re-treat when AE 
is resolved or 
improved to mild 
rash (Grades 1 and 
2) after discussion 
with the study 
medical monitor. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal 
detachment), <<Add 
text for France only: 
including Stevens-
Johnson syndrome (all 
grade), and toxic 
epidermal 
necrolysis>> 
Initiate IV methylprednisolone 
1 to 2 mg/kg/day. Convert to 
oral prednisolone and taper 
over ≥ 4 weeks. 
Admit to a hospital and seek 
urgent dermatology 
consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN 
to 3 x ULN 
Check LFTs within 1 week 
and before the next dose check 
LFTs to verify that there has 
been no worsening. 
If LFTs are worsening, 
recheck every 48 to 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 to 5 x  
ULN 
Recheck LFTs every 48 to 72 
hours:  
For persistent ALT/AST 
elevation: consider oral 
prednisolone 0.5 to 
1 mg/kg/day for 3 days then 
taper over 2 to 4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and 
taper over 2 to 4 weeks; 
re-escalate dose if LFTs 
worsen, depending on clinical 
judgment.  
Hold study 
treatment; treatment 
may be resumed 
when 
resolved/improved 
to baseline Grade 
and prednisolone 
tapered to ≤ 10 mg. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
3 
ALT or AST 5 x to 
20 x  ULN 
Guidance to authors: 
Note that 
ASCO/ESMO 
guidance is to 
discontinue for 
Grade 3.  Labels for 
other PD-(L)1 
inhibitors recommend 
treatment 
discontinuation for 
ALT or AST levels as 
follows: 
Atezolizumab: > 8 x 
ULN 
Nivolumab: > 8 x 
ULN 
Pembrolizumab: > 8 x 
ULN 
ALT/AST < 400 IU/L and 
normal bilirubin/INR/albumin: 
Initiate oral prednisolone 
1 mg/kg and taper over ≥ 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 ≥ 4 weeks.  
If ALT and AST 
≤ 10 x ULN: 
Hold study 
treatment until 
improved to 
baseline Grade; 
reintroduce only 
after discussion 
with the study 
medical monitor.  
If ALT or 
AST > 10 x ULN: 
Discontinue study 
treatment. 
For France only: If 
ALT or AST ≤ 8 x 
ULN or total 
bilirubin ≤ 5 x 
ULN: Hold study 
treatment until 
improved to 
baseline grade; 
reintroduce only 
after discussion 
with the study 
medical monitor 
For France only: If 
ALT or AST > 8 x 
ULN or total 
bilirubin > 5 x 
ULN: 
Discontinue study 
treatment. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment. 
4 
ALT or AST > 20 x 
ULN 
Initiate IV methylprednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over 
≥ 6 weeks.  
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Worsening LFTs despite steroids: 
If on oral prednisolone, change to pulsed IV methylprednisolone 
If on IV methylprednisolone, add MMF 500 to 1000 mg twice a day 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5 x 
baseline 
or > ULN to 1.5 x 
ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage 
as per criteria below. 
Continue study 
treatment. 
2 
Creatinine > 1.5 x to 
3 x baseline or > 1.5 x 
to 3 x ULN 
Ensure hydration and review 
creatinine in 48 to 72 hours; if 
not improving, consider 
creatinine clearance 
measurement by 24-hour urine 
collection.  Discuss with 
nephrologist the need for 
kidney biopsy. 
If attributed to study drug, 
initiate oral prednisolone 
0.5 to 1 mg/kg and taper over 
≥ 2 weeks. 
Repeat creatinine/U&E every 
48 to 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 > 3 x 
baseline or > 3 x to 6 x 
ULN 
Hospitalize patient for 
monitoring and fluid balance; 
repeat creatinine every 24 
hours; refer to a nephrologist 
and discuss need for biopsy.  
If worsening, initiate IV 
(methyl)prednisolone 1 to 
2 mg/kg. Taper corticosteroids 
over ≥ 4 weeks. 
Hold study 
treatment until the 
cause is 
investigated.  
If study drug 
suspected: 
Discontinue study 
treatment. 
<<Add text for 
France only: For 
recurrent Grade 3: 
Discontinue study 
treatment.>> 
4 
Creatinine > 6 x ULN 
As per Grade 3, patient should 
be managed in a hospital 
where renal replacement 
therapy is available. 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat 
according to local guideline.  
Check for C-peptide and 
antibodies against glutamic 
acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160 to 250 mg/dL; 
8.9 to 13.9 mmol/L 
Obtain a repeat blood glucose 
level at least every week.  
Manage according to local 
guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  
Resume treatment 
when blood glucose 
is stabilized at 
baseline or 
Grades 0 and 1. 
3 
Fasting glucose value 
250 to 500 mg/dL; 
13.9 to 27.8 mmol/L 
Admit patient to hospital and 
refer to a diabetologist for 
hyperglycemia management.  
Corticosteroids may 
exacerbate hyperglycemia and 
should be avoided. 
Hold study 
treatment until 
patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or 
Grades 0 and 1. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
4 
Fasting glucose 
value > 500 
mg/dL; > 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency 
diabetes management.  Refer 
the patient to a diabetologist 
for insulin maintenance and 
monitoring. 
Hold study 
treatment until 
patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or 
Grades 0 and 1. 
For France only: 
(split Grade 3 and 
4): Discontinue 
study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Ocular Toxicity 
1 
Asymptomatic eye 
examination/test 
abnormality 
Consider alternative causes 
and prescribe topical treatment 
as required. 
Continue study 
treatment. 
2 
Anterior uveitis or 
mild symptoms 
Refer patient to an 
ophthalmologist for 
assessment and topical 
corticosteroid treatment.  
Consider a course of oral 
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 to 2 mg/kg and 
taper over ≥ 4 weeks. 
Hold study 
treatment until 
improved to 
Grades 0 and 1; 
reintroduce only 
after discussion 
with the study 
medical monitor. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
4 
Blindness (≥ 20/200) 
in the affected eyes 
Initiate IV 
(methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over 
≥ 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, 
nausea and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1 to 
2 mg/kg/day.  Convert to oral 
prednisolone when 
amylase/lipase improved to 
Grade 2, and taper over 
≥ 4 weeks. 
Hold study 
treatment; 
reintroduce only 
after discussion 
with the study 
medical monitor. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for 
emergency management and 
appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, 
swelling 
Management per local 
guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, 
swelling, limited 
instrumental (fine 
motor) activities 
Management as per local 
guideline.  Consider referring 
patient to a rheumatologist.  If 
symptoms worsen on 
treatment manage as a Grade 3 
event. 
Continue treatment 
or, if symptoms 
continue worsens, 
hold study 
treatment until 
symptoms improve 
to baseline or 
Grades 0 and 1. 
3 
Severe pain with 
inflammation or 
permanent joint 
damage, daily living 
activity limited 
Refer patient urgently to a 
rheumatologist for assessment 
and management.  Initiate oral 
prednisolone 0.5 to 1 mg/kg 
and taper over ≥ 4 weeks. 
Hold study 
treatment unless 
improved to Grades 
0 and 1; reintroduce 
only after 
discussion with the 
study medical 
monitor. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for 
appropriate management.  
Initiate IV 
(methyl)prednisolone 1 to 
2 mg/kg/day.  Convert to oral 
prednisolone when symptoms 
improved to Grade 2 and taper 
over ≥ 4 weeks. 
Hold study 
treatment until 
improved to Grades 
0 and 1. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for 
emergency care.  Consider IV 
corticosteroids if not 
contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/Rhabdomy
olysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated 
and patient has symptoms, 
consider oral steroids and treat 
as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 x ULN or worse, 
initiate oral prednisolone 
0.5 to 1 mg/kg and taper over 
≥ 4 weeks 
Hold study 
treatment until 
improved to Grades 
0 and 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 to 2 mg/kg/day maintenance 
for severe activity restriction 
or dysphagia.  If symptoms do 
not improve add 
immunosuppressant therapy.  
Taper oral steroids over ≥ 4 
weeks 
For Grade 3: Hold 
study treatment 
until improved to 
Grades 0 and 1. 
Discontinue if any 
evidence of 
myocardial 
involvement. 
For France only: 
For recurrent Grade 
3: Discontinue 
study treatment. 
For Grade 4: 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Myocarditisa 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation 
under close monitoring with 
repeat serum testing and ECG, 
cardiac echo/MUGA, and /or 
other interventions per 
institiutional guidelines; 
consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed, 
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 to 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 
3 
Severe symptoms with 
mild exertion 
 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
4 
Life-threatening 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered immune 
related, 
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. 
For France only: 
Discontinue study 
treatment 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ASCO, American Society of Clinical Oncology; 
AST, aspartate aminotransferase; BSA, body surface area; CHF, congestive heart failure; CK, creatine kinase; CK-
MB, creatine kinase cardiac isoenzyme; ESMO, European Society for Medical Oncology; INR, international 
normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; MUGA, multigated 
acquisition; NYHA, New York Heart Association; PD-(L)1, programmed death (ligand)-1; T4, thyroxine; TB, 
tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, 
upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 10. CYP3A INHIBITORS AND INDUCERS  
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Food products: grapefruit juice a 
Other: cobicistat, conivaptan, elvitegravir, nefazodone, diltiazem, idelalisib 
Protease inhibitors: nelfinavir, ritonavir or ritonavir b in combination with 
danoprevir/elvitegravir/indinavir/lopinavir/paitprevir and (obitasvir and/or 
dasabuvir)/saquinavir/tipranavir 
 
Moderate CYP3A Inhibitors 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
Calcium channel blockers: verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib, crizotinib 
Others: aprepitant, cimetidine, cyclosporine, dronedarone, tofisopam, fluvoxamine  
 
Strong CYP3A Inducers 
Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
 
Moderate CYP3A Inducers 
Bosentan, efavirenz, etravirine, modafinil 
Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers (9/26/2016). 
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A; HCV, hepatitis C virus. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of concomitant 
medication to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
a. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low 
dose, single strength). 
b. Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on 
CYP3A activities. 
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APPENDIX 11. DOSE MODIFICATION TABLE FOR ZANUBRUTINIB 
WHEN COADMINISTERED WITH 
STRONG/MODERATE CYP3A INHIBITORS OR 
INDUCERS  
CYP3A 
Coadministered Drug 
Recommended Use 
Inhibition 
Strong CYP3A inhibitor (eg, ketoconazole, 
conivaptan, clarithromycin, indinavir, itraconazole, 
lopinavir, ritonavir, telaprevir, posaconazole, 
voriconazole) 
80 mg once daily 
Moderate CYP3A inhibitor (eg, erythromycin, 
ciprofloxacin, diltiazem, dronedarone, fluconazole, 
verapamil, aprepitant, imatinib, grapefruit products) 
80 mg twice daily 
Induction 
Strong CYP3A inducer (eg, carbamazepine, 
phenytoin, rifampin, St. John’s wort) 
Avoid concomitant use; consider 
alternative agents with less 
induction potential 
Moderate CYP3A inducer (eg, bosentan, efavirenz, 
etravirine, modafinil, nafcillin) 
160 mg twice daily, use with 
caution; monitor for potential lack 
of efficacy 
Source: Food and Drug Administration Center for Drug Evaluation Research.  FDA Guidance for Industry: Drug 
Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations. 2012. 
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A; FDA, Food and Drug Administration . 
Note: The list of drugs in this table is not exhaustive.  Please refer to the prescribing information of concomitant 
medication to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
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APPENDIX 12. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (Levey et al 2009) and the Modification of Diet in Renal Disease Study equation.  The 
National Kidney Disease Education Program calculators rely on creatinine determinations which 
are isotope dilution mass spectrometry traceable.  All laboratories should be using creatinine 
methods calibrated to be isotope dilution mass spectrometry traceable. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL.  This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1)α x max(Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if 
Black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators. 
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APPENDIX 13. THE LUGANO CLASSIFICATION FOR NON-HODGKIN 
LYMPHOMA (CHESON 2014)  
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Response 
Complete metabolic response 
Complete radiologic response (all of the 
following): 
Lymph nodes 
and 
extra-lymphatic 
sites 
Score 1, 2, 3a with or without a residual 
mass on 5PSb 
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 
lesions 
Not applicable 
Absent 
Organ 
enlargementc 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology (if BMA involved 
at screening)  
If indeterminate, IHC negative 
Partial Response 
Partial metabolic response: 
Partial remission (all of the following): 
Lymph nodes 
and 
extra-lymphatic 
sites 
Score 4 or 5b 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 
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
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 
No Response or 
Stable Disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, extra-
nodal lesions 
Score 4 or 5b 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 ≥ 1 of the 
following: 
Individual 
target 
nodes/nodal 
masses 
Score 4 or 5b 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 
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 
Non-measured 
lesions 
None 
New lesions or clear progression of pre-
existing non-measured lesions: 
• 
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 
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
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 
 
Organ 
enlargement 
Not applicable 
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 
≥ 2 cm from baseline 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, [18F] fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion;; PET, positron emission tomography 
Note: Modified from Cheson BD, Fisher RJ, Barrington SF, et al.  J Clin Oncol 2014;32(27):3059-68. 
a A score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan.  However, in studies involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to 6 of the 
largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 2 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 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 extranodal 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 extranodal sites (eg, gastrointestinal 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). 
b PET 5PS (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 
Note: Temporary withholding of study drug (eg, for drug-related toxicity, surgery, or intercurrent illness) for as little 
as 7 days can cause a transient worsening of disease and/or of constitutional symptoms.  In such circumstances, 
and if medically appropriate, patients may resume therapy and relevant clinical, laboratory, and/or radiologic 
assessments should be performed to document whether tumor control can be maintained or whether actual disease 
progression has occurred.   
c Isolated increase in lymph nodes and/or splenomegaly during periods of zanubrutinib hold will not be considered 
as disease progression unless confirmed by a repeat imaging study ≥ 6 weeks after restarting study drug 
administration.  The response category “indeterminate due to zanubrutinib hold” should be selected for such 
instances.  Following the repeat imaging 6 weeks after restarting study drug, response should be in comparison to 
the imaging at baseline 
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APPENDIX 14. CLL RESPONSE DEFINITIONS (IWCLL 2018)  
Parameter 
CRa                    PR 
PR-L 
PD 
Stable Disease 
Group A 
Lymph Nodes 
None ≥ 1.5 cm 
Decrease 
≥ 50% (from 
baseline)b                
Decrease ≥ 50% 
from baseline 
Increase 
≥ 50% from 
baseline or 
from response 
Change of 
− 49% to + 49% 
Liver and/or 
Spleen Sizec            
Spleen size 
< 13 cm; liver 
size normal 
Decrease 
≥ 50% (from 
baseline) 
Decrease ≥ 50% 
from baseline 
Increase 
≥ 50% from 
baseline or 
from response 
Change of 
− 49% to + 49% 
Constitutional 
Symptoms 
None 
Any 
Any 
Any 
Any 
Circulating 
Lymphocyte 
Count 
Normal 
Decrease 
≥ 50% from 
baseline 
Decrease < 50% 
or increase from 
baseline 
Increase 
≥ 50% from 
baselined                  
Change of 
− 49% to + 49% 
Group B 
Platelet Count 
≥ 100 x 109/L 
≥ 100 x 109/L 
or increase 
≥ 50% over 
baseline 
> 100,000/μL or 
increase ≥ 50% 
over baseline 
Decrease of 
≥ 50% from 
baseline 
secondary to 
CLL 
Change of 
− 49% to + 49% 
Hemoglobin 
≥ 11.0 g/dL 
(untransfused 
and without 
erythropoietin) 
≥ 11 g/dL or 
increase 
≥ 50% over 
baseline 
> 11 g/dL or 
increase ≥ 50% 
over baseline 
Decrease of 
≥ 2 g/dL from 
baseline 
secondary to 
CLL 
Increase < 11.0 
g/dL or < 50% 
over baseline, or 
decrease < 2 
g/dL 
Bone Marrow 
Biopsy 
Normocellular, 
no CLL cells, 
no B-
lymphoid 
nodules 
Presence of 
CLL cells, or 
of B-
lymphoid 
nodules, or 
not done 
Presence of CLL 
cells, or of B-
lymphoid 
nodules, or not 
done 
Increase of 
CLL cells by 
≥ 50% on 
successive 
biopsies 
No change in 
marrow infiltrate 
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Source: Hallek et al 2018; Cheson et al 2012 
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete remission (response); CRi, CR with incomplete 
bone marrow recovery; CT, computed tomography; PD, disease progression; PR, partial remission (response); PR-
L, partial remission (response) with lymphocytosis 
Note: Parameters of Group A assess the lymphoid tumor load and constitutional symptoms; parameters of Group B 
assess the hematopoietic system. 
CR: all of the criteria have to be met; PR: ≥ 2 of the parameters of Group A and 1 parameter of Group B need to 
improve if previously abnormal; if only 1 parameter of both Groups A and B is abnormal before therapy, only 1 of 
either Group A or Group B needs to improve; PR-L: presence of lymphocytosis, plus ≥ 50% reduction in 
lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for platelets, hemoglobin, or bone 
marrow biopsy have to be met; PD: ≥ 1 of the criteria of Group A or Group B has to be met; SD: all of the criteria 
have to be met, constitutional symptoms alone do not define PD. 
a Some patients fulfill all the criteria for a CR, but have a persistent anemia, thrombocytopenia, or neutropenia 
apparently unrelated to CLL, but related to drug toxicity. These patients should be considered as a different 
category of remission, CR with incomplete marrow recovery (CRi). For the definition of this category, the marrow 
evaluation should be performed with scrutiny and not show any clonal disease infiltrate. 
b Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and by physical examination). 
c Spleen size is considered normal if < 13 cm.   
d In the absence of other objective evidence of PD, lymphocytosis alone should not be considered an indicator of PD 
(Cheson et al 2012). 
Temporary withholding of study drug (eg, for drug-related toxicity, surgery, or intercurrent illness) for as little as 7 
days can cause a transient worsening of disease and/or of constitutional symptoms.  In such circumstances, and if 
medically appropriate, patients may resume therapy and relevant clinical, laboratory, and/or radiologic 
assessments should be performed to document whether tumor control can be maintained or whether actual disease 
progression has occurred. 
Isolated increase in lymph nodes and/or splenomegaly (defined as vertical spleen length > 13 cm) during periods of 
zanubrutinib hold will not be considered as disease progression unless confirmed by a repeat imaging study ≥ 6 
weeks after restarting study drug administration.  The response category “indeterminate due to zanubrutinib hold” 
should be selected for such instances.  Following the repeat imaging 6 weeks after restarting study drug, response 
should be in comparison to the imaging at baseline. 
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APPENDIX 15. GRADING SCALE FOR HEMATOLOGIC TOXICITY IN 
CLL STUDIES  
Gradea 
Decrease in Plateletsb or Hgbc (Nadir) 
From Pretreatment Value 
Absolute Neutrophil Count (Nadir) 
x 109/Ld 
0 
No change to 10% 
≥ 2 
1 
11% to 24% 
≥ 1.5 and < 2 
2 
25% to 49% 
≥ 1 and < 1.5 
3 
50% to 74% 
≥ 0.5 and < 1 
4 
≥ 75% 
< 0.5 
Source: Hallek et al 2018. 
Abbreviation: ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia; Hgb, hemoglobin; 
WBC, white blood cell.  
a. Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be reported as Grade 5. 
b. Platelet counts must be below normal levels for Grades 1 to 4.  If, at any level of decrease, the platelet count 
is < 20 x 109/L, this will be considered Grade 4 toxicity, unless a severe or life-threatening decrease in the initial 
platelet count (eg, < 20 x 109/L) was present pretreatment, in which case the patient is not evaluable for toxicity 
referable to platelet counts. 
c. Hgb levels must be below normal levels for Grades 1 to 4. Baseline and subsequent Hgb determinations must be 
performed before any given transfusions. The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
d. If the ANC reaches < 1 x 109/L, it should be judged to be Grade 3 toxicity.  Other decreases in the WBC, or in 
circulating granuloctyes are not to be considered because a decrease in the WBC is a desired therapeutic endpoint. 
A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity.  If the ANC 
was < 1 x 109/L before therapy, the patient is not evaluable for toxicity referable to the ANC. The use of growth 
factors such as granulocyte colony-stimulating factor is not relevant to the grading of toxicity but should be 
documented. 
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APPENDIX 16. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982).  Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX 17. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
The text below was obtained from the following reference: 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228 47. 
Definitions 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1).  Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in ≥ 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 10 mm by CT and MRI (no less than double the slice thickness and a minimum of 
10 mm). Assumes a scan slice thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
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• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above 
• Blastic bone lesions are nonmeasurable 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. 
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
Guidelines For Evaluation Of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions.  However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (eg, for body scans). 
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• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain).  When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease. 
Response Criteria 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of ≥ 5 mm.  (Note: the appearance of one 
or more new lesions is also considered progression). 
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• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  Case report form may be designed to have target 
nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis <10 mm.  For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
• Target lesions that become “too small to measure”.  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”. 
When this occurs, it is important that a value be recorded on the eCRF.  If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well).  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this 
default value will prevent false responses or progressions based upon measurement 
error.  To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
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• CR: Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions.  
(Note: the appearance of one or more new lesions is also considered progression.) 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy”.  If “unequivocal progression” 
is seen, the patient should be considered to have had overall PD at that point.  While 
it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must 
be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
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necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression.  An example of this is the 
patient who has visceral disease at baseline and while on trial has a CT or MRI brain ordered 
which reveals metastases.  The patient’s brain metastases are considered to be evidence of PD 
even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
• Timepoint Response 
o It is assumed that at each protocol specified time point, a response assessment 
occurs. The following table provides a summary of the overall response status 
calculation at each time point for patients who have measurable disease at 
baseline: 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When patients have non-measurable (therefore non-target) disease only, the following table is to 
be used: 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
Non-CR/non-PD 
Not all evaluated 
Unequivocal PD 
Any 
No 
No 
No 
Yes or No 
Yes 
CR 
SD (Non-CR/non-PD) 
NE 
PD 
PD 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment taking into account any requirement for confirmation.  On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and nontarget disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “best overall response”. 
The BOR is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a BOR of PR).  When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline.  If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments.  For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD.  The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero.” 
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In trials where confirmation of response is required, repeated "NE" time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results.  However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
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Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
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APPENDIX 18. 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 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  
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Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 19. SIGNATURE OF INVESTIGATOR  
PROTOCOL TITLE: 
A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a 
Phosphatidylinositol 3-Kinase Delta (PI3Kδ) Inhibitor, Combined 
With Zanubrutinib in Patients With Mature B-Cell Malignancies and 
Combined With Tislelizumab in Patients With Solid Tumors 
PROTOCOL NO: 
BGB-A317-3111-10188-101 
This protocol is a confidential communication of BeiGene, Ltd., and its affiliates.  I confirm that 
I have read this protocol, I understand it, and I will work according to this protocol and the terms 
of the clinical study agreement governing the study.  I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its affiliates. 
Instructions to the Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol.  PRINT your name, title, and the name and 
address of the center in which the study will be conducted. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: 
Date: 
Printed Name: 
Investigator Title: 
Name/Address of Center: 
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APPENDIX 20. EVALUATION OF RESPONSE ACCORDING TO CA-125  
The text below was obtained from the following reference (Gordon John Sampson Rustin): 
Definitions for Response and Progression in Ovarian Cancer Clinical Trials Incorporating 
RECIST 1.1 and CA-125 Agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol 
Cancer. 2011;21:419-23. 
Definition of Response: 
A carcinoma antigen-125 (CA-125) response is defined as at least a 50% reduction in CA-125 
levels from a pretreatment sample. The response must be confirmed and maintained by using the 
next scheduled CA-125 data (at least 28 days). Patients can be evaluated according to CA-125 
only if they have a pretreatment sample that is at least twice the upper limit of the reference 
range and within 2 weeks before starting the treatment. 
To calculate CA-125 responses accurately, the following rules apply: 
• Intervening samples and the 28-day confirmatory sample must be less than or equal to 
(within an assay variability of 10%) the previous sample. 
• Variations within the reference range of CA-125 levels will not interfere with the 
response definition. 
• For each patient, the same assay method must be used, and the assay must be tested in 
a quality control scheme. 
• Patients are not evaluable by CA-125 if they have received mouse antibodies (unless 
the assay used has been shown not to be influenced by human anti-mouse antibody) 
or if there has been medical and/or surgical interference with their peritoneum or 
pleura during the previous 28 days (eg, paracentesis). If assessing a therapy that 
includes 2 treatment modalities for relapse (eg, surgery and chemotherapy), any CA-
125 response could be a result from either or both treatment modalities. In this case, 
CA-125 cannot distinguish between the effects of the 2 treatments. 
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response.  
To calculate response, an intent-to-treat analysis should be used that includes all patients with an 
initial CA-125 level of at least twice the upper limit of the reference range as eligible and 
evaluable. In addition, as a separate analysis, those patients who have a CA-125 response and 
whose CA-125 level falls to within the reference range can be classified as CA-125 complete 
responder. Patients who have a fall of CA-125 to within the reference range but whose initial 
CA-125 was less than twice the upper limit of the reference range cannot therefore be classified 
as a CA-125 complete responder.
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CA-125 Response Measurement 
CA-125 Level 
CA-125 Measurement 
Baseline CA-125 more than twice the upper limit of normal, later 
reduced by 50% to normal and maintaining for at least 28 days 
CR 
Baseline CA-125 more than twice the upper limit of normal, later 
reduced by 50% but not to normal 
PR 
CA-125 change out of range of PR and PD 
Non-PR, non-PD 
CA-125 increased at baseline returning to normal after treatment, later 
twice or higher than the upper limit of normal (2 consecutive 
measurements at an interval of at least 1 week) 
Progressive disease (date of first 
evaluation of progression) 
CA-125 increased at baseline not returning to normal after treatment, 
later twice or higher than the lowest value (2 consecutive 
measurements at an interval of at least 1 week) 
Progressive disease (date of first 
evaluation of progression) 
CA-125 within the reference range at baseline, later twice or higher 
than the upper limit of normal (2 consecutive measurements at an 
interval of at least 1 week) 
Progressive disease (date of first 
evaluation of progression) 
Abbreviations: CA-125, carcinoma antigen-125; CR, complete response; PR, partial response
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Evaluation of Best Overall Response in Patients With Measurable Disease and Who Are 
Also Evaluable by CA-125 
Target 
Lesion* 
Nontarget† 
New Lesion 
CA-125 
Overall Best Response 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR or non-PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR but not normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or NAE 
No 
Not PD 
PR 
NAE 
Non-PD 
No 
PR 
PR 
PD or New > 28 days from CA-125 PR‡ 
PR 
PR 
Stable 
disease§ 
Non-PD 
No 
PR 
PR 
Stable 
disease§ 
Non-PD or NAE 
No 
Not PR and not PD 
Stable disease 
PD or New ≤ 28 days from CA-125 PR‡ 
PR 
PD 
PD 
Any 
Yes or no 
Any 
PD 
Any 
PD 
Yes or no 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Yes or no 
PD 
PD 
Abbreviations: CA-125, carcinoma antigen-125; CR, complete response; NE, not evaluated; NAE, not all evaluated; 
PR, partial response. 
*Target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST v1.1. 
†Nontarget lesions include ascites and peritoneal thickening, which are not measurable according to RECIST 1.1. 
‡Patients who have a CA-125 response that occurs more than 28 days from PD according to RECIST 1.1 are 
considered a PR, according to best response, but PD if the RECIST 1.1 PD is within 28 days (including) of CA-
125 response. 
§The protocol should specify the minimum time interval between 2 measurements for classification as stable 
disease. 
Approved Date
4/10/2024

Signature Page 
Approval with eSignature
Clinical Development
11-Apr-2024 03:07:53 GMT+0000
Approved Date
4/10/2024